Risk-Based CMC Review - OGD Perspective

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

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

3. Original ANDA Receipts

4. ANDA Chemistry Supplements

6. WHAT is QUALITY?

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

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

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

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

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. 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. 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. 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. 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. 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. 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. 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. Office of Generic Drugs (HFD-600)7500 Standish PlaceRockville, MD 20855301-827-5845