Title: Comparability Protocols, Manufacturing Changes, and CMC Issues
1Comparability Protocols, Manufacturing Changes,
and CMC Issues
- Rebecca A. Devine, Ph.D.
- Associate Director for Policy, CBER
- 1998 PDA/FDA Joint Conference
- October 6, 1998
2Comparability Protocols, Manufacturing Changes,
and CMC Issues
- FDAMA
- Management of CMC Issues
- BLA-CMC Issues
- Comparability Protocols
- Summary
3FDA 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
4MANUFACTURING 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
5PDUFA Performance GoalsManufacturing
SupplementsNo Prior Approval
- FY 98
- FY 99
- FY 00
- FY 01
- FY 02
6PDUFA 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
7CHANGES 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
8GUIDANCE 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
9GUIDANCE TO INDUSTRY
- Changes to an Approved Application Biological
Products - http//www.fda.gov/cber/cberftp.html
- CHANGES_at_a1.cber.fda.gov
10BIOLOGICS 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
11FAST 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
12Comparability Protocols, Manufacturing Changes,
and CMC Issues
- FDAMA
- Management of CMC Issues
- BLA-CMC Issues
- Comparability Protocols
13POLICY COORDINATING COMMITTEES
14CHEMISTRY, 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
15COMPARABILITY 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
16Comparability Protocols, Manufacturing Changes,
and CMC Issues
- FDAMA
- Management of CMC Issues
- BLA-CMC Issues
- Comparability Protocols
17BLA-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
18Comparability Protocols, Manufacturing Changes,
and CMC Issues
- FDAMA
- Management of CMC Issues
- BLA-CMC Issues
- Comparability Protocols
19PURPOSE 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
20COMPARABILITY 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...
21COMPARABILITY PROTOCOLS
- PAS
- Used to reduce reporting category
- Reduces the risk of an adverse effect on
identity, strength, quality, purity or potency
22QUESTIONS AND CONCERNS
- Time Frames for Comparability Protocol Supplement
Review - Dispute Resolution Concerning the Applicability
of Comparability Protocol - Increased Numbers of Supplements
23QUESTIONS AND CONCERNS
- Single vs. Multiple Protocols
- Broad vs. Narrow Protocols
- Usefulness for a One Time Event
24Comparability Protocols, Manufacturing Changes,
and CMC Issues
- FDAMA
- Management of CMC Issues
- BLA-CMC Issues
- Comparability Protocols
- Summary
25SUMMARY
- 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
26HOW TO GET INFORMATION FROM CBER
- REQUEST DOCUMENTS THROUGH THE INTERNET!
- SEND E-MAIL TO CBER_INFO_at_A1.CBER.FDA.GOV
- FOR A LIST OF DOCUMENTS DOC_LIST_at_A1.CBER.FDA.GOV
- To visit CBERs Home Page
- www.fda.gov/cber/