1. Challenges and Opportunities in Enhancement of the CMC Section of NDAs: Quality – by - Design Ajaz S. Hussain, Ph.D. Deputy Director Office of Pharmaceutical Science CDER, FDA DIA Annual Meeting, Washington D.C., June 2004

2. Background: Yesterday at DIA ► Risk Based CMC Review - Moheb Nasr:  The 21 st Century Initiative and the new paradigm for Pharmaceutical Quality  The “Desired State”  New Quality Assessment Paradigm at ONDC (under construction)  Assessment conducted by interdisciplinary scientists (chemists, pharmacists, engineers and others as needed)  Focus on critical quality attributes and their relevance to safety and efficacy (chemistry, formulations, manufacturing processes, dosage forms, product performance, etc.)  Reliance on knowledge provided by firms  Utilization of Risk-based analysis

3. Opportunity ► Over the last two decades we have improved our ability to solve complex multi-factorial problems  A systems approach to development – pre-formulation, formulation development, and clinical relevance  Multivariate empirical methods (e.g., Response Surface Methods) ► New measurement and information technologies  Measurements that can predict performance ► Such information is often filtered out of regulatory submissions  “fear” or “regulatory uncertinty” ► ICH Q8 can open the door for sharing and utilizing this information

4. Opportunity ► For companies that acquire extensive understanding about their product and manufacturing process and share this with the regulators  Enhanced science and risk-based regulatory quality assessment will be possible ► Setting specifications ► Reduction in the volume of data to be submitted – replaced by more knowledge based submissions ► Flexible post approval continuous improvement

5. Janet Woodcock, M.D. May 19, 2004

6. Desired State  Product quality and performance achieved and assured by design of effective and efficient manufacturing processes  Product specifications based on mechanistic understanding of how formulation and process factors impact product performance  Continuous "real time" assurance of quality http://www.fda.gov/cder/gmp/21stcenturysummary.htm ICH Q8 agreed “Desired State”

7. What do we wish to accomplish with ICH Q8 ► Ensure Q8 facilitates movement towards the “desired state” we have articulated ► This will  Help us better understand the proposed product and process design and its relation to the intended use ► improve process of establishing regulatory specifications  Improve our ability to identify and understand critical product and process factors ► improve our understanding and confidence in risk mitigation strategies  Allow us to utilize risk based approaches and recognize good science and facilitate continuous improvement  Improve communication and systems thinking ► More efficient review and inspection process  Be a “win win win” for public health, regulators and industry

8. ICH Q8: Integrating QbD and Risk Mitigation Dimensions Risks to Quality Risk of incorrect identity Poor 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 bioavailability Risk of incorrect expiry date Risk of inadequate controls Risks After Approval [Risk of SUPAC,..] [Risk of unrepresentative test samples] [Risk of Inadequate Facility and QS] Intended Use Route of administration Patient population ….. Product Design Design Specifications (Customer requirements) Manufacturing Process and its Control Regulatory Specs. Tests & Controls -Risk Mitigation ICH Q9 Illustrative Examples of points to consider Development Objectives

9. CTD-P2 Sec. QbD and Risk Drug Substance or API Intended Use Route of administration Patient population ….. Product Design Design Specifications (Customer requirements) P2.1 and 2.6 P2.2, 2.4, 2.5, 2.6 Drug Product Container Closure System Microbiological Attributes Compatibility (e.g., recon) Manufacturing Process Components of drug product P2.3 Manufacturing Process Development

10. Continuous Improvement – Emerging ICH Q8 “Design Space” Concept ► Multi-dimensional space defined by critical vectors of product quality and performance  Examples of critical vectors ► Robust manufacturing process – consistent, reproducible delivery of product meeting its specifications  Manufacturing options ► Stability (shelf-life) and ► Bioavailability

11. What could/should be the ICH Q8 “Design Space” Concept?  Within this space, available knowledge (derived from established scientific literature, in-house experiments from previous and current projects) provides a basis for reliable (degree of reliability can be linked to risk based decisions) estimation and/or prediction of: ► manufacturing process capability, ► stability and ► bioavailability

12. More on the “Design Space” Concept ► This knowledge (preferably – quantitative; e.g., a valid multivariate mathematical model) is utilized to identify and define formulation and manufacturing factors ranges that provide acceptable product quality and performance  Regulatory assessment and utility for establishing specifications and controls (wider range than the current approach)  Manufacturing options (e.g., process, equipment; scale, etc.), parameters within this space should not require prior review/approval and should be addressed within a companies quality system and subject to CGMP inspections ► Change the “change” to Continuous Improvement

13. Data based decisions: No Generalization Current CMC Submissions environmental raw material properties process conditions

14. Knowledge based decisions: Improved Ability to Generalize Pharmaceutical Development Knowledge environmental raw material properties process conditions Robust process Stable and Bioavailable product

15. Process Understanding Post approval change Risk CMC regulatory oversight Company’s Quality system cGMP regulatory oversight ICH Q8 ICH Q8&9

16. Process Understanding Risk (P/R) CMC regulatory oversight Company’s Quality system cGMP regulatory oversight Post approval change Continuous Improvement Process Understanding Risk CMC regulatory oversight Company’s Quality system cGMP regulatory oversight PAC to Continuous Improvement Process Understanding Risk CMC regulatory oversight Company’s Quality system cGMP regulatory oversight ICH Q8 + Q9 Proposed ICH Q 10

17. To illustrate the current state: A “Case Study” – Dissolution Attribute The “case study” attempts to connect many dots ICH Q6A ICH Q8 Dissolution SUPAC BCS BA/BE 1 2 4 5 3 Desired State Current State Testing to Document Quality Quality By Design

18. ICH Q6A DECISION TREES #7: SETTING ACCEPTANCE CRITERIA FOR DRUG PRODUCT DISSOLUTION What specific test conditions and acceptance criteria are appropriate? [IR] dissolution significantly affect BA? Develop test conditions and acceptance distinguish batches with unacceptable BA YES NO YES NO YES NO Do changes in formulation or manufacturing variables affect dissolution? Are these changes controlled by another procedure and acceptance criterion? Adopt appropriate test conditions and acceptance criteria without regard to discriminating power, to pass clinically acceptable batches. Adopt test conditions and acceptance criteria which can distinguish these changes. Generally, single point acceptance criteria are acceptable. How? What? Why? How do we currently establish dissolution specifications

19. Without adequate product and process development and/or knowledge sharing ► Without “design” consideration, high level of uncertainty with respect to critical attributes, “representative” test sample, and adequacy of risk coverage (e.g., compendail tests) to assure batch quality [Regulatory Concern/Risk] ► Reduce concern/risk by covering all apparent attributes with acceptance criteria based on capability of test methods and/or manufacturing process plus very inflexible SOP’s [Current Regulatory Risk Mitigation Strategy]

20. Without adequate product development and/or knowledge sharing we debate frequently …… And then, have CGMP problems?

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

22. OOS or Exceptions Further Increase Cycle Times (Source: G. K. Raju, M.I.T. FDA Science Board Meeting, November 16, 2001) Dissolution

23. Testing to Document Quality: Requires Less Variable Test Methods ► The current USP 10-mg Prednisone Calibrator Tablets exhibit slower dissolution over time ► If the acceptable test equipment calibration limit is 28-54; what can we say about use of f2 criteria (~mean profile difference of 10%) as a way to document unchanged quality (e.g., SUPAC)? LotDate Mean (n=6) SD (%) USP Limit (%) M4/0034.82.228-42 M10/0028.90.928-42 N12/0135.71.628-54 N11/0235.41.428-54 N6/0328.00.728-54 DPA/FDA Data using Apparatus 2; data from only one apparatus shown. Note the USP adjusts the limits of each new lot of calibration tablets to reflect the anticipated decrease in dissolution.

24. Dissolution Experience at the FDA Division of Pharmaceutical Analysis ► Dissolution testing with USP Apparatus 1 and 2 requires diligent attention to details: mechanical and chemical ► Dosage forms can respond differently to small variations in apparatus set up or degassing ► Large differences in dissolution results are possible unless all parameters are carefully controlled ► The experience at DPA indicates that differences in reproducibility can often be traced to improper mechanical calibration and/or degassing

25. False Positives and False Negatives!!! 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)).

26. Do we need a dissolution specification of every solid oral drug product? No ICH Q6A: Decision Tree #7 (1) Modified release? High solubility? Rapid dissolution? Relationship between Disintegration - Dissolution? No Yes Generally single-point dissolution acceptance criteria with a lower limit Generally disintegration acceptance criteria with an upper limit Establish drug release acceptance criteria: ER: Multiple time point MR: Two stage, parallel or sequential Yes No Yes How? Test – Test Comparison?

27. Disintegration - Dissolution Relationship 10# screen Fraction dissolved Note: Disintegration and dissolution process in a dissolution apparatus may differ from that in a disintegration apparatus (different hydrodynamics and other conditions)

28. “Testing to Document Quality” ► The phrase has many dimensions  In-process and end-product release and stability testing  Reliability of specifications (attribute, test method, and acceptance criteria)  Managing post approval changes/continuous improvement (e.g., reduce variability, improve efficiency,..)  Product and process knowledge acquisition and generalization

29. How can pharmaceutical development knowledge help? ► Demonstrate quality was designed in? ► Specifications based on mechanistic understanding? ► Continuous "real time" assurance of quality? ► Flexible continuous improvement?

30. ICH Q6A DECISION TREES #7: SETTING ACCEPTANCE CRITERIA FOR DRUG PRODUCT DISSOLUTION What specific test conditions and acceptance criteria are appropriate? [IR] dissolution significantly affect BA? Develop test conditions and acceptance distinguish batches with unacceptable BA YES NO YES NO YES NO Do changes in formulation or manufacturing variables affect dissolution? Are these changes controlled by another procedure and acceptance criterion? Adopt appropriate test conditions and acceptance criteria without regard to discriminating power, to pass clinically acceptable batches. Adopt test conditions and acceptance criteria which can distinguish these changes. Generally, single point acceptance criteria are acceptable. Overall Risk-based CMC: Why? Overall CMC Systems approach (e.g., link to morphic form, particle size, stability failure mechanisms) CMC: Why? Then How? Clin. Pharm. What? Design of Manufacturing and Controls How (reliable)? Product Design (Postulate - Confirmed Based on mechanism and/or empirically) So what?

31. Based on Quality of Pharmaceutical Development Knowledge can we not evaluate ► ► Overall CMC Systems approach (e.g., link to morphic form, particle size, stability failure mechanisms) and address concerns and risks  Is a dissolution specification needed?  Instead of wet dissolution test, can we use disintegration test?  Real time release and stability based on process controls, and NIR test for capsules?

32. Not all information “mandatory” ► We are okay with this ► But we wish to avoid confusion and the potential vocabulary that may evolve from this – “two different systems” ► Instead we see this as one system with different levels of QbD  we will use the “process understanding – predictive ability” vocabulary as a means to create a continuous framework and avoid “two different systems” March 2004 ICH Q8 Meeting: FDA’s Goals

33. Challenges we face ► Common approach to, and more clear articulation of  Not all information “mandatory”  Improved process understanding and control technologies may be afforded reductions in regulatory requirements  An inverse relation is expected between the effectiveness of the Quality by Design and the risk to a patient being exposed to product that is not fit for use  Ensuring continuous improvement and a process for continuous learning and updating of the knowledge base March 2004 ICH Q8 Meeting: FDA’s Goals