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Manufacturing SubcommitteeManufacturing Subcommitteeof the Advisory Committee for of the Advisory Committee for
Pharmaceutical SciencePharmaceutical Science
July 20-21, 2004July 20-21, 2004
Ajaz S. Hussain, Ph.D.Ajaz S. Hussain, Ph.D.Deputy DirectorDeputy Director
Office of Pharmaceutical ScienceOffice of Pharmaceutical ScienceCDER, FDACDER, FDA
PAT InitiativeJuly 2001
CGMP for 21st Century Initiative
Medical Innovation
Critical Path Initiative
“Desired State”
Dimensions of the FDA’s Initiative on Dimensions of the FDA’s Initiative on Pharmaceutical Quality for the 21Pharmaceutical Quality for the 21stst
CenturyCentury
FDA Unveils New Initiative To Enhance Pharmaceutical Good Manufacturing Practices http://www.fda.gov/bbs/topics/NEWS/2002/NEW00829.html (August 21, 2002 )
Strong Public Health
Protection
Integrated quality systems orientation
Science-based policies and standards
Risk-based orientation
International cooperation
Time
Directional VectorsDirectional Vectors► Ensure regulatory review and inspection policies are Ensure regulatory review and inspection policies are
based on state-of-the-art pharmaceutical science based on state-of-the-art pharmaceutical science ► Encourage new technological advancesEncourage new technological advances► Encourage risk-based approaches that focus both Encourage risk-based approaches that focus both
industry and Agency attention on critical areas industry and Agency attention on critical areas ► Facilitate modern quality management techniques, Facilitate modern quality management techniques,
including implementation of quality systems including implementation of quality systems ► Enhance the consistency and coordination of FDA's Enhance the consistency and coordination of FDA's
drug quality regulatory programs, in part, by drug quality regulatory programs, in part, by integrating enhanced quality systems approaches integrating enhanced quality systems approaches into the Agency's business processes and regulatory into the Agency's business processes and regulatory policies concerning review and inspection activities policies concerning review and inspection activities
Second Progress Report and Implementation Plan. http://www.fda.gov/cder/gmp/2ndProgressRept_Plan.htm (September 3, 2003)
Covering the Space Defined by Covering the Space Defined by the Directional Vectorsthe Directional Vectors
Risk
Science
Preapproval Inspection Compliance Program
Dispute Resolution Process
Comparability Protocol
PATPAT
Pharmaceutical Inspectorate
Product Specialists on Inspection Process
Aseptic Processing
Guidance on CFR Part 11
Systems/
Integrat
ionICH P2, QbD, & RiskICH P2, QbD, & Risk
The Scientific OpportunityThe Scientific Opportunity
► Pharmaceutical (development and) Pharmaceutical (development and) manufacturing is evolving from an manufacturing is evolving from an artart form to form to one that is now one that is now sciencescience and engineering and engineering based.based.
► Effectively using this Effectively using this knowledgeknowledge in regulatory in regulatory decisions in establishing specifications and decisions in establishing specifications and evaluating manufacturing processes can evaluating manufacturing processes can substantially improve the substantially improve the efficiencyefficiency of both of both manufacturing and regulatory processes. manufacturing and regulatory processes.
http://www.fda.gov/cder/gmp/21stcenturysummary.htm
The Risk Mitigation and The Risk Mitigation and Communication OpportunityCommunication Opportunity
► Intuitive/Subjective to QuantitativeIntuitive/Subjective to Quantitative HCCPHCCP FMEAFMEA Quality by DesignQuality by Design
► ““Reliability is a design engineering discipline which Reliability is a design engineering discipline which applies scientific knowledge to assure a product will applies scientific knowledge to assure a product will perform its intended function for the required duration perform its intended function for the required duration within a given environment. This includes designing in within a given environment. This includes designing in the ability to maintain, test, and support the product the ability to maintain, test, and support the product throughout its total life cycle. Reliability is best throughout its total life cycle. Reliability is best described as product performance over time.” described as product performance over time.”
http://www.ewh.ieee.org/soc/rs/Reliability_Engineering/index.html
The Quality Systems The Quality Systems Opportunity Opportunity
A Historical Note on Quality: Milestones in Quality A Historical Note on Quality: Milestones in Quality Journey or Lurching from Fad to Fad?Journey or Lurching from Fad to Fad?
► Sampling Plans (‘50s)Sampling Plans (‘50s)► Zero-Defect Movement (‘60s)Zero-Defect Movement (‘60s)► ISO-9000 (‘80s)ISO-9000 (‘80s)► QS-9000QS-9000► Malcolm Baldrige AwardMalcolm Baldrige Award► European Quality AwardEuropean Quality Award► Total Quality ManagementTotal Quality Management► Six SigmaSix Sigma
The Ultimate Six Sigma - “The Big Q”The Ultimate Six Sigma - “The Big Q”
cGMPs
K. R. Bhote and A. K. Bhote. World Class Quality (2000) ISBN 0-8144-0427
PharmaceuticalQualitySystem
for the 21st
Century
A Two Year Journey? What is A Two Year Journey? What is the Destination? the Destination?
► ““Vision 2020 - I can see Vision 2020 - I can see clearly now”clearly now”
► The “Desired State” The “Desired State”
http://www.fda.gov/ohrms/dockets/ac/01/slides/3804s1_02_hussain.ppt
Desired StateDesired State Product quality and performance Product quality and performance achieved and achieved and
assured by designassured by design of effective and efficient of effective and efficient manufacturing processesmanufacturing processes
Product Product specifications based on mechanisticspecifications based on mechanistic understandingunderstanding of how formulation and process of how formulation and process factors impact product performancefactors impact product performance
Continuous "real time" assurance of quality Continuous "real time" assurance of quality
http://www.fda.gov/cder/gmp/21stcenturysummary.htm
Desired StateDesired State Regulatory policies tailored to recognize the Regulatory policies tailored to recognize the
level of scientific level of scientific knowledgeknowledge supporting product supporting product applications, process validation, and process applications, process validation, and process capability capability
Risk based regulatory scrutiny relate to the:Risk based regulatory scrutiny relate to the: level of scientific understandinglevel of scientific understanding of how formulation of how formulation
and manufacturing process factors affect product and manufacturing process factors affect product quality and performance, and quality and performance, and
the capability of the capability of process control strategies to process control strategies to prevent or mitigate riskprevent or mitigate risk of producing a poor quality of producing a poor quality product product
http://www.fda.gov/cder/gmp/21stcenturysummary.htm
Meeting ObjectivesMeeting Objectives
►Seek input and advise on charting the Seek input and advise on charting the most efficient path towards the most efficient path towards the “desired state”“desired state” Review assessment of Chemistry, Review assessment of Chemistry,
Manufacturing, and Controls (CMC) Manufacturing, and Controls (CMC) sections of submissionssections of submissions
Risk based cGMP Inspections: Selection of Risk based cGMP Inspections: Selection of Manufacturing sites for inspectionsManufacturing sites for inspections
What do we wish to accomplish What do we wish to accomplish with ICH Q8with ICH Q8
► Ensure Q8 facilitates movement towards the Ensure Q8 facilitates movement towards the “desired state” we have articulated“desired state” we have articulated
► This will This will Help us better understand the proposed Help us better understand the proposed product and product and
process designprocess design and its relation to the intended use and its relation to the intended use ► improve process of establishing regulatory specificationsimprove process of establishing regulatory specifications
Improve our ability to identify and understand Improve our ability to identify and understand critical critical product and process factorsproduct and process factors
► improve our understanding and confidence in risk improve our understanding and confidence in risk mitigation strategiesmitigation strategies
Allow us to utilize risk based approaches and recognize Allow us to utilize risk based approaches and recognize good science and facilitate continuous improvement good science and facilitate continuous improvement
Improve communication and systems thinkingImprove communication and systems thinking► More efficient review and inspection processMore efficient review and inspection process
Be a “win win win” for public health, regulators and Be a “win win win” for public health, regulators and industryindustry
ICH Q8: Integrating QbD and Risk Mitigation ICH Q8: Integrating QbD and Risk Mitigation DimensionsDimensions
Risks to QualityRisk of incorrect identityPoor product & process
Changes in clinical trial product(Bridging studies)
Inadequate Design Specifications(e.g., TDS adhesive attribute)
Critical to quality and performance?Risk of unqualified impurities
Risk of poor bioavailabilityRisk of incorrect expiry dateRisk of inadequate controls
Risks After Approval[Risk of SUPAC,..]
[Risk of unrepresentative test samples]
[Risk of Inadequate Facility and QS]
Intended UseRoute of administration
Patient population…..
Product Design
Design Specifications(Customer requirements)
Manufacturing Processand its Control
RegulatorySpecs.
Tests
& C
on
trols
-R
isk M
itig
ati
on
ICH Q9
Illustrative Examples of points to consider
Development Objectives
Continuous Improvement – Continuous Improvement – Emerging ICH Q8 “Design Space” Emerging ICH Q8 “Design Space”
ConceptConcept►Multi-dimensional space defined by Multi-dimensional space defined by
critical vectors of product quality and critical vectors of product quality and performanceperformance Examples of critical vectorsExamples of critical vectors
►Robust manufacturing process – consistent, Robust manufacturing process – consistent, reproducible delivery of product meeting its reproducible delivery of product meeting its specificationsspecifications
Manufacturing options Manufacturing options
►Stability (shelf-life) and Stability (shelf-life) and ►BioavailabilityBioavailability
Data based decisions: No Data based decisions: No Generalization Generalization
Current CMC Submissions
environmental
raw material properties
process conditions
Knowledge based decisions: Knowledge based decisions: Improved Ability to Generalize Improved Ability to Generalize
Pharmaceutical Development Knowledge
environmental
raw material properties
process conditions
Robust process
Stable and Bioavailable product
Process Understanding
Post approval change
Risk
CMC regulatory oversight
Company’sQuality system
cGMP regulatory oversight
ICH Q8
ICH Q8&9ICH Q8&9
Process Understanding
Risk(P/R)
CMC regulatory oversight
Company’sQuality system
cGMP regulatory oversight
Post approval change
ContinuousImprovement
Process Understanding
Risk
CMC regulatory oversight
Company’sQuality system
cGMP regulatory oversight
PAC to Continuous
Improvement
Process Understanding
Risk
CMC regulatory oversight
Company’sQuality system
cGMP regulatory oversight
ICH Q8 + Q9
ProposedICH Q 10
Moving towards the “Desired Moving towards the “Desired State”State”Day 1 Day 1
► Update on Current EffortsUpdate on Current Efforts ICH Q8, Q9 and proposed Q10ICH Q8, Q9 and proposed Q10 ASTMASTM
► Awareness topic: Filling the gaps – Research Awareness topic: Filling the gaps – Research planningplanning Bayesian approaches in CMC?Bayesian approaches in CMC? Critical Path InitiativeCritical Path Initiative
► Implementing the concepts developed in Implementing the concepts developed in ONDC and OGDONDC and OGD Manufacturing ScienceManufacturing Science Quality by DesignQuality by Design
Moving towards the “Desired Moving towards the “Desired State”State”Day 2 Day 2
► Risk based CGMP InspectionsRisk based CGMP Inspections Update on research study on pharmaceutical Update on research study on pharmaceutical
industry practicesindustry practices Pilot model for prioritizing selection of Pilot model for prioritizing selection of
manufacturing sites for inspectionsmanufacturing sites for inspections CGMPs for the Production of Phase I INDsCGMPs for the Production of Phase I INDs
► Efforts on facilitating continuous Efforts on facilitating continuous improvement through reduction in the need improvement through reduction in the need for “Prior Approval Supplements”for “Prior Approval Supplements” PAT ExamplePAT Example Comparability protocol conceptComparability protocol concept