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Changes without Prior Approval
Breakout Session Summary
Rick SmithAventis Pasteur, Inc.
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Issues Discussed Risk Analysis for Post Approval
Changes Comparability Protocols Development Reports Other Risk-Based Approaches and
Next Steps
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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
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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
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Comparability Protocols
Types of Comparability Protocols: General Comparability Protocols
Product Specific Technology Specific
Single Product
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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
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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
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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timing) Draft guidance has too many exclusions Does require extra submissions unless in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)
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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
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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
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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
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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
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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.
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Other Risk-Based Approaches Develop system to permit less
burdensome filing requirements based on company: Compliance history Robustness of quality system Quality of filings
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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
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Other Systems European procedure for Type I and
Type II Variations Re-registration every 5 years
Canadian system Use as learning experience
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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
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Next Steps Guidances
Have industry draft guidance for FDA Finalize draft guidances Draft more guidances Update existing guidances
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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