COMPARABILITY PROTOCOL

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COMPARABILITY PROTOCOL UPDATE ADVISORY COMMITTEE
FOR PHARMACEUTICAL SCIENCE Manufacturing
Subcommittee July 20-21, 2004 Stephen Moore,
Ph.D. Chemistry Team Leader Office of New Drug
Chemistry Center for Drug Evaluation and
Research Food and Drug Administration
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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

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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

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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

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Regulations Pertaining to Comparability
Protocols21CFR 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."

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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 gtgtgt

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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

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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

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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

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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

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Current Thinking on Comparability ProtocolsTwo
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

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Current Thinking on Comparability
ProtocolsSingle-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

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Current Thinking on Comparability
ProtocolsRepetitive-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

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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

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Current Thinking on Comparability Protocols
Advantages/Disadvantages To FDA

• Advantages
• FDA being responsive in finding ways to reduce
  manufacturers down time
• May reduce overall number of post-approval
  supplements
• Disadvantage
• May increase FDA workload initially

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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

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Current Thinking on Comparability
ProtocolsPrinciples 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

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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

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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

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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)

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Current Thinking on Comparability Protocols
Reduced Reporting Category

• PAS to AR
• Substantial knowledge and understanding gtgtgt
• 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

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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

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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

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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

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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

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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)

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Summary

• Comparability protocols can be useful for
  industry to shorten time line for distribution of
  drug products
• FDA exploring ways to make protocols more
  flexible and useful