Changes without Prior Approval

Breakout Session Summary

Rick SmithAventis Pasteur, Inc.

Issues Discussed Risk Analysis for Post Approval

Changes Comparability Protocols Development Reports Other Risk-Based Approaches and

Next Steps

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

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

Comparability Protocols

Types of Comparability Protocols: General Comparability Protocols

Product Specific Technology Specific

Single Product

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

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

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timing) Draft guidance has too many exclusions Does require extra submissions unless in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)

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

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

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

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

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.

Other Risk-Based Approaches Develop system to permit less

burdensome filing requirements based on company: Compliance history Robustness of quality system Quality of filings

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

Other Systems European procedure for Type I and

Type II Variations Re-registration every 5 years

Canadian system Use as learning experience

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

Next Steps Guidances

Have industry draft guidance for FDA Finalize draft guidances Draft more guidances Update existing guidances

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