FDA PAT Sub-Committee of Advisory Committee for Pharmaceutical Sciences June 12-13, 2002; Gaithersburg, MD Regulatory Challenges: Post-Approval PAT Applications

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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

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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

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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

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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

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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

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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?

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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?

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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?

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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?

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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 FDAs this important initiative