Alston & Bird Law Firm - INTRODUCTION TO DRUG …...2 REGULATION OF DRUG MANUFACTURING Presented by:...

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Food and Drug Law Institute's

Workshop on

INTRODUCTION TODRUG LAW AND REGULATION:

REGULATION OF DRUG MANUFACTURING

November 8-9, 2010

Park Hyatt HotelWashington, D.C.

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REGULATION OF

DRUG MANUFACTURING

Presented by:

Cathy L. Burgess, Esq.Crowell & Moring LLP1001 Pennsylvania Avenue, N.W.

Washington, D.C. 20004

202.624.2851 phone

202.628.5116 fax

[email protected]

Dean R. Cirotta, MBAEAS Consulting Group, LLC1940 Duke Street, Suite 200

Alexandria, Virginia 22314

703.684.4408 phone

703.684.4428 fax

[email protected]

www.easconsultinggroup.com

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DRUG ESTABLISHMENT

REGISTRATION

AND DRUG LISTING

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Authority To Require EstablishmentRegistration And Drug Listing

• Initial Registration. § 510(c), 21 U.S.C. § 360(c);21 C.F.R. § 207.21

• Annual Registration and Fees. § 510(b), 21 U.S.C.§ 360(b); §§ 736(a)(2), (3), (b)(1); 21 U.S.C. § 379h§§ (a)(2), (3), (b)(1); 21 C.F.R. § 207.21

• Semi-Annual Reports. 21 C.F.R. § 207.30; §510(j)(2),21 U.S.C. § 360(j)(2)

• Failure to Register, List Drugs, or File Semi-AnnualReports. § 505(e), 21 U.S.C. § 355(e); § 301(p),21 U.S.C. § 331(p)

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• Purpose. § 510; 21 U.S.C. § 360; 21 C.F.R. § 207.20

• Scope.

– Domestic Establishments. 21 C.F.R. § 207.20

– Establishments and Activities Requiring Registration.21 C.F.R. § 207.3(a)(7-8)

– Private Label Distributors. 21 C.F.R. § 207.20(b);Forms FDA 2656, 2657, 2658

– Foreign Drug Establishments. § 501(i), 21 U.S.C. §360(i); 21 C.F.R. § 207.40 (66 F.R. 59138, Nov. 26,2002)

Purpose And Scope Of EstablishmentRegistration And Drug Listing

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Exemptions From Registration

• Pharmacies regulated by local laws; dispensing drugs at

retail.

• Practitioners’ use in professional practices.

• Research, teaching or chemical analysis and not for

sale.

• Other Classes: e.g. hospitals, clinics, farmers, common

carriers. § 510(g); 21 U.S.C. § 360(g); 21 C.F.R. §

207.10

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Information Required forRegistration and Drug Listing

• Purpose of Form(registrant, distributor,foreign)

• Report Date (current)

• Type of Owner (soleproprietor, partnership,corporation, etc.)

• Reason for Submission

(annual, new, private label,

name change, etc.

• Business Type (human,

veterinary)

• Name and Site Address

(street, city, state, country)

Information Required on Initial Registration of DrugEstablishments (Form FDA 2656).

21 C.F.R. §§ 207.20 - 207.35

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• Mailing Address (ifdifferent from SiteAddress)

• Type of Ownership orOperation (partnership,corporation)

• Names(s) of Owner(s)

• Parent Company Name

• Name and PhoneNumber of submitter

• Other EstablishmentNames at same site

• Signature of AuthorizingOfficial (must besigned)

Information Required ForRegistration And Drug Listing

Information Required on Initial Registration -(continued)

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Amendments to Establishment

Registration 21 C.F.R. § 207.26

• Changes in ownership, structure, location oractivity--within five (5) days.

• Change in an establishment’s firm name.

• Changes in the names of officers and directors ofcorporations--annual registration.

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Information Required For Registration AndDrug Listing

Drug Product Listing (Form FDA 2657)21 C.F.R. § 207.25

• New drugs, authority for the marketing, application number,labeling. § 510(j)(1)(A); 21 U.S.C. § 360(j)(1)(A)

• Prescription drugs subject to § 503(b)(1), all labeling andrepresentative sampling of advertisements. § 510(j)(1)(B)(I);21 U.S.C. § 360(j)(1)(B)(I)

• Quantitative listing of active ingredient(s)§ 510(j)(1)(C); 21 U.S.C. § 360(j)(1)(C)

• Quantitative listing of all ingredients as necessary.§ 510(j)(1)(C); 21 U.S.C. § 360(j) (1)(C)

• Over-the-counter drugs, label, package insert, sampling of anyother labeling. § 510(j)(1)(C); 21 U.S.C. § 360(j)(1)(C)

• Drug Listing Number using the National Drug Code (NDC).21 C.F.R. § 207.35

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Updating Drug Listing Information.21 C.F.R. § 207.30

• Updates semi-annually, in June and December

• Information to be submitted in the updates:

– Drugs not on a previously submitted list;

– Drugs that have been discontinued;

– Reintroduction of discontinued drugs;

– Material change in previously submittedinformation; and

– No changes; no report.

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Public Inspection Of RegistrationsAnd Drug Listings; 21 C.F.R. § 207.37;

510(f), 21 U.S.C. § 360(f)

• Registration of Drug Establishment (Form FDA 2656) ispublicly available at Drug Listing Branch, CDER and FDADistrict Offices. (21 C.F.R. § 207.37)

• Types of Information Available for Public Disclosureinclude:– List of all drug products– List of all drug products by labeled indications or

pharmacological category– Drug products listed by manufacturer– List of active ingredients– Discontinued drugs, newly marketed drugs and drugs

for which marketing is resumed– Labeling– Advertising

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Public Inspection Of RegistrationsAnd Drug Listings; 21 C.F.R. § 207.37;

510(f), 21 U.S.C. § 360(f)

Information Not Available for PublicDisclosure

• Basis for determination not subject to drug provisionsof the Act.

• Drug product’s inactive ingredients. §502(e)(i)(A)(iii)

• Drugs containing a particular inactive ingredient.

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Adulteration/Misbrandingand

GMPs

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Adulterated Drugs(21 U.S.C. § 351)

Drug is deemed adulterated if:

• contains any filthy or decomposed substance(FDCA § 501(a)(1), 21 U.S.C. § 351(a)(1));

• prepared, packed or held under unsanitaryconditions (FDCA § 501(a)(2)(A),21 U.S.C.§ 351(a)(2)(A);

• methods used do not conform to goodmanufacturing practices (FDCA § 501 (a)(2),21 U.S.C. § 351 (a)(2)(b), 21 CFR Part 210 &211);

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Adulterated Drugs (21 U.S.C. § 351)

• container composed of poisonous or deleterioussubstance may cause contents to be injurious tohealth(FDCA § 501 (a)(3), 21 U.S.C. § 351 (a)(3));

• contains an unsafe coloring additive (§ 501 (a)(4),21 U.S.C. § 351 (a)(4));

• strength, quality or purity falls below compendialstandards § 501 (b), 21 U.S.C. § 351 (b));

• strength or purity falls below what it purports topossess(§ 501 (c), 21 U.S.C. § 351 (c));

• mixed or packaged to reduce quality or strength(§ 501 (d), 21 U.S.C. § 351 (d)).

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MISBRANDING of DRUG PRODUCTS(21 U.S.C. § 331)

A drug is deemed misbranded if:

• labeling is false or misleading (FDCA § 502 a),21 U.S.C. § 352(a));

• label fails to bear the name and place of business,an accurate statement of contents, weight, measureor numerical count (FDCA § 502(b), 21 U.S.C. §352(b));

• labeling required is not prominently displayedand understandable (FDCA § 502(c),21 U.S.C. § 352(c));

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DEEMED MISBRANDED - continued

• labeling does not contain the established name and namesand quantities of active ingredients(FDCA § 502(e), 21 U.S.C. § 352(e);

• labeling does not prominently display the established nameat least half as large as the proprietary name(FDCA § 502(e)(1)(B), 21 U.S.C. § 352(e)(1)(B));

• labeling doesn’t bear adequate directions for use(FDCA § 502(f), 21 U.S.C. § 352(f));

• not packaged or labeled as prescribed in the officialcompendium(FDCA § 502(g), 21 U.S.C. § 352(g)).

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Misbranding Of Drug Products

• Reference to Registration or Registration Numberdenoting FDA’s approval of firm or products.21 C.F.R. § 207.39

• Manufacture in a Non-Registered Establishment.§ 502(o) 21 U.S.C. § 352(o)

• Drugs Not Included in Drug Listing. § 502(o);21 U.S.C. § 352(o); 21 U.S.C. § 510(j)

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Regulation of Drug Manufacturing

Current Good Manufacturing Practices (cGMPs)

History

• First Regulations - June 20, 1963 (28 FR 6385)

• Now codified as 21CFR parts 210 through 226

• Major revisions to regulations

January 15, 1971 (36 FR 601)

September 29, 1978 (43 FR 45014)

January 20, 1995 (60 FR 4087)

December 8, 2008 (73 FR 51919)

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Current Good Manufacturing Practice (cGMP)

Principles:

(1) Quality, safety, and effectiveness must bedesigned and built into a product;

(2) Quality cannot be inspected or tested into afinished product; and

(3) Each step of the manufacturing processmust be controlled to maximize the likelihoodthat the finished product will be acceptable.

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Current Good Manufacturing Practice(cGMP)

Regulations

Drugs Generally21 CFR Parts 210 and 211

Blood and Blood Components21 CFR Part 600 et seq.

Note: For Blood Establishments, Parts 210through 226 and Parts 600 through 680supplement rather than supersede each other.

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Case Law

United States v. Barr Labs, Inc. 812 F. Supp. 458(D.N.J. 1993)

Established cGMP Standards for industry

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Guidance

Proposed cGMP regulations (May 3, 1996,

Based on Barr Labs decision; WithdrawnDecember 4, 2007)

Draft Guidance on OOS Results (Based onBarr Labs decision)

Guidelines for Quality Assurance in BloodEstablishments (July 11, 1995)

Guidance on OOS Results (October 2006)



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Pharmaceutical cGMPs for the 21st Century

• Risk Based Model for Prioritizing Sites for ManufacturingInspections

• Science Based Regulation of Product Quality

• Guidance on Quality Systems Approach toPharmaceutical cGMPs (September 2006)http://www.fda.gov/cder/guidance/7260fnl.htm

• Amendments to Current Good Manufacturing PracticeRegulations for Finished Pharmaceuticals. (73 FR 51919)Effective December 8, 2008



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FDA Inspections

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Statutory Authority to ConductEstablishment Inspections

• Section 704 21 U.S.C. §374; 21 U.S.C. §360(h)

• Reasonableness of the Inspection (time, limits, manner)

• Frequency of Inspections 21 U.S.C. §360(h)

• Consent Unnecessary

• Search Warrant Unnecessary

• Miranda Warnings Unnecessary

• Inspection Warrants

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Scope of Inspection

FDA Authority To Inspect

FDA may not inspect:

• Financial data.

• Sales data other than shipping figures.

• Pricing data.

• Personnel data other than information establishingthe qualifications of technical and professionalpersonnel.

• Certain research data except to the extent suchinformation may be required to be made available forinspection or submitted to FDA for particularproducts.

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Scope of Inspection


• No general subpoena authority, but in certain civilproceedings FDA may issue a subpoena forproduction of evidence and records.

• If FDA initiates an enforcement action, records areavailable under the rules of discovery.

• During a criminal investigation the JusticeDepartment can subpoena records relevant to anongoing grand jury investigation.

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Scope of Inspection

• FDA’s Authority to Inspect Records of Interstate Shipmentby Common Carriers and Recipients

– Section 703

– If requested in writing

• Sample Types

– Official sample

– Documentary sample (DOC sample)

– 301(k) sample

– Post-seizure sample

– Investigational sample (INV sample)

– Induced sample

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Scope of Inspection

• What FDA is Not Expressly Authorized to Obtain, butMay Attempt to Obtain

– In-plant photographs

• Not specifically authorized

* Dow Chemical Co.

* Acri Wholesale Grocery Co

– Affidavits from individuals

– Interview of employees

• FDCA does not expressly authorize investigatorsto interview a company’s employees; with/withoutcompany’s counsel:

* Managerial employees

* Non-managerial employees

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Scope of Inspection

• Limitations to the Scope of Inspection

– Retail pharmacies

– Licensed practitioners

– Research, teaching, or chemical analysis

– Exempted by regulation

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Procedure for Conducting Inspections

• Investigation Operations Manual(www.fda.gov/ora/inspect_ref/iom/IOMTC.html)

• Present Credentials and Notice of Inspection

• Inspectional Observations (Form FDA 483)

• Discussion with Management

• Establishment Inspection Report

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How FDA prepares for Inspections

• Review of FDA inspection proceduresand compliance policy guides.

• Review of a firm’s most recentEstablishmentInspection Reports (EIRs) and responses to

483s and Warning Letters.

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Refusal to Permit Entry or Inspection;Refusal to Permit Accessto or Copying of Records

• Prohibited Acts

• Administrative InspectionWarrant

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Reasons forFood and Drug Administration (FDA)

Administrative Inspections

• Routine

• For Cause

• Follow Up to Warning Letter or Enforcement Action

• Complaints from Consumers, Industry, and Current orFormer Employees

• Recall Effectiveness Check

• Pre-Approval Inspection

• Special Enforcement Initiative

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Scope of Inspection

Scope of FDA Inspections

• The scope of the inspection depends on “theinformation desired, or upon the violationssuspected or likely to be encountered.”

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FDA may inspect and copy:

records, files, papers, processes, controls anddocuments related to a facility’s bearing onwhether drugs are adulterated, misbranded orotherwise violative.

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Scope of Inspection

Pre-Approval Inspections

CDER’s Role

• Review data in applications(s)

• Establish specifications for manufacture andcontrol based on data

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Scope of Inspections


Districts’ Role:

• Assure cGMP compliance

• “Data audit” – verify authenticity andaccuracy of data submitted

• Report other data or information withimpact on cGMP compliance

• Verify compliance with applicationcommitments

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Inspection Teams (Investigators, Analysts, Engineers,etc.)

Areas Covered:

• Manufacturing (Dosage form, bulk drug/API, GMP)

• Reprocessing (if in application)

• Laboratory (Equipment and Procedures qualified and validated,raw data)

• Components (API-supplier, source of bio-batch, clinical batch)

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Areas Covered (cont.):

• Buildings and Facilities (impact on other products,structure – e.g., cross-contamination)

• Equipment (cleaning validated)

• Packaging and Labeling Controls (accountability, pastmix-ups, recalls)

• Stability (data audit)

• Process Validation (including pre-approval andcommercial batches.

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Field Recommendations:

• Approve (NAI, VAI)

• Withheld approval (OAI - with reasons why)

• Delay approval pending pre-approval inspection

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“Show Stoppers”

• Application misrepresents date or conditions relatingto pre-approval batches

• Inconsistencies and/or discrepancies raisingsignificant questions about the validity of records

• Pre-approval batches not made in cGMP compliance

• Failure to report adverse findings or test data withoutadequate justification

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How FDA Prepares For Inspections

Selection of team and designation of team leader

• The team leader:– Plans the inspection– Schedules and coordinates team

memberpre-inspection preparations

– Assesses progress of theinspection

– Coordinates preparation ofinvestigation

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FDA Inspection Goals

• To determine a firm’s compliance with FDArules and regulations.

• To obtain evidence to support legal actionwhen violations are found, or to obtain specificinformation as directed by counsel.

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What To Do Before An Inspection

• Evaluate Relationship with FDA

• Assess Systems, Procedures and Controls

•. Review Company Performance

• Establish Team & Plan

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What To Do During An Inspection:

The Team Approach

• The Daily Record

• Entry and Observation: What is allowed

• Access to Documents

– Types of documents

– Reasonable access

– Provide what is requested

– Keep good records; keep copies

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Closing the Inspection

The Team Approach

• The Exit Meeting - A Critical Part of the Inspection

• Presentation of Form FDA 483 – written report ofthe Inspection Observations

• Discussion of a Reply

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After the Inspection

• Report to Regulatory Affairs and Senior Management

• Response to Form FDA 483 is critical

– Provide tangible evidence that you are correctingproblems

– Allocate necessary resources to make corrections

– Address major quality system or safety issues first

– Demonstrate that you understand issues and whatcorrections are necessary

• Follow-Up

Establishment Inspection Reports

• Establishment Inspection Report (EIR) –

– report written by the investigators thatsummarizes all the findings from theinspection.

– Investigators submit EIR to the District Officefor a classification decision

Establishment Inspection ReportsDistrict Classifications

• No Action Indicated (NAI) No objectionable conditions or practices were foundduring the inspection (or the significance of the documented objectionable conditionsfound does not justify further action).

• Voluntary Action Indicated (VAI) Objectionable conditions were found anddocumented but the District and/or Center is not prepared to take or recommend anyof the regulatory (advisory, administrative, or judicial) actions listed below since theobjectionable conditions do not meet the threshold for regulatory action. The districtmay use an Untitled Letter, Regulatory Meeting or other communication withresponsible individuals to inform the establishment of findings that should becorrected. A written response by the establishment may be an option, but is notnecessary. Any corrective action is left to the establishment to take voluntarily.

•

• Official Action Indicated (OAI) Objectionable conditions were found and one of theregulatory actions listed below should be recommended. Includes voluntary recallswhere the district has decided conditions warrant regulatory (advisory, administrative,or judicial) action. Typically, an OAI classification should be made only if a FDA-483has been issued and the documented evidence supports the action recommended.

Establishment Inspection ReportsDistrict Classifications

• Referred to State (RTS) Referred to State, local, or other federaloffice. This classification can be used only when either there is no federaljurisdiction over the apparent violation in question or it is determined thatState action is the most efficient method of obtaining the establishment’scompliance with applicable Federal Laws, Regulations or Administrativerequirements.

• Referred to Center (RTC) This “District Decision Type” can only be usedwhen the objectionable conditions or apparent violations noted constitute acompliance area for which no clear policy has been established orsignificant technical issues exist which require Center review anddecision. An RTC classification should be made only if a FDA-483 hasbeen issued.

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Field Alert Reports (FAR)

• 21 CFR 314.81(b)(1)(i) and (ii); NDAs andANDAs(Effective May 23, 1985)

• Any incident that causes the drug product orits labeling to be mistaken for, or applied to,another article

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FAR - Required Reporting21 CFR 314.81(b)(1)(ii)

• Bacterial contamination

• Significant chemical, physical or other change

• Product deterioration

• Out-of-specification batch(es)

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FAR - Reporting Requirements

• Applicant holders are required to submitNDA/ANDA Field Alert reports on drugproducts manufactured or distributed withinor outside the U.S.

• U.S. Office/Agent - responsible for reportingto FDA district office where registered/located

• Notify the district office within 3 working days

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FAR - Reporting Requirements

• Information may be provided by telephone or other rapidcommunication means, with prompt written follow-up

• Form FDA 3331

• Internet Availability of Form 3331 - Word Format

http://www.fda.gov/opacom/morechoices/fdaforms/cder.html

or

http://forms.psc.gov/forms/MSWFDA/FDA-3331.doc

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FAR - Timeframe: 3 Working Days

• Starts

– Firm becomes aware of a reported problem

• Complaint

• Internal testing

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FAR - Firm Reporting

• FAR Required

– Further investigation required

– Corrective action initiated

• e.g., Formulation revision, labeling change

– Product Recall

• FAR Not Required

– Problem is resolved within 3 working days

• e.g., Analytical lab error

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FAR - Regulatory Actions

• Warning Letter

– When appropriate

• Significance

• Previously cited

• Concurrence with headquarters

• Withdrawal of Approval - CFR 314.81(d)

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FAR - Impact on Public Protection

• Recalls(types 21 CFR Section 7.3)

• Corrective Actions

• Discontinuation

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Further Action by FDA

• Warning Letters

• Adverse Publicity

• FDA “Requested” Recalls (21 CFR §7.45)

• Suspension or Withdrawal of Product Approval

• Impact on Award of Government Contracts

• Seizures

• Injunctions

• Criminal Prosecutions

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Thank You

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