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COMPARABILITY PROTOCOLUPDATEUPDATE
ADVISORY COMMITTEE FOR ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCEPHARMACEUTICAL SCIENCE
Manufacturing SubcommitteeManufacturing SubcommitteeJuly 20-21, 2004July 20-21, 2004
Stephen Moore, Ph.D.Stephen Moore, Ph.D.Chemistry Team LeaderChemistry Team Leader
Office of New Drug ChemistryOffice of New Drug ChemistryCenter for Drug Evaluation and ResearchCenter for Drug Evaluation and Research
Food and Drug AdministrationFood and Drug Administration
Topics
Definition and General Aspects Regulations Pertaining to Comparability
Protocols Draft Guidances for Industry on C.P.s Public Comments on Draft Guidances Current Thinking and Preliminary
Comments on C.P.s
Definition of a Comparability Protocol
A comprehensive, detailed plan that describes the specific type of proposed change tests and studies to be performed analytical procedures that will be utilized acceptance criteria to be achieved
to demonstrate lack of an adverse effect on the product quality as it may relate to the safety and effectiveness of the drug product
General Aspects of a Comparability Protocol
Well-planned in advance Scientifically and technically sound (based on
knowledge and understanding) Adequate and current to implement the change Drug, process, controls and change specific
Regulations Pertaining to Comparability Protocols
21CFR 314.70(e) and 601.12(e)
"Protocols. An applicant may submit one or more protocols describing the specific tests and studies and acceptance criteria to be achieved to demonstrate the lack of adverse effect for specified types of manufacturing changes on the identity, strength, quality, purity, and potency of the drug product as these factors may relate to the safety or effectiveness of the drug product. Any such protocols, if not included in the approved application, or changes to an approved protocol, must be submitted as a supplement requiring approval from FDA prior to distribution of a drug product produced with the manufacturing change. The supplement, if approved, may subsequently justify a reduced reporting category for the particular change because the use of the protocol for that type of change reduces the potential risk of an adverse effect."
Draft Guidances for Industry on Comparability Protocols
Guidance for Industry, Comparability Protocols —Chemistry, Manufacturing, and Controls Information (draft issued Feb., 2003). (Applies to chemical entities and synthetic peptides)
Guidance for Industry, Comparability Protocols — Protein Drug Products and Biological Products —Chemistry, Manufacturing, and Controls Information (draft issued Sept., 2003)
Public comments under review for final publication of guidances >>>
Highlights of Public Comments on Draft Guidances on C.P.s
(Excerpted and Paraphrased) Efficient use of comparability protocols should
provide regulatory relief by expediting review and approval of postapproval changes
Many changes are not anticipated at time of filing a marketing application
Highlights of Public Comments (cont.)
Level of specificity requested may define the protocol so narrowly as to diminish its future usefulness
Key to use of comparability protocols is the availability of sufficient manufacturing science data to demonstrate adequate understanding of the product and critical process controls
Highlights of Public Comments (cont.)
Clarify what is meant by comparability protocols for changes of a repetitive nature
Provide examples of reduction in reporting category from PAS to AR
Highlights of Public Comments (cont.)
Modifications to a comparability protocol in categories lower than PAS should be permitted (e.g., CBE-30, CBE)
CGMP aspects of postapproval changes should be addressed
We applaud the FDA for its efforts
Current Thinking on Comparability Protocols:Two Basic Kinds
Single-use comparability protocol:
For a specific, one-time CMC change
Repetitive-use Comparability Protocol:
Used more than once to make a specified type of CMC change
Current Thinking on Comparability Protocols:Single-use C.P.
For a single change or multiple related changes For multiple related changes:– Assessment of each of the individual changes– Combined effects of all of the changes on the product
quality
Examples: Drug substance or drug product manufacturing process
changes Changes in scale and related changes
Current Thinking on Comparability Protocols:
Repetitive-Use C.P.
Specific (specified) type of change narrowly defined
Boundaries established for extent of changes In general, multiple related changes comprised
only of subcategories of specified type of change
Examples: Container and closure system change Changes to a unit operation
Current Thinking on Comparability Protocols: Advantages/Disadvantages
To Industry
Advantages: Shortened time line for distribution of
drug product Reduced filing burden for commonly
made changes
Disadvantage: Risk of adverse effect not eliminated
Current Thinking on Comparability Protocols: Advantages/Disadvantages
To FDA
Advantages: FDA being responsive in finding ways to
reduce manufacturer’s down time May reduce overall number of post-
approval supplements
Disadvantage: May increase FDA workload initially
Current Thinking on Comparability Protocols: Appropriateness of a C.P.
Appropriate: Lack of adverse effect can be demonstrated
by analysis of product quality characteristics
Not considered appropriate: Nonspecific plans for CMC changes Nonclinical safety, nonclincal
pharmacology, PK/PD, clinical safety and/or effectiveness studies required
Current Thinking on Comparability Protocols:Principles and Recommendations
C.P. based on and provides evidence of scientific and technological knowledge and understanding of:– Drug, manufacturing process, controls– Proposed change– Potential effect of change on product quality
Gained from:– Pharmaceutical development information (drug and
manufacturing process)– Commercial scale production experience– Scientific and technical literature
Current Thinking on Comparability Protocols: Principles and Recommendations (cont.)
All potential effects of a change identified, not just the obvious
Pre- and postchange drugs compared for all changes Combination of routine quality controls testing and
characterization studies Analytical procedures sufficiently discriminatory to detect
potential differences Integrated analysis of all available data prior to
concluding lack of adverse effect
Current Thinking on Comparability Protocols: Demonstration of Lack of Adverse Effect
Based on knowledge and understanding Product quality characteristics of pre- and postchange
drugs:– Conform to specifications– Conform to acceptance criteria for characterization studies– Comparable: mean and standard deviation / qualitatively
Manufacturing process and process controls considerations:– Process controls met– Effect on process and process controls as they relate to the product
quality
Current Thinking on Comparability Protocols: Reduced Reporting Category
Factors to Consider: Degree of demonstrated knowledge and understanding Normal reporting category for change Drug-, process- controls- and change- specific
considerations (e.g., complexity) Validity of C.P. (e.g., scientifically and technically sound)
Current Thinking on Comparability Protocols: Reduced Reporting Category
PAS to AR– Substantial knowledge and understanding >>>– Use of protocol substantially reduces potential of adverse
effect on product quality
PAS to CBE / CBE-30– Adequate knowledge and understanding – Use of protocol moderately reduces potential of adverse
effect– Depending on drug and change, CBE or CBE-30
designated
CBE-30 or CBE to AR– Adequate knowledge and understanding
Preliminary Comments onReduction PAS to AR under C.P.
Approach
Substantial knowledge and understanding of drug, process, controls, proposed change and potential effects of change on product quality
Relevance and adequacy of tests, studies, analytical procedures and acceptance criteria to assess effects of change
Preliminary data to support a lack of adverse effect FDA will determine whether information provided is
sufficient
Preliminary Comments onReduction PAS to AR under C.P.
Examples Data from pharmaceutical development studies
relevant to proposed change included with C.P.:– Definition of change– Identification of critical process steps, parameters,
variables and/or controls pertinent to the change and interactions
– Data from pilot batch(es) – Data from full-scale production batch(es), if available
Preliminary Comments onReduction PAS to AR under C.P.
Examples (cont.)
Previously approved similar change to same drug referenced in C.P.
Previously approved same change to similar drug referenced in C.P.
Subsequent change of same specified type under approved repetitive-use C.P., if justified– First time: CBE or CBE-30– Second and subsequent times: AR
Preliminary Comments onReduction PAS to AR under C.P.
Exceptions
Change too complex Impurity profile changed for drug
substance or drug product Manufacturing change that requires
specification change
Preliminary Comments onModifications to an Approved
Comparability Protocol
Examples where modification of C.P. may be useful:
Modify change so acceptance criteria achieved Modify change to increase assurance of product
quality Update C.P. to keep it current and valid FDA identifying examples of modifications to
C.P. in all FDAMA reporting categories (PAS, CBE-30, CBE, AR)