Comparability Plan by ljh74808

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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
                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 on
        Reduction 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 on
         Reduction 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 on
       Reduction 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 on
     Reduction 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 on
     Modifications 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)
                   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

								
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