FDA PAT SubCommittee of Advisory Committee for Pharmaceutical

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

Outline ® Need for post-approval (PA) PAT Applications ® Challenges in PA-PAT Applications ® PA- PAT Applications to – APIs ® Drug Products ® ® Guidance Development ® CMC Review ® ® ® Consideration– 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 2

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 3

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 ® ® 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 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 nonvalue-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 5

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 6

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

Guidance Development for PA-PAT-based Controls CMC Review ® Equivalence to conventional controls ® Enhanced assurance that the product meet SIPPQ – How to show? ® Scientific basis for PAT controls ® Type/amount of CMC information requirement – will 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 8

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

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 10