1. Integrating CMC Review & Inspection Industry Recommendations Joe Anisko April 24, 2003

2. Integrated CMC Review & Inspection Summary of breakout session discussions General issues discussed Areas of agreement Concerns and suggestions Next steps

3. Application Documentation Pharmaceutical Development Information on key chemical, physical, pharmaceutical characteristics of drug substance and drug product that may influence product performance Discussion of critical quality attributes in design and manufacture of drug substance and drug product Discussion of critical tests and controls used to assure product quality and consistency

4. Application Documentation Pharmaceutical Development Discussion on use of innovative technologies and how these approaches are utilized to enhance overall quality and efficiency of the manufacturing process Proposals and rationale/justification for interim drug substance and drug product specifications Overview of initial continuous improvement plans Discussion of parameters or steps to be evaluated during validation

5. Application Documentation Pharmaceutical Development Risk assessments of product, manufacturing processes, and controls Need to define how this information would be reviewed (fyi vs. cGMP auditable) General concurrence that submission of Pharm Dev would be beneficial for industry and FDA Submission of additional ‘development data’ should not be mandatory (e.g., resources) Need to determine how including these data could lead to lower risk and possible reduction in regulatory burden and scrutiny

6. Application Documentation Pharmaceutical Development Submission of product development and supporting data or summaries vs. complete development history Concerns raised regarding a need to define how and who would review this information and the resources needed to prepare the documentation Questions raised as to whether submitting additional data would facilitate or delay approval

7. Interim Specs/Continuous Improvement Welcome the concept of interim specifications Good concept but additional discussions or guidance may be necessary Globally harmonized approach to interim specifications would be desirable Need to realize that interim specifications are only one component of a larger continuous improvement process, and industry should be given some latitude to ‘act’ on interim limits based on process optimization efforts

8. Interim Specs/Continuous Improvement Mechanistic understanding of specifications and/or continuous improvement studies may lead to tightening, widening, shifting, or possibly elimination of a specification FDA should consider broadening the scope of interim specifications to include process parameters and in-process controls

9. Inspections Generally, industry favors the elimination of the PAI in its current form Inspections may be warranted prior to approval and should be for cause or risk-based (recent company inspection history, new facilities, etc.) FDA should reallocate inspection resources to focus on most critical issues based on risk General GMP inspections should focus on the appropriate quality systems being in place Move towards mutual recognition for inspection of European facilities

10. Inspections Generally, there is value in having a highly trained pharmaceutical inspectorate Training should include appropriate academic background and relevant industry experience Industry should help develop training program Major role would be the assessment of quality systems/procedures that have the greatest risk of impacting product quality and consistency

11. Inspections Based on expertise of trained inspectorate, many technical issues/concerns could be resolved on site Inspectorate could audit/evaluate manufacturing data and results of continuous improvement studies prior to finalizing specifications Establishing a highly trained inspectorate should lead to better industry/FDA relationships and should enhance the overall efficiency, quality, and value of inspections for industry and FDA

12. Product and Technology Specialists Role or need for specialists should be discussed at pre-submission meetings (e.g., EOP2) Specialists could be engaged during CMC review or on site to help resolve technical issues Specialists could provide input to the evaluation and risk assessment of critical steps and controls Specialist input on technology and risk could lead to reduced need for prior approval supplements

13. Product and Technology Specialists Use of specialists should increase knowledge base at FDA and help encourage the use of innovative technology Need to clarify and coordinate roles of reviewer, inspectorate, technology specialists

14. Next Steps More thorough analysis of lessons learned with ‘Team Bio’ and pre-license inspection process Workshop on processes for setting interim acceptance criteria and final limits. Animal Health Industry and CVM need to assess practicality of using the CTD format Need for an ICH guideline on Pharmaceutical Development

15. Next Steps Agency needs, to the extent possible, standardize pre-approval and pre-license review and communications across Center/Office lines Suggest a workshop to further discuss the scientific information (e.g., documentation) to be made available to FDA