1. Quality by Design & Question-Based Review: Observations by the Generic Pharmaceutical Industry Advisory Committee for Pharmaceutical Science October 5, 2006 Gordon Johnston Generic Pharmaceutical Association

2. Outline Introduction Quality by Design Question-Based Review Summary

3. Introduction QbD/QbR –Requires significant changes to cross-functional coordination within firms –Shift to QbR content represents a major change Cautiously optimistic A steep learning curve for industry Conversion to CTD format Aggressive implementation schedule by FDA ~ 800 ANDAs expected in CY 2006 –Increased burden for industry

4. Quality by Design Extensive manufacturing expertise in the industry –Generic firms often manufacture 50 - >100 products –Product and process understanding is critical for efficiency Concepts of QbD have been in use by industry for many years – QbD represents a more organized and integrated approach to product development

5. Quality by Design Opportunities –Value in ‘prior knowledge’ –Extensive experience with common formulations Excipient properties well understood Critical attributes impacting manufacturing process known

6. Quality by Design Opportunities (cont’d) –Keen knowledge of equipment and common manufacturing processes Blending, coating, etc. –Potential for reduced review time –Potential for reduced post-approval burden

7. Quality by Design Are QbD expectations clearly defined? –GMP implications? Experience to date is mixed ICH Q8 concepts still being integrated by Field Field often expects full design space validation Prior knowledge not universally accepted by investigators at this time

8. Quality by Design Should FDA modify its focus? –Generic industry still required to accept FDA dissolution specifications –Continued requirements to set specifications typically based on process capabilities and not product performance For example, residual solvents –More guidance on non-oral dosage forms needed

9. Question-Based Review Represents a tool to efficiently assess QbD approach Industry is supportive of the initiative Industry and OGD still learning

10. Question-Based Review OGD Model QOS –2 years in the making –Open dialogue between OGD and generic industry during evolution –OGD responsive to Q&A sessions

11. Question-Based Review OGD Model QOS –OGD-industry collaboration has accelerated industry’s understanding of QbR –Ongoing communication critical during full implementation

12. Question-Based Review OGD Model QOSs –Help industry recognize issues OGD generally considers critical –Guide industry toward quality by design –Assist industry to prepare a high quality QOS

13. Question-Based Review OGD Questions –Allow industry to address some questions with prior knowledge –Industry has been active in submitting QbR applications Over 35 ANDAs First ANDA Approval last month

14. Question-Based Review Challenges –Simultaneous conversion to CTD format and QBR data elements –Implementation schedule has been challenging for some companies Some companies have been submitting QbR applications since this summer –Substantial internal training and coordination required for implementation

15. Question-Based Review Challenges –Still uncertain on OGD expectations for QOS and product development reports –Oct 20 OGD training on how to prepare a high quality QOS Initial response is very positive –More OGD training if needed

16. Question-Based Review Recommendation –Post-approval reduction in regulatory burden? Industry requests clarity on types of supplements where regulatory burden may be ‘downgraded’ –Extending QbR concept to already approved products (>8000)? –Extending QbR concept to drug substance DMF

17. Summary Excellent communications by OGD –Numerous meetings, webcasts, teleconferences during development phase of QbR –Ongoing industry-OGD communications critical Increased burden

18. Summary Need to expand QbR to already approved ANDAs and drug substance DMF Post-approval regulatory relief a critical outcome of initiative Industry remains cooperative and hopeful Reassess in a year