Comparability Protocols, Manufacturing Changes, and CMC Issues

1
Comparability Protocols, Manufacturing Changes,
and CMC Issues

• Rebecca A. Devine, Ph.D.
• Associate Director for Policy, CBER
• 1998 PDA/FDA Joint Conference
• October 6, 1998

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Comparability Protocols, Manufacturing Changes,
and CMC Issues

• FDAMA
• Management of CMC Issues
• BLA-CMC Issues
• Comparability Protocols
• Summary

3
FDA Modernization Act of 1997(FDAMA)

• Signed into law November 21, 1997
• Amends the FDC Act
• Amends the PHS Act
• Renews the Prescription Drug User Fee Program
  with amendments (PDUFA 2)
• Effective 90 days after enactment unless
  otherwise specified

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MANUFACTURING CHANGES SECTION 116

• Validation of all changes
• Prior approval for major changes
• CBE (30 day or immediate)
• Annual report for other changes
• Major changes
• Change in qualitative or quantitative formulation
• Requires clinical study of equivalence
• Other changes the Secretary determines
  w/substantial potential to have an adverse affect

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PDUFA Performance GoalsManufacturing
SupplementsNo Prior Approval

• 90 in 6 months

• FY 98
• FY 99
• FY 00
• FY 01
• FY 02

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PDUFA Performance GoalsManufacturing
SupplementsPrior Approval

• FY 98
• FY 99
• FY 00
• FY 01
• FY 02

• 90 in 6 mos
• 30 in 4 mos
• 90 in 6 mos
• 50 in 4 mos
• 90 in 6 mos
• 70 in 4 mos
• 90 in 6 mos
• 90 in 4 mos

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CHANGES TO AN APPROVED APPLICATION - 21 CFR
601.12, 314.70(g)

• Supplement - Prior Approval (PAS)
• 30 Day Supplement - Changes Being Effected (CBE)
• CBE (30 days waived)
• Annual Report

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GUIDANCE FOR INDUSTRY

• Changes to an Approved Application for Specified
  Biotechnology and Specified Synthetic Biological
  Products
• http//www.fda.gov/cber/cberftp.html
• CHARACTER_at_a1.cber.fda.gov

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GUIDANCE TO INDUSTRY

• Changes to an Approved Application Biological
  Products
• http//www.fda.gov/cber/cberftp.html
• CHANGES_at_a1.cber.fda.gov

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BIOLOGICS MODERNIZATION

• Amends Section 351 of the PHS Act to provide for
  BLA and Biologics license
• Clarifies that the FD C Act applies to
  biologics
• Requires the facility to be available for
  inspection and standards must be met
• Retains safe, pure and potent language
• Puts the REGO initiative into law

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FAST TRACK PRODUCTS

• Expedite development and review
• Product request for designation
• Serious and life threatening
• Potential to address unmet need
• Review of portions of incomplete applications
• Expedited withdrawal
• Guidance within 1 year

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Comparability Protocols, Manufacturing Changes,
and CMC Issues

• FDAMA
• Management of CMC Issues
• BLA-CMC Issues
• Comparability Protocols

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POLICY COORDINATING COMMITTEES
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CHEMISTRY, MANUFACTURING AND CONTROLS
COORDINATING COMMITTEE

• Identify, coordinate, prioritize and develop CMC
  policy
• Promote consistency in CMC reviews
• Forum for specific CMC issue
• Serve as liaisons to other agency initiatives
• Will have subcommittees performing tasks for them

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COMPARABILITY PROTOCOL SUBCOMMITTEE

• Joint CBER/CDER committee
• Reports to CBER CMC-CC
• Reports to CDER CDS-CC
• Preparing guidance on Comparability protocols per
  601.12 and 314.70(g)
• Initial focus on Biotech/Biologics

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Comparability Protocols, Manufacturing Changes,
and CMC Issues

• FDAMA
• Management of CMC Issues
• BLA-CMC Issues
• Comparability Protocols

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BLA-CMC Issues

• Elimination of the PLA/ELA (Proposed rule)
• Preparation of CMC guidances for BLAs
• Revision of manufacturing changes guidance
• Fast track rolling review
• Inspectional issues

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Comparability Protocols, Manufacturing Changes,
and CMC Issues

• FDAMA
• Management of CMC Issues
• BLA-CMC Issues
• Comparability Protocols

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PURPOSE OF COMPARABILITY TESTING

• To assess impact of a change on the product
• Demonstration of comparability of product made
  before and after a manufacturing change
• May preclude additional clinical trials to
  demonstrate efficacy
• Provides assurance that product will perform the
  same as before the change was made

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COMPARABILITY PROTOCOL21 CFR 601.12 (e)

• An applicant may submit one or more protocols
  describing the specific tests and validation
  studies and acceptable limits to be achievedfor
  specified types of manufacturing changes...

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COMPARABILITY PROTOCOLS

• PAS
• Used to reduce reporting category
• Reduces the risk of an adverse effect on
  identity, strength, quality, purity or potency

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QUESTIONS AND CONCERNS

• Time Frames for Comparability Protocol Supplement
  Review
• Dispute Resolution Concerning the Applicability
  of Comparability Protocol
• Increased Numbers of Supplements

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QUESTIONS AND CONCERNS

• Single vs. Multiple Protocols
• Broad vs. Narrow Protocols
• Usefulness for a One Time Event

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Comparability Protocols, Manufacturing Changes,
and CMC Issues

• FDAMA
• Management of CMC Issues
• BLA-CMC Issues
• Comparability Protocols
• Summary

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SUMMARY

• FDAMA effects under consideration
• Implementation is proceeding
• CBER/CDER collaboration
• Guidance on comparability protocols is under
  active preparation
• Protocols are being reviewed on a case by case
  basis

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HOW TO GET INFORMATION FROM CBER

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• SEND E-MAIL TO CBER_INFO_at_A1.CBER.FDA.GOV
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• To visit CBERs Home Page
• www.fda.gov/cber/