1. COMPARABILITY PROTOCOLUPDATE ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE Manufacturing Subcommittee July 20-21, 2004 Stephen Moore, Ph.D. Chemistry Team Leader Office of New Drug Chemistry Center for Drug Evaluation and Research Food and Drug Administration

2. Topics l Definition and General Aspects l Regulations Pertaining to Comparability Protocols l Draft Guidances for Industry on C.P.s l Public Comments on Draft Guidances l Current Thinking and Preliminary Comments on C.P.s

3. Definition of a Comparability Protocol l A comprehensive, detailed plan that describes the specific l type of proposed change l tests and studies to be performed l analytical procedures that will be utilized l acceptance criteria to be achieved to demonstrate lack of an adverse effect on the product quality as it may relate to the safety and effectiveness of the drug product

4. General Aspects of a Comparability Protocol l Well-planned in advance l Scientifically and technically sound (based on knowledge and understanding) l Adequate and current to implement the change l Drug, process, controls and change specific

5. Regulations Pertaining to Comparability Protocols 21CFR 314.70(e) and 601.12(e) "Protocols. An applicant may submit one or more protocols describing the specific tests and studies and acceptance criteria to be achieved to demonstrate the lack of adverse effect for specified types of manufacturing changes on the identity, strength, quality, purity, and potency of the drug product as these factors may relate to the safety or effectiveness of the drug product. Any such protocols, if not included in the approved application, or changes to an approved protocol, must be submitted as a supplement requiring approval from FDA prior to distribution of a drug product produced with the manufacturing change. The supplement, if approved, may subsequently justify a reduced reporting category for the particular change because the use of the protocol for that type of change reduces the potential risk of an adverse effect."

6. Draft Guidances for Industry on Comparability Protocols l Guidance for Industry, Comparability Protocols — Chemistry, Manufacturing, and Controls Information (draft issued Feb., 2003). (Applies to chemical entities and synthetic peptides) l Guidance for Industry, Comparability Protocols — Protein Drug Products and Biological Products — Chemistry, Manufacturing, and Controls Information (draft issued Sept., 2003) l Public comments under review for final publication of guidances >>>

7. Highlights of Public Comments on Draft Guidances on C.P.s (Excerpted and Paraphrased) l Efficient use of comparability protocols should provide regulatory relief by expediting review and approval of postapproval changes l Many changes are not anticipated at time of filing a marketing application

8. Highlights of Public Comments (cont.) l Level of specificity requested may define the protocol so narrowly as to diminish its future usefulness l Key to use of comparability protocols is the availability of sufficient manufacturing science data to demonstrate adequate understanding of the product and critical process controls

9. Highlights of Public Comments (cont.) l Clarify what is meant by comparability protocols for changes of a repetitive nature l Provide examples of reduction in reporting category from PAS to AR

10. Highlights of Public Comments (cont.) l Modifications to a comparability protocol in categories lower than PAS should be permitted (e.g., CBE-30, CBE) l CGMP aspects of postapproval changes should be addressed l We applaud the FDA for its efforts

11. Current Thinking on Comparability Protocols: T wo Basic Kinds l Single-use comparability protocol: For a specific, one-time CMC change l Repetitive-use Comparability Protocol: Used more than once to make a specified type of CMC change

12. Current Thinking on Comparability Protocols: Single-use C.P. l For a single change or multiple related changes l For multiple related changes: –Assessment of each of the individual changes –Combined effects of all of the changes on the product quality Examples: l Drug substance or drug product manufacturing process changes l Changes in scale and related changes

13. Current Thinking on Comparability Protocols: Repetitive-Use C.P. l Specific (specified) type of change narrowly defined l Boundaries established for extent of changes l In general, multiple related changes comprised only of subcategories of specified type of change Examples: l Container and closure system change l Changes to a unit operation

14. Current Thinking on Comparability Protocols: Advantages/Disadvantages To Industry Advantages: l Shortened time line for distribution of drug product l Reduced filing burden for commonly made changes Disadvantage: l Risk of adverse effect not eliminated

15. Current Thinking on Comparability Protocols: Advantages/Disadvantages To FDA Advantages: l FDA being responsive in finding ways to reduce manufacturer’s down time l May reduce overall number of post- approval supplements Disadvantage: l May increase FDA workload initially

16. Current Thinking on Comparability Protocols: Appropriateness of a C.P. Appropriate: l Lack of adverse effect can be demonstrated by analysis of product quality characteristics Not considered appropriate: l Nonspecific plans for CMC changes l Nonclinical safety, nonclincal pharmacology, PK/PD, clinical safety and/or effectiveness studies required

17. Current Thinking on Comparability Protocols: Principles and Recommendations l C.P. based on and provides evidence of scientific and technological knowledge and understanding of: –Drug, manufacturing process, controls –Proposed change –Potential effect of change on product quality l Gained from: –Pharmaceutical development information (drug and manufacturing process) –Commercial scale production experience –Scientific and technical literature

18. Current Thinking on Comparability Protocols: Principles and Recommendations (cont.) l All potential effects of a change identified, not just the obvious l Pre- and postchange drugs compared for all changes l Combination of routine quality controls testing and characterization studies l Analytical procedures sufficiently discriminatory to detect potential differences l Integrated analysis of all available data prior to concluding lack of adverse effect

19. Current Thinking on Comparability Protocols: Demonstration of Lack of Adverse Effect l Based on knowledge and understanding l Product quality characteristics of pre- and postchange drugs: –Conform to specifications –Conform to acceptance criteria for characterization studies –Comparable: mean and standard deviation / qualitatively l Manufacturing process and process controls considerations: –Process controls met –Effect on process and process controls as they relate to the product quality

20. Current Thinking on Comparability Protocols: Reduced Reporting Category Factors to Consider: l Degree of demonstrated knowledge and understanding l Normal reporting category for change l Drug-, process- controls- and change- specific considerations (e.g., complexity) l Validity of C.P. (e.g., scientifically and technically sound)

21. Current Thinking on Comparability Protocols: Reduced Reporting Category l PAS to AR –Substantial knowledge and understanding >>> –Use of protocol substantially reduces potential of adverse effect on product quality l PAS to CBE / CBE-30 –Adequate knowledge and understanding –Use of protocol moderately reduces potential of adverse effect –Depending on drug and change, CBE or CBE-30 designated l CBE-30 or CBE to AR –Adequate knowledge and understanding

22. Preliminary Comments on Reduction PAS to AR under C.P. Approach l Substantial knowledge and understanding of drug, process, controls, proposed change and potential effects of change on product quality l Relevance and adequacy of tests, studies, analytical procedures and acceptance criteria to assess effects of change l Preliminary data to support a lack of adverse effect l FDA will determine whether information provided is sufficient

23. Preliminary Comments on Reduction PAS to AR under C.P. Examples l Data from pharmaceutical development studies relevant to proposed change included with C.P.: –Definition of change –Identification of critical process steps, parameters, variables and/or controls pertinent to the change and interactions –Data from pilot batch(es) –Data from full-scale production batch(es), if available

24. Preliminary Comments on Reduction PAS to AR under C.P. Examples (cont.) l Previously approved similar change to same drug referenced in C.P. l Previously approved same change to similar drug referenced in C.P. l Subsequent change of same specified type under approved repetitive-use C.P., if justified –First time: CBE or CBE-30 –Second and subsequent times: AR

25. Preliminary Comments on Reduction PAS to AR under C.P. Exceptions l Change too complex l Impurity profile changed for drug substance or drug product l Manufacturing change that requires specification change

26. Preliminary Comments on Modifications to an Approved Comparability Protocol Examples where modification of C.P. may be useful: l Modify change so acceptance criteria achieved l Modify change to increase assurance of product quality l Update C.P. to keep it current and valid l FDA identifying examples of modifications to C.P. in all FDAMA reporting categories (PAS, CBE-30, CBE, AR)

27. Summary l Comparability protocols can be useful for industry to shorten time line for distribution of drug products l FDA exploring ways to make protocols more flexible and useful