Implementation of Quality-by-Design (QbD) Principles in CMC Review of Generic Drugs

1. Implementation of Quality-by-Design (QbD) Principles in CMC Review of Generic Drugs Lawrence X. Yu, Ph. D. Director for Science Office of Generic Drugs Food and Drug Administration Advisory Committee for Pharmaceutical Science October 26, 2005

2. OGD Question-based Review System • Why? • How? • And What?

3. Receipts of ANDAs

4. Receipts of Supplements

5. cGMP Initiative “Desired State”: Regulatory • “Regulatory policies and procedures are tailored to recognize the level of scientific knowledge…” • “Risk based regulatory scrutiny is associated with the level of scientific understanding...”

6. Current OGD CMC Review • One size fits all – Risk is not systematically considered • Does not adjust review to the level of scientific understanding • All products (simple and complex) use the same approach • All products are subject to the same post-approval supplements

7. Why Question-based Review? • Workload • Quality • cGMP for 21st Century; Quality by Design • Continuous improvement of our review process

8. OGD Question-based Review System • Why? • How? • And What?

9. cGMP Initiative “Desired State”: Manufacturing • 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 • An ability to effect continuous improvement and continuous "real time" assurance of quality

10. Discussions Internally • Question-based Review: Timetable • 1/2005 – 2/2005: Question-based Review Drafted • 3/2005 – 4/2005: Division Directors Discussion • 5/2005 – 6/2005: Team Leaders Discussion • 7/2005 – 8/2005: Reviewers Discussion • 2/2005 – 12/2005: Discussions with Stakeholders and Upper Management • 9/2005 – 12/2006: Trial Period and Gradual Implementation • 1/2007: Full Implementation

11. Discussions Externally • February 24, 2005: GPhA Technical Committee meeting • June 8, 2005: GPhA Technical Steering Committee meeting • June 29, 2005: GPhA Technical Meeting • October 5, 2005, AAPS Workshop • October 21, 2005: GPhA QbR WG Meeting • October 25, 2005: OGD QbR Report • More…

12. Question-Based Review for CMC Evaluations of ANDAs The Office of Generic Drugs (OGD) is developing a question-based review (QbR) for the Chemistry, Manufacturing, and Controls (CMC) evaluation of an Abbreviated New Drug Application (ANDA) that is focused on critical pharmaceutical quality attributes. The QbR initiative began in early 2005 with the development of a revised review template and is approaching the early implementation phase as we gain feedback through wide internal and external discussions. The QbR will transform the CMC review into a modern, science and risk-based pharmaceutical quality assessment that incorporates and implements the concepts and principles of the FDA’s Pharmaceutical cGMPs for the 21st Century: A Risk-Based ApproachandProcess Analytical Technology initiatives …….. ……..   August, 2005

13. How is Question-based Review Developed? • Quality built in by design, development, and manufacture and confirmed by testing • Risk-based approach to maximize economy of time, effort, and resources • Preserve the best practices of current review system and organization • Best available science and wide consultation to ensure high quality questions

14. OGD Question-based Review System • Why? • How? • And What?

15. Question-based Review • Question-based Review is a general framework for a science and risk-based assessment of product quality • Question-based Review contains the important scientific and regulatory review questions to • Comprehensively assess critical formulation manufacturing process variables • Determine the level of risk associated with the manufacture and design of the product

16. What Does a CMC Reviewer do? • Evaluates identity, strength, stability, purity, and quality • Definition of Quality: the drug product is free from contamination and will reproducibly deliver the therapeutic benefit promised in the label to the consumer (Janet Woodcock) • Determines that the generic drug product • is appropriately designed (a pharmaceutical equivalent to the brand name product) • can be reproducibly manufactured

17. Questions to Whom? • CMC Reviewer • Questions guide reviewers to provide a consistent and comprehensive evaluation of the application • Industry • Questions also alert the industry to what issues we generally consider critical in the evaluation of their applications

18. CMC Review Under QbR • Questions guide reviewers to provide a high quality and comprehensive evaluation of the application • Some CMC deficiencies under the current system are related to reviewer chemists’ education and experience • Allow reviewers to derive bioequivalence inferences • Pharmaceutical development/quality by design information and prior knowledge

19. CMC Review Under QbR • The risk and science-based regulatory assessment • Level of assessment is associated with complexity of drug products • Post-approval change supplements are related to scientific understanding

20. CMC Review Under Question-based Review (Continued) • Three-tiered assessment of manufacturing • Tier 1 applies to all dosage forms • Tier 2 applies to dosage forms that are not solutions (equivalent to current practice) • Tier 3 applies to dosage forms that are not solutions, IR tablets, or IR capsules

21. CMC Review Under Question-based Review (Continued) • Proposed Risk-based Scoring System • ANDA drugs: Risk score NTI Drugs +1 Complex dosage form +1 Insufficient or missing PD reports +1 Application of poor quality (> 2 CMC cycles) +1

22. CMC Review Under Question-based Review (Continued) • Post-approval Change Recommendation • Total risk score of 1 or less • Many CBE-0 and CBE-30 changes shifted to annual report • Possible to downgrade certain PAS changes to CBE/annual report • Total risk score of >1 • No change in supplement submission and review • At the time of ANDA approval the review team will propose a risk assessment score for the application

23. CMC Review Under Question-based Review (Continued) • Risk-based Conclusion and Post-approval Supplements Reduction • Should the application be approved? • What post-approval waivers/commitments are appropriate for this product? • Eliminate/ downgrade up to 80% of CMC supplements, and thus free up scarce review resources • Allow sponsors freedom to execute changes in manufacturing processes for which they have demonstrated process understanding

24. Generic Drug Applications Under Question-based Review • Common Technical Document Format • Quality Overall Summary that will • directly address the reviewers’ questions and guide reviewers through the application • eliminate unnecessary copying of information such as composition, specification, and manufacturing process, etc., resulting in shorter review time

25. Generic Drug Applications Under Question-based Review (Continued) • Product Development Report (Quality by Design) that will explain • how drug substance and formulation variables affect the performance of the drug product • how the sponsor identifies the critical manufacturing steps, determines operating parameters, selects in-process tests to control the process, and scales up the manufacturing process

26. Generic Drug Applications Under Question-based Review (Continued) • The 1999 Guidance for Industry “Organization of an ANDA” • Does not include Quality by Design principles • Does not provide for a QoS • Is no longer current for the OGD Question-based Review

27. Generic Drug Applications Under Question-based Review (Continued) • Future Generic Applications • We strongly recommend that generic sponsors submit generic applications based on the format of ICH CTD, preferably, electronically • Module 1: Administrative Information • Module 2: Quality Overall Summary and Clinical Summary • Module 3: Quality • Pharmaceutical Development; Quality by Design • Module 4: Nonclinical • Module 5: Clinical (Bioequivalence)

28. Benefits of Question-based Review • Risk based reduction of supplements • Science based specifications • Consistency and transparency of review • Efficient and timely review process

29. Reviewer Education • Regulatory Science Training Series • Past training workshops • Polymorphism, Controlled Release, Injectable Drug Products, Aerosols and Sprays, Impurities, Excipients, and Manufacturing • Future training workshops • Quality by Design (OPS) • Preformulation, Biopharmaceutics, Dissolution • Process Identification, Simulation, Monitoring, and Control

30. Expectations • Office of Generic Drugs • Ask the right questions • Produce a concise, consistent, and comprehensive review • Industry • Consistent, science and risk-based assessment • Accelerated approval of applications • Reduced supplements

31. OGD Question-based Review System • Why? • Workload, cGPM initiative, and current review process • How? • Quality by design, risk and science-based approach, and wide consultation • What? • A modern, science and risk-based pharmaceutical quality assessment system • More Information on Question-based Review • www.fda.gov/cder/ogd/QbR.htm

32. Acknowledgement • Andre Raw Robert Lionberger • Radhika Rajagopalan Lai Ming Lee • Frank Holcombe Rashmikant Patel • Florence Fang Vilayat Sayeed • Paul Schwartz Richard Adams • Lawrence Yu (Chair) Gary Buehler, Robert West, Rita Hassall, Brenda Arnwine, Gururaj Bykadi, James Fan, Scott Furness, Dave Gill, Shing Hou Liu, Albert Mueller, Michael Smela, Glen Smith, Ubrani Venkataram, Karen Bernard, Neeru Takiar, Roslyn Powers, Mouna Selvam, Ramnarayan Randad, Shanaz Read, Quan Zhang, Andrew Langowski, Susan Rosencrance, Barbara Scott, Robert Iser, Guoping Sun, Yanping Pan, Raman Murali, Aloka Srinivasan, Ruth Warzala, Barbara Davit, Christina Bina, Koung Lee, and Tom Hinchliffe