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DRUG QUALITY SYSTEM FOR THE 21ST CENTURY PQRI/FDA April 22-24

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Title: DRUG QUALITY SYSTEM FOR THE 21ST CENTURY PQRI/FDA April 22-24


1
DRUG QUALITY SYSTEM FOR THE 21ST CENTURYPQRI/FDA
April 22-24
  • CHANGES WITHOUT PRIOR APPROVAL
  • AN FDA PERSPECTIVE
  • Dennis M. Bensley, Jr., Ph.D.
  • Center for Veterinary Medicine, FDA

2
OUTLINE
  • INTRODUCTION
  • BACKGROUND
  • CURRENT FDA ASSESSMENT
  • CURRENT RISK ANALYSIS
  • COMPARABILITY PROTOCOL
  • STRATEGIC GOALS
  • CONCLUSION

3
INTRODUCTION
  • Changes Without Prior Review working group
    established by FDAs Drug GMP Steering Committee
  • Working Group members
  • -Ajaz Hussain, Co-chair (CDER)
  • -Nancy Sager, Co-chair (CDER)
  • -Kathy Jordan, Project Manager (CDER)
  • -Nick Buhay (CDER)
  • -Chris Joneckis (CBER)
  • -John Finkbohner (CBER)
  • -Dennis Bensley (CVM)
  • -Nancy Rolli (ORA)
  • -Patricia Alcock (ORA)
  • -Marybet Lopez (ORA)
  • -Janet Showalter (OC, OIP)
  • -Lynn Whipkey (OC, OCC)

4
INTRODUCTION
  • Charge of Working Group
  • -examine current state of the supplemental
    change approval process, specifically those
    manufacturing changes requiring prior FDA
    approval.

5
INTRODUCTION
  • Charge of Working Group
  • -examine current state of the supplemental
    change approval process, specifically those
    manufacturing changes requiring prior FDA
    approval.
  • -identify and recommend implementation of other
    means to reduce reporting requirements, for
    example the use of risk management tools,
    comparability protocols, product development
    information, and process control improvements
    (e.g., PAT).

6
INTRODUCTION
  • Purpose of Workshop
  • -Present a summary of FDAs current thinking and
    activities regarding the supplemental change
    approval process.

7
INTRODUCTION
  • Purpose of Workshop
  • -Present a summary of FDAs current thinking and
    activities regarding the supplemental change
    approval process.
  • -Stimulate discussion and constructive feedback
    from stakeholders regarding the current and
    desired future state of the change approval
    process.

8
BACKGROUND
  • Legal Requirements
  • - The applicant must notify FDA of each
    manufacturing change in accordance with section
    506A of the Federal Food, Drug, and Cosmetic Act
    and, when finalized 21 CFR 314.70 (CDER) and
    514.8(CVM).

9
BACKGROUND
  • Legal Requirements
  • - The applicant must notify FDA of each
    manufacturing change in accordance with section
    506A of the Federal Food, Drug, and Cosmetic Act
    and, when finalized 21 CFR 314.70 (CDER) and
    514.8(CVM).
  • An applicant must inform the FDA about each
    change in the product, production process,
    quality controls, equipment, facilities,
    responsible personnel, or labeling established in
    the approved license application(s) (CBER 601.12).

10
BACKGROUND
  • Legal Requirements
  • The applicant must assess the effects of any
    change on the identity, strength, quality,
    purity, and potency of the drug as they may
    relate to the safety and effectiveness of the
    drug before distributing product made with the
    change (Section 506A of Act, Section 116 FDAMA).
  • Four legal reporting categories under FDAMA
    prior-approval, CBE (immediate), CBE-30 and
    annual report.

11
BACKGROUND
  • Filing Categories
  • -Prior-approval (major change) Substantial
    potential to adversely affect the identity,
    strength, quality, purity, or potency of a
    product as they may relate to the safety or
    effectiveness of the product. Product made with
    change may not be distributed until approval.

12
BACKGROUND
  • Filing Categories
  • -Prior-approval (major change) Substantial
    potential to adversely affect the identity,
    strength, quality, purity, or potency of a
    product as they may relate to the safety or
    effectiveness of the product. Product made with
    change may not be distributed until approval.
  • -CBE or CBE-30 (moderate change) Moderate
    potential.Product distribution upon receipt of
    application to FDA (CBE) or 30 days after receipt
    of application to FDA, if acceptable (CBE-30).

13
BACKGROUND
  • Filing Categories
  • -Prior-approval (major change) Substantial
    potential to adversely affect the identity,
    strength, quality, purity, or potency of a
    product as they may relate to the safety or
    effectiveness of the product. Product made with
    change may not be distributed until approval.
  • -CBE or CBE-30 (moderate change) Moderate
    potential.Product distribution upon receipt of
    application to FDA (CBE) or 30 days after receipt
    of application to FDA, if acceptable (CBE-30).
  • -Annual Report (minor change) Minimal
    potential.Annual reportable and immediate
    product distribution.

14
CURRENT FDA ASSESSMENT
  • Did Section 116 of FDAMA (506A of the Act) meet
    the expectation of
  • -providing regulatory relief by lessening the
    reporting requirements of manufacturing changes
    without compromising the drugs quality, safety
    or effectiveness?

15
CURRENT FDA ASSESSMENT
  • The reporting of many manufacturing changes has
    been provided through regulations and guidances
  • -Section 506A of FFDC Act (CDER, CBER and CVM)
  • -Regulations (being revised 314.70, 514.8,
    601.12).
  • -Changes Guidances
  • Changes to an Approved NDA or ANDA (CDER)
  • Changes to an Approved Application Biological
    Products (CBER)
  • Changes to an Approved Application for Specified
    Biotechnology and Specified Synthetic Biological
    Products (CDER/CBER)
  • Changes to an Approved NADA or ANADA (CVM)
  • -Various PAC and SUPAC Guidances

16
CURRENT FDA ASSESSMENTImpact of FDAMA on Filing
  • CVM
  • A significant number of CMC changes are currently
    being reported in CBE supplements or in annual
    reports.

17
CURRENT FDA ASSESSMENTImpact of FDAMA on Filing
  • CDER Data (Prior Approval/CBE Supplements)
  • FY99 FY00 FY01
  • NDAs
  • Prior Approval 62 48 39
  • CBE 38 52 61
  • ANDAs
  • Prior Approval 82 26 34
  • CBE 18 74 66

18
REPORTING CBER CMC CHANGES IMPACT OF FDAMA/
GUIDANCE
NON-PDUFA PRODUCTS
PDUFA PRODUCTS
19
CURRENT FDA ASSESSMENT
  • FDAMA has significantly reduced the reporting
    requirements for manufacturing changes, however
    FDA recognizes that there could be additional
    improvements in the change reporting process.

20
CURRENT FDA ASSESSMENT
  • Concerns with current regulatory supplemental
    change process
  • -Though the relative percentage of prior-approval
    supplements as compared to other reporting
    categories have significantly decreased, the
    number of prior-approval supplements are starting
    to increase.

21
CURRENT FDA ASSESSMENT
  • Concerns with current regulatory supplemental
    change process
  • -Though significantly reduced overall from
    pre-FDAMA times, the number of reported prior
    approval changes remain high for certain product
    types/processes (e.g., sterile products).

22
CURRENT FDA ASSESSMENT
  • Concerns with current regulatory supplemental
    change process
  • -Recognize that any prior approval change could
    impact business planning and possibly impede
    innovation.

23
CURRENT FDA ASSESSMENT
  • Concerns with current regulatory supplemental
    change process
  • -No guarantee that the prior approval supplement
    will be approved during first round. CVMs
    experience is that approximately 40 of first
    round prior approval supplements are found to be
    incomplete (data from 2000-2003).

24
CURRENT FDA ASSESSMENT
  • Concerns with current regulatory supplemental
    change process
  • -Regulatory compliance dilemma in finding
    unacceptable, i.e., inadequately assessed or
    documented, CMC changes in CBE or annual reports.

25
CURRENT FDA ASSESSMENT
  • Potential solutions identified by FDA to lessen
    reporting requirements
  • Use of comparability protocols

26
CURRENT FDA ASSESSMENT
  • Potential solutions identified by FDA to lessen
    reporting requirements
  • Use of comparability protocols
  • Drafting and publishing more PAC/SUPAC guidance
    documents

27
CURRENT FDA ASSESSMENT
  • Potential solutions identified by FDA to lessen
    reporting requirements
  • Use of comparability protocols
  • Drafting and publishing more PAC/SUPAC guidance
    documents
  • Identifying potential risk management tools

28
CURRENT FDA ASSESSMENT
  • Potential solutions identified by FDA to lessen
    reporting requirements
  • Use of comparability protocols
  • Drafting and publishing more PAC/SUPAC guidance
    documents
  • Identifying potential risk management tools
  • Encouraging the use of product development
    information and process control improvements
    (e.g., Process Analytical Technologies).

29
CURRENT RISK ANALYSIS
Potential for CMC Change To Adversely Affect Drug
Prior Approval Supplement?
Levels of Risk
HIGH
YES
SIGNIFICANT
SOME
NO
MODERATE
CBE Supplements Required
LOW
NO
MINIMAL
30
CURRENT RISK ANALYSIS
  • FDAs determination of a CMC change as major or
    requiring prior approval
  • -What is the likely impact of the change on the
    identity, strength, quality, purity and/or
    potency of the drug product? If FDA believes
    there is a potential adverse affect, then major
    change.

31
CURRENT RISK ANALYSIS
  • FDAs determination of a CMC change as major or
    requiring prior approval
  • -Will additional clinical or other non-CMC
    (e.g., toxicological) studies be required? If
    yes, then likely major change.

32
CURRENT RISK ANALYSIS
  • FDAs determination of a CMC change as major or
    requiring prior approval
  • -Is the reported change either not well
    described, too complex or is the potential
    impact on the drugs safety or effectiveness
    not certain? If yes, then likely major change.

33
CURRENT RISK ANALYSIS
  • FDAs determination of a CMC change as major or
    requiring prior approval
  • -If applicable, what is the current GMP status?
    If unacceptable, then likely major change.

34
CURRENT RISK ANALYSIS
  • The question to address when a risk assessment is
    performed regarding a CMC change
  • What is the potential (risk) for the change to
    adversely affect the identity, strength, quality,
    purity, or potency of a product as they may
    relate to the safety or effectiveness of the
    product?

35
CURRENT RISK ANALYSIS
  • The potential risk for a CMC change increases
    when the knowledge regarding the potential impact
    of the change decreases.

36
CURRENT RISK ANALYSIS
  • The potential risk for a CMC change increases
    when the knowledge regarding the potential impact
    of the change decreases.
  • What is the purpose of prior approval supplements
    for specified CMC changes?

37
CURRENT RISK ANALYSIS
  • The potential risk for a CMC change increases
    when the knowledge regarding the potential impact
    of the change decreases.
  • What is the purpose of prior approval supplements
    for specified CMC changes?
  • -Identified major changes are those changes
    that have a substantial potential to adversely
    affect the drug.

38
CURRENT RISK ANALYSIS
  • The potential risk for a CMC change increases
    when the knowledge regarding the potential impact
    of the change decreases.
  • What is the purpose of prior approval supplements
    for specified CMC changes?
  • -Identified major changes are those changes
    that have a substantial potential to adversely
    affect the drug.
  • -Allows FDA time to review and concur (or not
    concur) with the proposed major change and its
    assessment prior to product distribution.

39
CURRENT RISK ANALYSIS
  • FDA tends to be conservative in regard to
    accepting levels of risk, i.e., if we are not
    certain about the potential risk, then a higher
    filing category will likely be required.

40
CURRENT RISK ANALYSIS
  • FDA employees use risk analysis daily, for
    example
  • -Deciding whether a change is major or moderate
    (30-day CBE assessment)
  • -Deciding whether the assessment of the change
    is satisfactory or not (review process)
  • -Deciding whether a cGMP inspection is required
    (e.g., CBERs SOPP 8410 Determining When
    Prelicense/Preapproval Inspections Are Necessary)

41
CURRENT RISK ANALYSIS
  • FDA employees use risk analysis daily, for
    example
  • -Deciding whether a change is major or moderate
    (30-day CBE assessment)
  • -Deciding whether the assessment of the change
    is satisfactory or not (review process)
  • -Deciding whether a cGMP inspection is required
    (e.g., CBERs SOPP 8410 Determining When
    Prelicense/Preapproval Inspections Are Necessary)
  • However, risk assessments for CMC changes are
    neither formalized nor uniformly structured
    throughout FDA.

42
CURRENT RISK ANALYSIS
  • Possible ways to reduce the risk potential
    include the use of
  • 1. Comparability protocols
  • Premise FDAs acceptance of proposed assessment
    of anticipated change will likely lessen risk for
    implementing the change and should lead to less
    burdensome reporting category

43
CURRENT RISK ANALYSIS
  • Possible ways to reduce the risk potential
    include the use of
  • 2. An applicant may establish their own filing
    criteria based on developmental information in
    original or supplemental applications (Make your
    own SUPAC).
  • Premise Increase in scientific
    understanding/knowledge of changes impact may
    lessen risk for implementing change and could
    lead to less burdensome reporting category

44
CURRENT RISK ANALYSIS
  • Possible ways to reduce the risk potential
    include the use of
  • 3. incorporating significant process control
    improvements (e.g., PAT).
  • Premise Improvement in process controls, may
    lessen risk for producing poor product and could
    lead to less burdensome reporting category

45
CURRENT RISK ANALYSIS
  • Can other risk analysis models be used to
    identify the level of risk for implementing CMC
    changes?
  • For example, can we identify, through risk
    assessment, low-risk drugs, dosage forms,
    processes, etc. and significantly reduce the
    number of changes requiring prior approval before
    implementation?

46
COMPARABILITY PROTOCOL
  • What is a CP?
  • A well-defined, detailed written plan that
    prospectively specifies the tests and studies
    that will be performed, analytical procedures
    that will be used, and acceptance criteria that
    will be achieved to assess the effect of specific
    CMC changes for specific products.

47
COMPARABILITY PROTOCOL
  • Draft Guidance for small molecules recently
    published (public comment by 6/25/03).
  • CP described in regulations (current and/or
    proposed 314.70, 514.8 and 601.12).
  • FDA believes that additional prior approval
    changes can be reported in CBEs or annual reports
    through the use of a CP.

48
COMPARABILITY PROTOCOL
  • Uses and benefits of CP
  • -Can allow for a reduced reporting category of
    CMC changes covered by the approved CP.
  • -CP can describe single or multiple-related CMC
    changes including those that may occur
    sequentially over a period of time.

49
COMPARABILITY PROTOCOL
  • Uses and benefits of CP (cont.)
  • -Earlier implementation of manufacturing changes.
  • -Likely reduction in incomplete/deficiency
    letters issued by FDA (more first-round
    approvals), because the means of assessing the
    change has been approved in the CP.

50
COMPARABILITY PROTOCOL
  • Uses and benefits of CP (cont.)
  • -Allows sponsors to design own changes filing
    and documentation criteria based on experiences
    with the drug product or similar drug product,
    e.g. developmental studies. Make your own
    SUPAC concept.

51
COMPARABILITY PROTOCOL
  • Uses and benefits of CP (cont.)
  • -Allows sponsors to continually improve
    manufacturing processes without necessarily
    requiring prior FDA approval (potential for PAT
    implementation).
  • -Reduces the potential risk for the change to
    adversely affect the drug.
  • -A potential win-win situation for public,
    industry, and FDA.

52
COMPARABILITY PROTOCOL
  • Limited CDER experience and no CVM experience.
  • CBER experience
  • -More than 100 comparability protocols have been
    successfully used for CMC changes for all product
    classes since 1997.
  • -Submission of developmental information in CPs
    has convinced CBER to accept reduced reporting
    categories for some CMC changes.

53
Strategic Goals
  • Publish Draft Comparability Protocol for Large
    Molecules

54
Strategic Goals
  • Publish Draft Comparability Protocol for Large
    Molecules
  • Finalize both CP Guidances.

55
Strategic Goals
  • Publish Draft Comparability Protocol for Large
    Molecules
  • Finalize both CP Guidances.
  • Continue to amend or introduce new PAC/SUPAC
    guidances.

56
Strategic Goals
  • Publish Draft Comparability Protocol for Large
    Molecules
  • Finalize both CP Guidances.
  • Continue to amend or introduce new PAC/SUPAC
    guidances.
  • Publish final changes regulations 314.70, 514.8
    and 601.12.

57
Strategic Goals
  • Conduct study to evaluate existing data on prior
    approval changes and identify opportunities for
    further reducing of reporting categories
  • -Determination of the number and types of prior
    approval supplements submitted to each Center
    over a designated time period.

58
Strategic Goals
  • Conduct study to evaluate existing data on prior
    approval changes and identify opportunities for
    further reducing of reporting categories
  • -Determination of the number and types of prior
    approval supplements submitted to each Center
    over a designated time period.
  • -Identify other potential risk models or other
    means for reducing reporting categories.

59
Strategic Goals
  • Conduct study to evaluate existing data on prior
    approval changes and identify opportunities for
    further reducing of reporting categories
  • -Determination of the number and types of prior
    approval supplements submitted to each Center
    over a designated time period.
  • -Identify other potential risk models or other
    means for reducing reporting categories.
  • -Consider additional ideas as result of
    discussion and feedback received during this
    workshop.

60
CONCLUSIONS
  • The following are the discussion points for
    consideration during the individual breakout
    sessions
  • Scientific risk-based approaches for identifying
    low risk manufacturing changes that can be
    implemented without prior FDA approval

61
CONCLUSIONS
  • The following are the discussion points for
    consideration during the individual breakout
    sessions
  • Draft guidance on comparability protocols for
    small molecules and development of a
    comparability protocol guidance for proteins

62
CONCLUSIONS
  • The following are the discussion points for
    consideration during the individual breakout
    sessions
  • Effective use of development data and other
    information to justify less burdensome filing
    requirements for post-approval manufacturing
    changes

63
CONCLUSIONS
  • This is your opportunity to comment on and
    provide your ideas on the current supplemental
    approval process and your view of the ideal
    future state!
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