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