1. Introduction to Topic #1: QbD approach for quality control and assurance of Dissolution Rate Ajaz S. Hussain, Ph.D. Deputy Director, Office of Pharmaceutical Science, CDER, FDA ACPS Meeting, May 2005

2. Topic #1 ACPS Discussion Goals Seek ACPS recommendations on a proposed regulatory tactical plan  QbD based regulatory decision system for quality assurance and control of optimal drug dissolution rate over the life cycle of a product Are the tactical steps outlined consistent with the QbD goals we seek to achieve? What additional steps and/or changes would you recommend to improve this plan? What additional scientific evidence is necessary to support the development and implementation of this plan? General considerations for identifying and developing statistical procedures Any other specific recommendations?  Prioritization?

3. Proposed Steps Alternate regulatory approach – suitability of dissolution measurement system Gauge Reproducibility and Repeatability Study Using Pivotal Clinical or Bio Lot Systems-based decision tree or establishing dissolution rate specification Opportunities for utilizing the PAT approach for controlling dissolution rate and development of real time quality assurance strategies Decision tree for “design space” concept articulated in the draft ICH Q8 Develop a side-by-side comparison New and Generic Drugs and explain why the level of QA/QC confidence in the proposed approach should be higher than what is achieved under the current system

4. Proposed Steps Seek ACPS recommendation at the May 2005 meeting on general considerations for identifying and developing statistical procedures Develop a detailed proposal for a subsequent meeting of the ACPS Seek harmonization on the approach with other regulatory authorities (starting with ICH Q8 Part 2)

5. Topic #1 ACPS Discussion Goals Seek ACPS recommendations on a proposed regulatory tactical plan  QbD based regulatory decision system for quality assurance and control of optimal drug dissolution rate over the life cycle of a product Are the tactical steps outlined consistent with the QbD goals we seek to achieve? What additional steps and/or changes would you recommend to improve this plan? What additional scientific evidence is necessary to support the development and implementation of this plan? Any other specific recommendations?

6. QbD & Goals? A systematic process of defining optimal design specifications of a product, its manufacturing process and its quality control and assurance methods  High degree process understanding  High confidence of low risk of releasing a poor quality product  High efficiency through continuous learning and improvement Intended Use Route of administration Patient population ….. Product Design Design Specifications (Customer requirements) Manufacturing Process

7. The Process R&DQualityManufacturing CMC Review Biopharm Review Clinical Review Pharm/Tox Review Process Validation Approval CGMP Inspection Compliance Quality Control

8. Need for a “Quality System” Orientation http://www.fda.gov/cder/gmp/gmp2004/manufSciWP.pdf

9. Quality System Requirements QS-9000 Third Edition element 4.2.5—Continuous Improvement (1998). For those product characteristics and process parameters that can be evaluated using variable data, continuous improvement means optimizing the characteristics and parameters at a target value and reducing variation around the value. For those product characteristics and process parameters that can only be evaluated using attribute data, continuous improvement is not possible until characteristics are conforming.  If attribute data results do not equal zero defects, it is by definition nonconforming product. Improvements made in these situations are definition corrective actions, not continuous improvement. Continuous improvement [shall be undertaken] in processes that have demonstrated stability, acceptable capability and performance.

10. USPXXIII 3-Stage Acceptance Rule Step 1, 6 tablets No Pass Yes Step 2, additional 6 tablets Yes No Step 3, additional 12 tablets Yes No Fail Pass

11. A Recent Proposal… A step in the right direction…..  Hauck, W.H., Foster, T., Sheinin, E., Cecil, T., Brown, W., Marques, M. and Williams, R.L. Oral Dosage Form Performance Test: New Dissolution Approaches. Pharm. Res. 22: 182-187 (2005) Conclusions  (a) hypothesis testing, with clear delineation of consumer and producer risks  (b) testing by variables as opposed to testing by attribute  (c) a tolerance interval approach to set acceptance criteria  (d) more flexible study design But …. Several challenges first need to be addressed (e.g., measurement system and robust estimates of variability) and then it will be essential to find an appropriate balance between statistics and pharmaceutical science  One has to start with pharmaceutical science discussion before developing an appropriate statistical tool

12. http://www.fda.gov/cder/gmp/gmp2004/manufSciWP.pdf

13. Corrective Actions Provide the leverage for Continuous Improvement? A case of an Approved and Validated product follows…. http://www.fda.gov/cder/gmp/gmp2004/manufSciWP.pdf

14. This can be catastrophic for the business and availability of Important drugs A Warning Letter

15. Inability to resolve Out of Specification Observations… Undermines the credibility of decision system  Raises questions - adequacy of the current decision system  Increases the risk of releasing unacceptable quality product to the consumer  Contributes to the low efficiency

16. CAPA: Challenges Hussain, A.S. Biopharmaceutics and Drug Product Quality: Performance Tests for Drug Products, A Look Into the Future. for Drug Products, A Look Into the Future. USP Annual Scientific Meeting "The Science of Quality“. September 26–30, 2004

17. CAPA: Challenges Hussain, A.S. Biopharmaceutics and Drug Product Quality: Performance Tests for Drug Products, A Look Into the Future. for Drug Products, A Look Into the Future. USP Annual Scientific Meeting "The Science of Quality“. September 26–30, 2004

18. Need for improvement is not just limited to CAPA We need to be confident on our analyses of  Surveillance samples  Consumer complaints  Other investigations

19. Is the Current Approach to “Calibration” Adequate? Hussain, A.S. Biopharmaceutics and Drug Product Quality: Performance Tests for Drug Products, A Look Into the Future. for Drug Products, A Look Into the Future. USP Annual Scientific Meeting "The Science of Quality“. September 26–30, 2004

20. More U.S. Marines contract Malaria Wednesday, September 10, 2003 Posted: 9:25 AM EDT (1325 GMT) WASHINGTON (CNN) -- Ten more U.S. military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria. We faced significant challenges in our analysis: Unexpected inter- laboratory differences that highlighted limitation of the current calibration procedure “We are at a loss to explain the difference between DPA’s and PHI-DO’s initial results. ……………….. We further contend that the Helium sparging does not remove dissolved air as well as the vacuum procedures and therefore could account for the additional 5 or 6% increase in the dissolution results. And finally, for this formulation basket wobble can significantly increase the dissolution values.” Prophylaxis compliance and not pharmaceutical quality was the reason DPA/CDER/FDA Memo B. J. Westenberger, 17 October 2003

21. Equally important is the need to Better understand the sources of variability in product performance and quality so as to establish the most appropriate design specifications  that support continuous improvement and address increasing complexity of product designs Develop measurements systems for products intended for non-oral route of administration and novel drug delivery systems Develop and implement globally harmonized proactive regulatory decision systems  For example: ICH Q6A and draft ICH Q8

22. Example: Pharmaceutical Development & Dissolution Specification Without pharmaceutical development information  Decision focus only on dissolution test data Test often used for both “in-process control” and final product testing  Decision characteristics focus only on “mean” Variability managed indirectly -“discriminating” test conditions and “tight” procrustean acceptance criteria Leads to a deterministic interpretation of specification (ignores the impact of random variability)  “Specifications are Standards” – can not be risk-based “Event Trees” not “Decision Trees”  Difficult to resolve “out of specification” observations  Post-approval changes and optimization or continuous improvement difficult

23. Dissolution specification without pharmaceutical development information Test 1 Test 2 Mean Dissolution Profiles (n=6) Pivotal clinical lots “Discriminating test” FDA 75% Applicant

24. Dissolution Test Problems: False +ives and -ives Test/Ref. Mean I. J. MacGilvery. Bioequivalence: A Canadian Regulatory Perspective. In, Pharmaceutical Bioequivalence. Eds. Welling, Tse, and Dighe. Marcel Dekker, Inc., New York, (1992)).

25. Differences between US & Japan? *Due to ACS restrictions on discussing specific drugs, names of drugs available in open literature have been erased.

26. Differences between US & Japan? Due to ACS restrictions on discussing specific drugs, names of drugs available in open literature have been blocked.

27. ICH Q6A: Goal and Characteristics of Pharmaceutical Quality Decision System “The quality of drug substances and drug products is determined by their design, development, in-process controls, GMP controls, process validation, and by specifications applied to them throughout development and manufacture.” Characteristics Goal Life-cycle

28. What is the ICH Q8 Opportunity? Specifications In process controls Development Design Process validation GMP Controls ICH Q6A Decision Characteristics “…where the provision of greater understanding of pharmaceutical and manufacturing sciences can create a basis for flexible regulatory approaches.”

29. ACPS May 2005 199519972000 SUPACDissolution IVIVC BCS ICH Q6A 2004, PAT & draft ICH Q8 Current State Desired State

30. ACPS Discussion The Measurement System  Cindy Buhse Overview of Current Regulatory Decision process  Mehul Mehta and Vibhakar Shah Current state of science  Lawrence Yu Basis of the proposed Tactical Plan  Ajaz Hussain ACPS recommendations for improving and/or modifying the proposed plan

31. Corrective Actions and Preventive Actions Hussain, A.S. Biopharmaceutics and Drug Product Quality: Performance Tests for Drug Products, A Look Into the Future. for Drug Products, A Look Into the Future. USP Annual Scientific Meeting "The Science of Quality“. September 26–30, 2004

32. Identifying Sources of Variability Hussain, A.S. Biopharmaceutics and Drug Product Quality: Performance Tests for Drug Products, A Look Into the Future. for Drug Products, A Look Into the Future. USP Annual Scientific Meeting "The Science of Quality“. September 26–30, 2004

33. CAPA: Steps necessary Hussain, A.S. Biopharmaceutics and Drug Product Quality: Performance Tests for Drug Products, A Look Into the Future. for Drug Products, A Look Into the Future. USP Annual Scientific Meeting "The Science of Quality“. September 26–30, 2004

34. CAPA: Challenges Hussain, A.S. Biopharmaceutics and Drug Product Quality: Performance Tests for Drug Products, A Look Into the Future. for Drug Products, A Look Into the Future. USP Annual Scientific Meeting "The Science of Quality“. September 26–30, 2004

35. CAPA: Challenges Hussain, A.S. Biopharmaceutics and Drug Product Quality: Performance Tests for Drug Products, A Look Into the Future. for Drug Products, A Look Into the Future. USP Annual Scientific Meeting "The Science of Quality“. September 26–30, 2004

36. CAPA: Challenges Hussain, A.S. Biopharmaceutics and Drug Product Quality: Performance Tests for Drug Products, A Look Into the Future. for Drug Products, A Look Into the Future. USP Annual Scientific Meeting "The Science of Quality“. September 26–30, 2004

37. CAPA: Challenges Hussain, A.S. Biopharmaceutics and Drug Product Quality: Performance Tests for Drug Products, A Look Into the Future. for Drug Products, A Look Into the Future. USP Annual Scientific Meeting "The Science of Quality“. September 26–30, 2004