1. FDA PAT Sub-Committee of Advisory Committee for Pharmaceutical Sciences June 12-13, 2002; Gaithersburg, MD Regulatory Challenges: Post-Approval PAT Applications Dhiren N. Shah, Ph.D. Director, DRA-CMC Aventis Pharmaceuticals

2. FDA Advisory Committee Meeting; Dhiren N. Shah, Ph.D., PA-PAT Applications; June 12-13, 20022 Outline  Need for post-approval (PA) PAT Applications  Challenges in PA-PAT Applications  PA- PAT Applications to –  APIs  Drug Products  Guidance Development Consideration–  CMC Review  Type and amount of CMC information required  Regulatory submission type  Compliance Audit  Summary & Conclusions

3. FDA Advisory Committee Meeting; Dhiren N. Shah, Ph.D., PA-PAT Applications; June 12-13, 20023 Need for PA-PAT Applications  Improve quality of existing products  Improve analytical testing  Increase manufacturing efficiency  Reduce/eliminate OOSs, avoid potential recalls, enhance compliance  Potential long-term cost-savings

4. FDA Advisory Committee Meeting; Dhiren N. Shah, Ph.D., PA-PAT Applications; June 12-13, 20024 Challenges in PA-PAT Applications Two kinds of post-approval situations 1. Products without PAT applications in the original submission  Identify process critical control parameters (PCCP)  Replacement or adjustments of in-process controls and possibly final specifications  Correlation between PAT-based controls and approved conventional controls  Review and compliance processes  OOSs – How to handle?  Difficult to apply for this type of product

5. FDA Advisory Committee Meeting; Dhiren N. Shah, Ph.D., PA-PAT Applications; June 12-13, 20025 Challenges in PA-PAT Applications Two kinds of post-approval situations 2. Products with PAT-based controls in the original submission  Changes to approved PAT-based controls  Addition of new PAT-based controls  Deletion of a specification to eliminate non- value-added controls  Review and Compliance processes  OOSs – How to handle?  Much easier to further apply PAT

6. FDA Advisory Committee Meeting; Dhiren N. Shah, Ph.D., PA-PAT Applications; June 12-13, 20026 PA-PAT Applications to APIs  No change to DS synthetic pathway  In-process controls such as –  Impurity levels  Residual solvents (including moisture)  Completion of reaction  Isolation/purification  Initiation and completion of crystallization  Correlation between the conventional IPCs and PAT-based IPCs  Final API specifications?  Parametric release?

7. FDA Advisory Committee Meeting; Dhiren N. Shah, Ph.D., PA-PAT Applications; June 12-13, 20027 PA-PAT Applications to DPs  No changes to drug product  Drug product type dependent – SODF (IR and MR), Sterile, Semi-solids, etc.  Raw materials controls – ID, assay, uniformity, physical properties  In-process controls such as –  Granulation end-point  Moisture content in granulation  Blend uniformity (direct compression and blending of running powders to wet granulation)  Content uniformity  Viscosity measurements  Co-relation between conventional IPCs and PAT-based IPCs  Parametric release?

8. FDA Advisory Committee Meeting; Dhiren N. Shah, Ph.D., PA-PAT Applications; June 12-13, 20028 Guidance Development for PA-PAT-based Controls Guidance Development for PA-PAT-based Controls CMC Review  Equivalence to conventional controls  Enhanced assurance that the product will meet SIPPQ – How to show?  Scientific basis for PAT controls  Type/amount of CMC information requirement –  Number/scale of batches requirements  Statistical support  Stability requirements?  Post-approval commitments?  Regulatory submission route –  AR, CBE-0, CBE-30, PAS?

9. FDA Advisory Committee Meeting; Dhiren N. Shah, Ph.D., PA-PAT Applications; June 12-13, 20029 Guidance Development for PA-PAT-based Controls Guidance Development for PA-PAT-based Controls Compliance Audit  PA PAT-based changes to controls –  Evaluate adequacy  Validation (IQ, OQ, PQ)  Any link with Part 11?  Investigator training  OOSs?

10. FDA Advisory Committee Meeting; Dhiren N. Shah, Ph.D., PA-PAT Applications; June 12-13, 200210 Summary & Conclusions  PA-PAT Applications –  Easier for original applications with PAT  Difficult for original applications with conventional controls  Proof of equivalence/enhancements  Validation  How to deal with OOSs?  Role of Compliance  Incentive for the Industry – Cost/Benefit  Training of Industry as well as FDA staff  Welcome FDA’s this important initiative