ACPS Manufacturing Subcommittee Report

1. ACPS Manufacturing Subcommittee Report October 19, 2004 Judy P. Boehlert, Ph.D. Chair

2. Meeting Dates and Topics • July 20, 2004 • Quality by Design Topic Updates • Introduction to Bayesian Approaches • Research and Training Needs: The Industrialization Dimension of the Critical Path Initiative • Manufacturing Science and Quality by Design as a Basis for Risk-based CMC Review • Risk-based CMC Review Paradigm

3. Meeting Dates and Topics • July 21, 2004 • Introduction to Pharmaceutical Industry Practices Research Study • Pilot Model for Prioritizing Selection of Manufacturing Sites for GMP Inspection • cGMPs for the Production of Phase I INDs • Applying Manufacturing Science and Knowledge; Regulatory Horizons

4. Quality by Design Topic Updates • ICH Q8 • Guidance on pharmaceutical development section of the CTD • Will describe baseline expectations and optional information • Requires FDA and industry to think differently • “Process understanding and predictive ability” can lead to regulatory flexibility • Framework for continuous improvement • Step 2 expected November 2004

5. Quality by Design Topic Updates • ICH Q9 - Quality Risk Management • Risk identification – should link back to potential risk to the patient • Risk assessment – What can go wrong? What is the likelihood? What are the consequences? • Risk control – Options for mitigating, reducing and controlling risks • Risk communication – Between decision makers and other shareholders • Step 2 – November, 2004?

6. Quality by Design Topic Updates • Quality Systems needed to realize potential of Q8 and Q9 (ICH Q10?) • Monitor and evaluate processes with feedback loops in a manner to identify trends and demonstrate control or the need for action • Manage and rectify undesirable occurrences • Handle improvements • Manage/implement/monitor change • Q10 “on hold”

7. Quality by Design Topics • ASTM E55 Committee • Development of standards for PAT • Consensus standards with input from industry, academia and regulators • Established process with an umbrella set of rules • ASTM recognized worldwide • Three functional committees • Management (Sub 1) • Implementation and practices (Sub 2) • Terminology (Sub 91) • Avoid duplication with other initiatives?

8. Introduction to Bayesian Approaches • “Reliability for the Analysis of Risk” • Reliability – the quantification of uncertainty • Utility – costs and rewards that occur as a consequence of any chosen decision • Risk Analysis – process assessing reliabilities and utilities including identification of consequences • Scales for measuring uncertainty, e.g., probability

9. Introduction to Bayesian Approaches • “When the quantification of uncertainty is solely based on probability and its calculus, the inference is said to be Bayesian.” • Discussion of use of Bayesian approaches for ICH Q8, Q9, Q10 and use of prior information

10. Industrialization Dimension - Critical Path Initiative • Examining innovational stagnation • Critical path – inadequate attention in areas of new or more efficient methodologies and development research • Industrialization – goes from physical design of prototype up to commercial mass production • Education and research infrastructure needs improvement

11. Industrialization Dimension - Critical Path Initiative • FDA strong interest in computational methodologies to support CMC • Putting together a chemometrics group • New FDA research program focusing on industrialization dimension • Training needs, e.g., pharmaceutical inspectorate training program

12. Manufacturing Science and Quality by Design • Basis for risk-based CMC review • Companies share product/process understanding with regulators • Base specifications on mechanistic understanding • Continuous improvement • “Real time” quality assurance

13. Science Perspective on Manufacturing • Define current and the desired state and steps to go from here to there • Define terms – manufacturing science, manufacturing system and manufacturing capability • Real case studies will help • Testing is mostly non-value added; quality be design is the desired state

14. Risk-Based CMC Review - ONDC • Provide regulatory relief by incorporating science based risk assessment • More product/process knowledge shared by industry • More efficient science based inspections • Focus resources on critical issues • Specifications based on risk based assessment

15. Risk-Based CMC Review - ONDC • Quality Assessment rather than a Chemistry Review • Conducted by interdisciplinary scientists • Risk-based assessment • Focus on critical quality attributes and their relevance to safety and efficacy • Reliance on knowledge provided by applicants • Comparability Protocols

16. Risk-Based CMC Review - ONDC • Role of process capability in setting specifications will need to be addressed – there may be no clinical relevance • Knowledge base at time of submission • Specifications should not be used as a tool to control the manufacturing process • Expand the Quality Overall Summary in the future

17. Risk-Based CMC Review - OGD • Extent of product knowledge is key • Risk-based decisions based on supportive data • Voluntary! • Supplement need based on knowledge of the risk of the change • Clear rationale for selection of specifications

18. Risk-Based CMC Review - OGD • Identify critical parameters for product manufacturing and stability • Train FDA staff and regulated industry • Yields greater flexibility in optimizing the process • Lessened supplement burden • Real examples would be an asset

19. Risk-Based CMC Review - OGD • Generic industry focus is on a bioequivalent product • Often patent issues to design around • Workload in OGD a significant issue • Provide advice to industry on improving quality of DMFs

20. Risk-Based CMC Review – Asking the Right Questions • Desired State • Include needed data in filing • Process and product design • Identify critical attributes • Identify process critical control points • Analyze data to produce meaningful summaries and scientific rationales • Reviewers assess adequacy of submission by asking the right questions

21. Additional Committee Comments – Day 1 • ICH and ASTM activities appear to be synergistic but ICH needs to be aware of ASTM focus • Is FDA getting ahead of ICH Q8, 9,10? • Need concrete examples • Need to clearly demarcate “minimum” and optional information necessary • “Optional” information comes in degrees as more is learned

22. Additional Committee Comments – Day 1 • Need to avoid implying two different quality approaches • Will need training programs and case studies – form a working group under the Manufacturing Subcommittee? • Need to find better terms than “minimal” and “optional” • Focus on process and then the tools

23. FDA Research Project • Identify attributes that impact inspection outcomes • Compile and link FDA databases • Look at variables for product/process, facility, firm and FDA • Status – collecting data; CDER completed, CBER ongoing Georgetown University & Washington University

24. Pharmaceutical Manufacturing Research Study • Focus - Are cGMP violations related to managerial, organizational and technical practices • Interview manufacturers • Internet based questionnaire in Fall 2003 • U.S. and EU Manufacturers • Data collection near completion Georgetown University & Washington University

25. Pharmaceutical Industry Practice Comments • Concern with just looking at numbers of deviations or field alerts, particularly, when investigation may have shown little concern • Also, very detailed SOPs can lead to more deviations • India and China not included in API manufacturers

26. Risk Ranking and Filtering • Risk ranking – series of decisions to start to rank within a class or across classes • Tools may be customized for each application • “Filters’ may be used to reflect resource limitations and/or program goals

27. Pilot Risk-Ranking Model to Prioritize Sites for GMP Inspections • Using ICH Q9 concepts of defining risk • Site Risk Potential (SRP) includes product, process and facility components • Look at probability and severity components that make up harm • Looking at other risk ranking models, e.g., EPA and USDA • Using the CDER Recall database

28. Pilot Risk-Ranking Model to Prioritize Sites for GMP Inspections • Comments: • Focusing on volume at a site may be misleading – the risk could actually be lower • Need to also consider risk of the loss of availability • Consider “hard to fabricate” products or products with difficulty controlling uniformity • Investigator consistency will be an issue • Look at high personnel turnover

29. Pilot Risk-Ranking Model to Prioritize Sites for GMP Inspections • Will sites know how they are ranked? • Self-inspections are a critical part of the Quality System but the value to the company is diminished if information is available to FDA

30. GMPs for the Production of Phase I Drugs • CMC review to ensure the identity, strength, quality and purity of the investigational new drugs as they relate to safety • Draft guidance for GMPs in process (CDER, CBER, ORA) • Risk-based approach • No regular inspection program – looked at on a “for cause” basis

31. Process Understanding and PAT • Update on the PAT initiative • Guidance recently finalized • Expand to biotech products • Continue training of FDA staff

32. Comparability Protocol • Update on guidances • Goal is to provide regulatory relief for postapproval changes • A detailed plan describing a proposed change with tests and studies to be performed, analytical procedures to be used and acceptance criteria to demonstrate lack of adverse effect on product • Many comments received from the public

33. Comparability Protocol • Committee Comments: • Single use protocol has limited utility; more utility for repetitive changes • Specificity of the protocol may limit repetitive use • How much specificity is needed? • For a well defined protocol, an AR should be sufficient

34. General Conclusions • General principles are good but case studies are needed to facilitate understanding • Case studies should cover all industries, e.g., dosage form, API, Pioneer and Generic • Committee expressed concern on what appears to be understaffing in OGD

35. General Conclusions • Failure Mode & Effect Analysis (FEMA) can be linked with risk based decision making wherein the results feed into decision trees • Training and education of both regulators and the industry in the new approaches is key • Historical inconsistency in regulator findings may limit the utility of surveys