# Presentation: 276401

## 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
- 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

## 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

## 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

## 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

## 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

## 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

## 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?

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

## 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?

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

## 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