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Changes without Prior Approval

Changes without Prior Approval

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Changes without Prior Approval

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  1. Changes without Prior Approval Breakout Session Summary Rick Smith Aventis Pasteur, Inc.

  2. Issues Discussed • Risk Analysis for Post Approval Changes • Comparability Protocols • Development Reports • Other Risk-Based Approaches and Next Steps

  3. Risk Analysis • Cost / market availability / approvability • Team approach to risk assessment • Change control • True risk comes from an assessment of whether product has changed from the product used to generate clinical data • Risk assessment capability is directly related to process knowledge and product experience

  4. Concerns and Suggestions • Industry wants a decision tree to assess risk (white paper from industry to FDA) • Dilemma: can’t afford some changes, can’t afford not to change (keep up with cGMPs) • Harmonization • Develop a system to identify low risk changes that were successful to lessen the change category • To bundle or not to bundle

  5. Comparability Protocols Types of Comparability Protocols: • General Comparability Protocols • Product Specific • Technology Specific • Single Product

  6. Experiences with Comparability Protocols • Protein drugs – wide use • Chemical drugs < 10 % use • CVM, GphA – no use • Application: • Single change for multiple products • Major changes to single product • Planned changes • Used during development

  7. Advantages with Comparability Protocols • Implementation timing can be immediate and consistent • Early FDA input • Greater assurance of acceptability and predictability • Increased efficiency for Comparability Protocols covering multiple products • Helps with changes not covered by SUPAC • Most useful for complex molecules

  8. Problems or Limitations with Comparability Protocols • Time required is not always worth the effort • Uncertainty regarding review time for non-PDUFA products • Not useful for unplanned changes (due to timing) • Draft guidance has too many exclusions • Does require extra submissions unless in original NDA (Agency and Company)

  9. Suggestions for Future • One CP guidance for all types of products • Utilize experiences from CPs to expand SUPACs • Do not try to use CP for large numbers of changes most of which will not be executed

  10. Development Reports Positive Feedback • Development report needed to explain development strategy, data and why something was done. • Easier to justify future changes • Proactively identify critical parameters and impact of changes on those parameters. • Gives FDA confidence that firms understand product and process

  11. Development Reports Positive Feedback • Helpful to maintain product history especially if employees leave the company • Description of full story – failures and successes are valuable • Helpful to have justification why certain tests are relevant and others not

  12. Development ReportsNegative Feedback • May not be applicable for older products or generics • Additional work or filing requirement with no obvious benefit • Goes against goals of filing less or reducing burden • Sharing failures is a concern • All development data isn’t relevant to commercial product

  13. Development ReportConcerns • How will FDA use the data? • Which data should be submitted? • Will development reports be reviewed by FDA and found to be deficient thereby holding up approval? • Would not want to submit data because it may contain data generated in non GMP lab.

  14. Other Risk-Based Approaches • Develop system to permit less burdensome filing requirements based on company: • Compliance history • Robustness of quality system • Quality of filings

  15. Specific Recommendations for Opportunities for Less Burdensome Filing Requirements: • SUPAC Guidances • Analytical changes • Packaging • Sterile Products • Common / repetitive changes • Concurrent validation / stability • Use of decision trees • Comparability Protocol Templates

  16. Other Systems • European procedure for Type I and Type II Variations • Re-registration every 5 years • Canadian system • Use as learning experience

  17. Next Steps • Need to be more global, not US centric • Prioritize activities based on FDA and industry impact • More dialogue with FDA / Industry on development data

  18. Next Steps • Guidances • Have industry draft guidance for FDA • Finalize draft guidances • Draft more guidances • Update existing guidances

  19. Future Workshops • Risk assessment of aseptic processing changes • Development reports: value, what is needed, how used and benefit to industry • Risk management systems and different approaches