1. Risk-Based CMC Review - OGD Perspective Gary J. Buehler, R.Ph. Director Office of Generic Drugs July 21, 2004 Advisory Committee for Pharmaceutical Science Manufacturing Subcommittee

2. 2 Mission To provide quality (safe and effective) generic drug products to the American public.

3. 3 Original ANDA Receipts

4. 4 ANDA Chemistry Supplements

6. 6 WHAT is QUALITY?

7. 7 Assurance of Pharmaceutical Quality Current Paradigm Quality standards comparable to Reference Listed Drug (RLD) established by Chemistry, Manufacturing, & Control (CMC) review Product manufactured in compliance with current Good Manufacturing Practices (cGMP) Process and specifications are conditions of approval that require approval for any subsequent changes

8. 8 Examples of Practical Effects Original ANDAs Extensive negotiations for specifications Internal study found 40% of all deficiency comments on first cycle review were requests to tighten specifications This takes time – contributing to estimated average of 18 months for approval High number of supplements necessary

9. 9 New Approach Extent of product knowledge is key Drives the range of risk-based decisions based on supportive data to assure a quality product That is, a product with established quality attributes, purity, potency/strength, identity, bioavailability/delivery, labeling/packaging, physical performance, etc)

10. 10 Voluntary!!! FDA will work with you We do not want to unnecessarily impede optimization of manufacturing processes We realize many firms will not be able to do this

11. 11 Desired State Review completed in one cycle within the statutory time frame Regulations based on knowledge and science providing flexibility in approval conditions Need for supplements based on knowledge of the risk of the change(s) affecting the quality of the product

12. 12 Internal Changes to Enhance Approvals Changing work assignment to optimize review resources Improve communications with DMF holders; re-review only as needed

13. 13 Internal Changes to Enhance Approvals (cont.) Incorporating aspects of CMC risk-based initiative Identify CBE supplements suitable for expedited approvals Expect to deal with comparability protocols Utilize in-house knowledge for specific drug products to identify review elements critical for product quality to provide PAS relief

14. 14 Industry Role Formulation and process design based on inherent mechanistic understanding of drug and its impact on product quality and performance Specifications determined by knowledge of process and product; clear rationale for selection

15. 15 Industry Role (cont.) Process understanding to mitigate risk associated with drug substance properties Continuous process improvement Identify parameters critical for product manufacture and product shelf life (stability)

16. 16 Making it Work – Reaching the Desired State Staff will follow guidances; current scientific literature Training of staff and regulated industry Represents a fundamental change in thinking – review based on knowledge of the product and what manufacturing changes will make a difference

17. 17 Why Should You Do This? Greater flexibility in optimizing your manufacturing process Lessened post-marketing supplement burden Reducing “No Assignable Cause” results in investigations

18. 18 International Conference on Harmonization (ICH) Provides Basic Outline for Communicating Product Understanding Common Technical Document (CTD)

19. 19 ICH – Q8 More fully defined, developed pharmaceutical development description in CTD Directed at product rationale instead of simple data reporting Better understanding of critical aspect effects on quality attributes

20. 20 ICH – Q9 Description of risk-based decision making and tool sets that might be helpful Supports Q-8 rationale

21. 21 ICH – Q10 Quality System Guidelines applicable to assuring the processes and evaluation addressed in Q-8 and Q-9

22. 22 ICH – Impact Potentially broader development programs for generic drug products Increased regulatory certainty for firms Organized approach allowing more efficient (effective?) regulatory decision making

23. 23 Additionally Dr. McClellan stated “other high-tech industries have achieved enormous productivity gains...we should expect nothing less from the pharmaceutical industry” Yet, the Wall Street Journal on September 3, 2003, stated “FDA regulations leave drug manufacturing processes virtually frozen in time”

24. 24 Continued... It is true that regulations designed to protect the public’s health make this a very special industry and they promote a conservative risk-averse mentality FDA also counters that the drug companies resistance to change is also partly to blame

25. 25 FDA Has Made the First Step: Encourage the use of equipment and protocols for continuous monitoring of manufacturing processes (PAT) Moving to risk-based cGMPs to free the industry from rules that do little or nothing to ensure quality We are willing to facilitate initiatives as long as they improve quality and reduce risk

26. 26 Acknowledge Generic Industry Experts in manufacturing drug products Know the advances in pharmaceutical sciences and manufacturing technologies Can identify and articulate the financial impact; both for changing and for losses with current technology

27. 27 Challenges Avoid perception of two-tiered product quality system The partnership assumes product quality is about providing flexible regulatory impact based on product understanding

28. 28 Challenges Because system includes a continuum of information, how this flexibility is applied needs to be well understood to ensure even treatment and outcomes

29. 29 Challenges FDA is not in the business of manufacturing Question to FDA: “What do we need to do?” Question to Generic Industry: “What do you think needs to be done?”

31. 31 Office of Generic Drugs (HFD-600) 7500 Standish Place Rockville, MD 20855 301-827-5845