Changes without Prior Approval

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 cant afford some changes, cant 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 lt 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• Draft guidance has too many exclusions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 isnt 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