Compliance Central with FDA Center Compliance Directors Part I
Tom Cosgrove Acting Director Office of Compliance Center for Drug Evaluation and Research FDA
Carl Fischer Senior Advisor Office of Compliance Center for Devices and Radiological Health FDA
Mary Malarkey Director Office of Compliance and Biologics Quality Center for Biologics Evaluation and Research FDA
Moderated by John R Manthei Partner Latham amp Watkins LLP
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
3
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
7
8
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
9
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
9
10
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
11
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
12
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
15
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
16
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
17
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
18
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
18
19Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
21
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
22
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)22
23
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
24
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
3
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
7
8
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
9
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
9
10
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
11
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
12
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
15
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
16
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
17
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
18
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
18
19Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
21
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
22
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)22
23
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
24
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
3
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
7
8
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
9
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
9
10
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
11
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
12
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
15
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
16
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
17
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
18
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
18
19Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
21
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
22
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)22
23
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
24
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
7
8
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
9
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
9
10
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
11
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
12
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
15
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
16
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
17
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
18
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
18
19Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
21
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
22
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)22
23
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
24
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
7
8
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
9
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
9
10
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
11
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
12
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
15
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
16
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
17
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
18
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
18
19Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
21
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
22
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)22
23
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
24
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
7
8
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
9
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
9
10
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
11
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
12
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
15
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
16
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
17
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
18
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
18
19Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
21
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
22
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)22
23
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
24
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
7
Office of Manufacturing Quality (OMQ) Focus
bull Compliance and enforcement for
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
7
8
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
9
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
9
10
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
11
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
12
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
15
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
16
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
17
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
18
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
18
19Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
21
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
22
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)22
23
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
24
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
8
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
9
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
9
10
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
11
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
12
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
15
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
16
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
17
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
18
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
18
19Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
21
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
22
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)22
23
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
24
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
9
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
9
10
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
11
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
12
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
15
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
16
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
17
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
18
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
18
19Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
21
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
22
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)22
23
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
24
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
10
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
11
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
12
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
15
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
16
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
17
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
18
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
18
19Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
21
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
22
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)22
23
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
24
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
11
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
12
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
15
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
16
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
17
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
18
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
18
19Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
21
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
22
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)22
23
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
24
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
Sheet1
11
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
12
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
15
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
16
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
17
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
18
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
18
19Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
21
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
22
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)22
23
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
24
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
11
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
12
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
15
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
16
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
17
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
18
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
18
19Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
21
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
22
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)22
23
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
24
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
15
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
16
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
17
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
18
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
18
19Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
21
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
22
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)22
23
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
24
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
13
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
15
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
16
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
17
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
18
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
18
19Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
21
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
22
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)22
23
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
24
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
15
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
16
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
17
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
18
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
18
19Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
21
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
22
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)22
23
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
24
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
16
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
17
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
18
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
18
19Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
21
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
22
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)22
23
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
24
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
17
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
18
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
18
19Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
21
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
22
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)22
23
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
24
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
21
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
22
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)22
23
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
24
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
21
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
22
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)22
23
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
24
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
21
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
22
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)22
23
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
24
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
24
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
24
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
24
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
24
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
24
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
24
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
25
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
26
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
27
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
28
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
29
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
30
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Center for Devices and Radiological Health
Carl Fischer PhDSenior Advisor
Office of ComplianceCenter for Devices and Radiological Health
32
Medical Device QS Surveillance Inspections CY2008mdashCY2015
1323 15091792 1931 1859 1741 1619 1484
210228
271341 393 460 594
620
0
500
1000
1500
2000
2500
2008 2009 2010 2011 2012 2013 2014 2015
ForeignDomestic
33
CY2015 QS Medical Device Inspections
Total Domestic Inspections Total Foreign Inspections
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
35
User Facility Inspectionsbull 17 facilitiesbull Related to contaminated duodenoscopes and morcellatorsbull Regulatory approachbull Public workshop on improving hospital-based surveillance
systems
36
Medical Device Single Audit Program
bull Auditing Organizations ndash 6 of 13 authorized to conduct MDSAP audits All 13 working toward recognition
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
bull 117 Audit Reports Received to Datendash 73 ndash US Auditsndash 44 ndash International Audits
bull Regulatory Exchange Platform ndash secure
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
37
Benefit-Risk GoalsOpportunity to develop and implement a set of principles thathellip
bull Allow CDRH to arrive at the same risk determinations for medical devices
bull Weigh the relative benefits and risks of options for pre and post market product quality and safety activities
bull Minimize disruption of care and protect the public health
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
38
Examples Related to Product Availability
Decisions
Recall and shortage
Evaluation of a variance petition
Continued Access to Nonconforming Product
Examples Related to Compliance and
Enforcement Decisions
Evaluation of whether to send an Warning Letter or
take an alternative approach
Evaluation of potential actions following an
inspection of a manufacturer with observed Quality
System deficiencies
Benefit-Risk -Decision Making
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
39
Compliance ne Qualitybull Quality is more than being free from defect and cannot
be achieved by complying with a set of rules
bull Quality is about products aligned with the needs of providers and patients that are produced in a reliable and trustworthy manner
Compliance to regulations is still important as it is requiredmdasha high quality product is not a substitute for a compliant product under our current statutory situation
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
40
Case for Quality Goalsbull Identify new metrics for measuring monitoring
and controlling device qualitybull Collaborate on performance and organizational
expectations that result in higher quality bull Explore policies and practices that foster a culture of
qualitybull Advance solutions for increasingly complex and
dynamic ecosystems
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
41
Case for Quality VisionShift the medical device ecosystem to focus beyond regulatory compliance to sustained device quality for improved patient outcomes
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
42wwwfdagov
Real World EvidenceWill build upon and leverage the
information created everyday as a part of routine health care or real
world evidence
Case for QualityWill identify and promote
practices that result in high-quality devices and adapt
FDA regulatory approaches to align with those
practices
Post Market Benefit Risk InitiativePatient focused
appropriately scoped and informed decisions by manufactures and FDA
Patient
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
December 7 2016Mary Malarkey Director
Office of Compliance and Biologics QualityCenter for Biologics Evaluation and ResearchFDA
wwwfdagov
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
44
Office of Compliance and Biologics QualityOCBQ ndash Director Mary MalarkeyOCBQ - Deputy Director ndash Melissa Mendoza
Division of Case Management DCM Director Bob Sausville
Division of Inspections and SurveillanceDIS Director Carrie Mampilly
Division of Manufacturing and Product QualityDMPQ Director Jay Eltermann
DMPQ Deputy Director ndash Laurie Norwood
Division of Biological Standards and Quality ControlDBSQC Director - Dr Bill McCormick
wwwfdagov
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market
review surveillance inspection outreach and compliance
45wwwfdagov
Compliance Actions
wwwfdagov
PostmarketInspectionalDrugs and Devices
0123456789
10
FY11 FY12 FY13 FY14 FY15 FY16
Warning Letters Untitled Letters
FY17
One Warning Letter based on inspection of multiple facilities as of November 30201647
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
bull Excludes blood and blood components vaccines allergenics and human cells tissues and cellular and tissue-based products
wwwfdagov
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
55
bull Facilitating development of donor screening tests and vaccines for Zika ndash providing guidance to industry
bull Working closely with our colleagues in ORA to provide guidance and support at present in SJN-DO and FLA-DO
bull Continue to be part of an intergovernmental working group facilitating importation and exportation by providing communication channels between all relevant government components CBP HHSBARDA FDA CDC USDAAPHIS DOT FWS DOCBIS
wwwfdagov
56
Prior to ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Cellular Tissue and Gene
Therapies (OCTGT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
Following ReorganizationOffice of the Director
(OD)
Office of Blood Research and Review
(OBRR)
Office of Tissues and Advanced Therapies
(OTAT)
Office of Vaccines Research and Review
(OVRR)
Office of Biostatistics and Epidemiology
(OBE)
Office of Compliance and Biologics Quality
(OCBQ)
Office of Communications
Outreach and Development (OCOD)
Office of Management (OM)
wwwfdagov
Effective Date October 16 2016
Internal CBER Restructuring
Public Access to CBERCBER websitehttpwwwfdagovBiologicsBloodVaccinesdefaulthtm
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
Manufacturers Assistance and Technical Training Branch (MATTB)Email industrybiologicsfdagovPhone 301-827-4081
Follow us on Twitter httpswwwtwittercomfdacber
57wwwfdagov
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
CDER Office of Compliance
Thomas J Cosgrove JDActing Director Office of Compliance
FDLI Enforcement Litigation and Compliance ConferenceDecember 7 2016
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
59
CDER Office of ComplianceOur mission to promote and protect the public health through strategies and actions that minimize consumer exposure to unsafe ineffective and poor quality drugs
Our vision to be a global leader in preventing consumer exposure to unnecessary risk from drugs throughout the drug lifecycle
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
63
Office of Manufacturing Quality (OMQ) Focus
bull Compliance and enforcement for
ndash Current Good Manufacturing Practices violations
ndash Data reliability issues
ndash Compounding
bull Global cooperationtrainingbull Policystandards development
63
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
64
Primary Considerations CGMP Enforcement
Is the drug ldquoadulteratedrdquobull Food Drug amp Cosmetic Actbull FDA regulations at 21 CFR 210 amp 211bull For API standards are set forth in ICH Q7
Most important ndash patient riskbull High risk FDA takes quick actionbull Sub or super-potentbull Contaminationbull Sterility concernsbull Other defects
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
65
Will FDA Issue an Import AlertCGMP Import Alert issued if
bull Violation could cause drug quality defect with potential adverse patient health consequences
bull Repeat violations
bull Refusal or delay of an inspection
bull Significant data integrity violations
65
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
66
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding
Letters 48
Regulatory Meetings 24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued ampCleared 41
Injunctions 2
Pharmacy CompoundingLetters 48
Regulatory Meetings 24
OMQ ActionsJanuary to October 31 2016
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
Chart1
January to October 31 2016
Import Alerts 99-32 25
21
25
3
41
2
48
24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
Import Alerts 66-40 21
Import Alerts 99-32 25
Untitled Letters 3
Warning Letters Issued amp Cleared 41
Injunctions 2
Pharmacy Compounding Letters 48
Regulatory Meetings 24
Sheet1
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
January to October 31 2016
Import Alerts 66-40 21
21
Import Alerts 99-32 25
25
Untitled Letters 3
3
Warning Letters Issued amp Cleared 41
41
Injunctions 2
2
Pharmacy Compounding Letters 48
48
Regulatory Meetings 24
24
67
Data Integrity Failure ExamplesCommon problems
bull Lack of controlled access to computer systemsbull ldquoTrialrdquo HPLC injections
ndash Trial injections in stand alone equipment outside a quality structure
bull Deleted databull Not recording activities contemporaneouslybull Backdatingbull Fabricating databull Copying existing data as new databull Re-running samples
68
Data Integrity Draft GuidanceData Integrity and Compliance With CGMP draft guidance for industry (April 2016)
QampA style guidance focused on frequently occurring data integrity lapses with definition of key terms
When final will represent our current thinking on data integrity and CGMP compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
69
2016 Example Warning Letters -Data Integrity Violation
bull ldquoYou repeatedly falsified and omitted information on the certificates of analysis (CoA) you issued to your customers For example your firm fabricated the name of an employee and you used that name as the false signatory authority on the CoA you sent to your customers You also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate Finally you included an ldquoexpiration daterdquo on your CoA that exceeded the manufacturerrsquos labeled expiration date but you had no basis for the extended retestexpiry periodrdquo
bull ldquoDuring the inspection the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse at your facilityrdquo
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
71
Now Final FDA Guidance on Quality Agreements
Quality agreements define expectations and
responsibilities in a contract manufacturing arrangement up front
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
72
FDA Guidance on Quality Agreements
What is a ldquoQuality Agreementrdquobull a comprehensive written agreement that defines responsibilities of the
Quality Units of each party in contract manufacturing of drugs subject to CGMP
Whybull to explain how quality agreements can be used to define establish and
document the responsibilities of parties involved in the contract manufacturing of drugs subject to CGMP
Clarifying roles and responsibilities improves efficiency and oversight of outsourced manufacturing operations and relationships between partieshellipUltimately improves the quality of drugs that patients consume
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
Column1
CI Warning Letter
7
Sponsor Warning Letter
2
IRB Warning Letter
4
PADE Warning Letter
3
Full Disqualification
1
BE Untitled Letter
1
To resize chart data range drag lower right corner of range
CI Warning Letter
Sponsor Warning Letter
IRB Warning Letter
PADE Warning Letter
Full Disqualification
BE Untitled Letter
73
Office of Scientific Investigations (OSI)Mission To ensure the safety efficacy and ethical development of drug products throughout the product lifespan using global strategies and actions that minimize unnecessary consumer risk via compliance and enforcement ofbull the integrity of safetyefficacy data submitted to FDAbull the application human subject protections in clinical trials andbull the implementation of Risk Evaluation and Mitigation Strategies
Visionbull Adapt to globalization and the evolving industrybull Master the information revolutionbull Foster innovation in public healthbull Maximize operational excellence
74
Nonclinical Phase 123 Post MarketingGood Laboratory Practice (Testing
Facilities)
Bioequivalence Bioavailability
(Clinical Investigators Contract Research
Organizations Sponsors)Post-Marketing Adverse
Drug Experience (Applicants)
Risk Evaluation and Mitigation Strategy
(Applicants)
Post-Marketing Requirements (Applicants)
Human Subject Protection (Radioactive Drug
Research Committee)
Good Clinical Practice(Sponsors Contract Research Organizations and
Clinical Investigators)
Human Subject Protection (Institutional Review Boards)
OSI Program Areas (inspected entities)
74
75Based on inspection start date ndash [Complis database as of January 20 2016]
Bioresearch Monitoring Program Inspections (CDER FY 2015)
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
Based on letter issue date [Complis database as of January 20 2016]NIDPOE = Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
77
7
24
3
1 1
FY 2016 OSI Enforcement
Chart1
Column1
7
2
4
3
1
1
Sheet1
78
Office of Drug Security Integrity and Response (ODSIR) Focus
bull Internet pharmaciesbull Counterfeit and foreign approved drug actions
ndash IndictmentsProsecutions
ndash Letters to doctors
bull Importsexportsbull Recallsbull Incident responsebull International collaborationsbull Drug Supply Chain Security Act (DSCSA) implementation
(ldquotrack and trace lawrdquo)78
79
The Drug Supply Chain Security Act (DSCSA) of 2013
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
bull 583 ndash Standards for licensure of wholesale distributors
bull 584 ndash Standards for licensure of third-party logistics providers (3PL)
bull 585 ndash Uniform national policy
Federal FDampC Act Sections
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
80
Goals of the DSCSAbull Develop an electronic interoperable system by 2023 to
identify and trace certain prescription drugs as they move through the US supply chainThe new system will
bull facilitate the exchange of information by trading partners at the individual package level
bull improve efficiency of recallsbull enable prompt response to suspect and illegitimate products when foundbull create transparency and accountability in the drug supply chain
bull Establish national standards for licensure for wholesale distributors and third-party logistics providers
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
81
3PL amp Wholesale Distributor
reporting to FDA
2014-2015
Product Tracing amp Verification
Authorized Trading Partners
2015
Product Identification (Serialization)
2017-2018
Product Verification (down to package level)
2019+
Electronic Interoperable
System (product tracing down to package
level) 2023
The DSCSA Path
Licensure standards for 3PLs and wholesale distributors
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
82
Compounding ActionsSince enactment of the DQSA on November 27 2013 FDA has
bull Conducted approximately 425 inspections of compoundersbull Overseen over 90 recall events by compounders and requested numerous compounders to
cease operationsbull Issued over 130 warning letters one addressed violations identified at four facilitiesbull Issued over 30 letters referring findings from inspections of pharmacies that compounded their
drugs in accordance with the conditions of section 503A to the statesbull Obtained 4 civil consent decrees of permanent injunctionbull Sought several criminal prosecutions
wwwfdagov
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
83
Inspection Observationsbull Continue to identify insanitary conditions at many of the
compounding facilities inspectedndash Dog beds and hairs in close proximity to sterile compounding roomndash Dead bugs in ceilingsndash Renovations being made without evidence of controls to prevent
contaminationndash Compounding by personnel with exposed skin
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
84
Other Compounding Actionsbull Issued over 20 guidance documents bull Issued final rule and proposed rule describing additions and modifications to the Withdrawn or
Removed List (503A and 503B)bull Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound
under sections 503A and 503Bbull Held 6 meetings of the Pharmacy Compounding Advisory Committeebull Held 4 sets of listening sessions with over 75 stakeholdersbull Held 4 intergovernmental working meetings with the states
wwwfdagov
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
85
Whatrsquos nexthellip
bull New legislationhellip ndash User fee reauthorization ndash 21st Century Cures
bull Continue implementation of DQSA (compoundingtrack and trace)
bull Focus on qualitysafety and data integritybull Guidance and standards for compliancebull Program alignmentbull Morehellip
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 70
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 75
Slide Number 76
Slide Number 77
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 81
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 86
86
Thank You
Thomas Cosgrove JDActing Director
Office of ComplianceThomasCosgrovefdahhsgov
Compliance Central with FDA Center Compliance Directors Part I
CDER Office of Compliance
CDER Office of Compliance
Office of Compliance Priorities
Office of Compliance Structure
Our Toolbox
Office of Manufacturing Quality (OMQ) Focus
Primary Considerations CGMP Enforcement
Will FDA Issue an Import Alert
Slide Number 10
Data Integrity Failure Examples
Data Integrity Draft Guidance
2016 Example Warning Letters -Data Integrity Violation
Slide Number 14
Now Final FDA Guidance on Quality Agreements
FDA Guidance on Quality Agreements
Office of Scientific Investigations (OSI)
OSI Program Areas (inspected entities)
Slide Number 19
Slide Number 20
Slide Number 21
Office of Drug Security Integrity and Response (ODSIR) Focus
The Drug Supply Chain Security Act (DSCSA) of 2013
Goals of the DSCSA
Slide Number 25
Compounding Actions
Inspection Observations
Other Compounding Actions
Whatrsquos nexthellip
Slide Number 30
Center for Devices and Radiological Health
Medical Device QS Surveillance Inspections CY2008mdashCY2015
CY2015 QS Medical Device Inspections
Foreign and Domestic WLs with QS Citations
User Facility Inspections
Medical Device Single Audit Program
Benefit-Risk Goals
Benefit-Risk -Decision Making
Compliance ne Quality
Case for Quality Goals
Case for Quality Vision
Slide Number 42
Compliance Central CBER UpdateFDLI Enforcement Litigation and Compliance Conference
Office of Compliance and Biologics Quality
OCBQrsquos mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection and post-market review surveillance inspection outreach and compliance