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Dhiren N. Shah, Ph.D. Director, DRA-CMC Aventis Pharmaceuticals

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. Outline. Need for post-approval (PA) PAT Applications

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Dhiren N. Shah, Ph.D. Director, DRA-CMC Aventis Pharmaceuticals

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

  2. 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 FDA Advisory Committee Meeting; Dhiren N. Shah, Ph.D., PA-PAT Applications; June 12-13, 2002

  3. 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 FDA Advisory Committee Meeting; Dhiren N. Shah, Ph.D., PA-PAT Applications; June 12-13, 2002

  4. Challenges in PA-PAT Applications Two kinds of post-approval situations • 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 FDA Advisory Committee Meeting; Dhiren N. Shah, Ph.D., PA-PAT Applications; June 12-13, 2002

  5. Challenges in PA-PAT Applications Two kinds of post-approval situations • 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 FDA Advisory Committee Meeting; Dhiren N. Shah, Ph.D., PA-PAT Applications; June 12-13, 2002

  6. 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? FDA Advisory Committee Meeting; Dhiren N. Shah, Ph.D., PA-PAT Applications; June 12-13, 2002

  7. 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? FDA Advisory Committee Meeting; Dhiren N. Shah, Ph.D., PA-PAT Applications; June 12-13, 2002

  8. Guidance Development for PA-PAT-based ControlsCMC 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? FDA Advisory Committee Meeting; Dhiren N. Shah, Ph.D., PA-PAT Applications; June 12-13, 2002

  9. Guidance Development for PA-PAT-based ControlsCompliance Audit • PA PAT-based changes to controls – • Evaluate adequacy • Validation (IQ, OQ, PQ) • Any link with Part 11? • Investigator training • OOSs? FDA Advisory Committee Meeting; Dhiren N. Shah, Ph.D., PA-PAT Applications; June 12-13, 2002

  10. 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 FDA Advisory Committee Meeting; Dhiren N. Shah, Ph.D., PA-PAT Applications; June 12-13, 2002

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