Product Quality Agreement - PowerPoint

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					     Implementation
  of Quality-by-Design:
   ONDQA Initiatives


          Chi-wan Chen, Ph.D.
            Deputy Director
Office of New Drug Quality Assessment


  Advisory Committee for Pharmaceutical Science
               October 5, 2006
                       Outline

   Implementation of QbD in ONDQA
       Reorganization
       Pharmaceutical Quality Assessment
        System
       CMC Pilot Program
            Objectives, goal/status, process, criteria,
             observation to date, benefits/challenges
       Public meetings
       Internal trainings
   Next steps
                                                           2
                Reorganization

   ONDC was reorganized to Office of New Drug
    Quality Assessment (ONDQA) in November 2005
   Objective: To implement PQAS
   Separation of pre-marketing (INDs/NDAs) from
    post-marketing (supplements/annual reports)
    review activities to better utilize limited resources
   Establishment of Manufacturing Science Branch
    and recruitment of pharmaceutical scientists,
    chemical engineers, and industrial pharmacists to
    complement current review staff
                                                            3
                Reorganization (cont’d)

   Pharmaceutical Assessment Lead (PAL) in Pre-
    Marketing Division
        Serves as liaison to clinical division
        Performs an Initial Quality Assessment (IQA), a “big-picture”
         assessment protocol focusing on critical CMC issues, and a
         timeline for completing the review
   PAL in Post-Marketing Division
        Performs a risk assessment to determine the extent of
         review needed
        Where in-depth review is needed, performs an IQA focusing
         on critical CMC issues

                                                                         4
          Pharmaceutical Quality
           Assessment System
   PQAS is ONDQA’s new science- and risk-
    based approach to CMC review that
       Emphasizes submissions rich in scientific
        information demonstrating product knowledge
        and process understanding
       Focuses on critical pharmaceutical quality
        attributes and their relevance to safety and
        effectiveness
       Enables FDA to provide regulatory flexibility for
        specification setting and post-approval changes
       Facilitates innovation and continuous
        improvement throughout product lifecycle
                                                            5
CMC Pilot Program - Objectives

   To provide participating firms an opportunity to
    submit CMC information demonstrating
       application of quality-by-design (QbD) principles
       product knowledge and process understanding
   To enable FDA to evaluate
       CQOS; new concepts and approaches (e.g., QbD,
        design space, real-time release) in Q8, Q9, Q10, and
        PAT Guidance; CMC Agreement; team review
   To enable FDA to seek public input in
    developing a guidance on the new PQAS
                                                               6
CMC Pilot – Timeline/Goal/Status

   Program timeline
       FR Notice re CMC Pilot: July 14, 2005
       Deadline to request for participation: March 31, 2006
       Deadline to submit NDA or supplement: March 31, 2007
   Goal: 12 original NDAs and supplements
   Status
       11 original and supplemental NDAs accepted
       4 submitted to date
       One approved; 3 under reivew
       Others are to be submitted within a year

                                                                7
    CMC Pilot - Submission Criteria

   An expanded Pharmaceutical Development (P.2)
   More relevant scientific information
       Demonstrating QbD, product knowledge, and process
        understanding
       Identifying critical quality attributes (CQAs) and how they
        relate to safety and effectiveness
       Linking material attributes and process parameters (CPPs)
        to quality attributes
       Identifying possible sources of variability and how associated
        risks can be mitigated
       Describing process controls and quality assurance strategies
   A comprehensive Quality Overall Summary (CQOS)
                                                                         8
        CMC Pilot - Review Process

   CMC assessment performed by a team of
    experienced reviewers with
       good understanding of the new PQAS, and
       strong background in pharmaceutical and
        manufacturing sciences
   Process managed and overseen by ONDQA
    IO with PM support
   Integrated review/inspection team
   Frequent meetings with applicant before
    submission, during review, and after approval
                                                    9
    CMC Pilot - Expanded P.2

   All pilot NDAs to date provided more scientific
    information than typical NDAs regarding
       Formulation and product development
       Process understanding and optimization
   Most demonstrated process reproducibility,
    but not necessarily process robustness
   The more relevant scientific information is
    useful in facilitating CMC review and justifying
    proposed regulatory flexibility

                                                       10
    CMC Pilot - Application of QbD

   All pilot NDAs to date contained some elements of QbD:
        Critical quality attributes (CQAs)
        Formulation development
        Risk assessment; design of experiments
        Impact of DS/excipient attributes on DP manufacturability
         and/or CQAs
        Process development; impact of process parameters on CQAs
        Design space for critical DS/excipient attributes and CPPs
   Other observations:
        Process reproducibility, but not necessarily process
         robustness, demonstrated
        Process analyzers used to collect data in development, but not
         for commercial production

                                                                          11
         CMC Pilot - Design Space


   Issues raised:
       How were design space and control space
        established for each unit operation?
       Is the design space for each unit operation
        independent of equipment design and batch size?
       How does control space relate to design space?
       How does control space relate to operational
        ranges in the Master Batch Record?

                                                          12
CMC Pilot - Regulatory Flexibility


   Examples of proposed regulatory flexibility:
       In-process testing in lieu of end-product testing, e.g.,
        blend uniformity in lieu of content uniformity
       Real-time release in lieu of end-product testing
       Annual report for post-approval changes within
        established design space
   Degree of flexibility granted would depend on level
    of knowledge and understanding demonstrated


                                                                   13
CMC Pilot - Regulatory Agreement
               (under consideration)

   An agreement between FDA and applicant on
    critical CMC issues which could potentially
       Enable applicant to share QbD information without
        concerns about regulatory implications
       Identify CQAs and CPPs, their ranges and
        interrelationship
       Describe design space for excipient attributes and
        process parameters
       Describe control strategy
       Describe change control protocols for assessing post-
        approval changes to CQAs, CPPs, process, equipment,
        scale, etc., and associated regulatory mechanisms
       Describe how design space will be reassessed, verified,
        or redefined
                                                                  14
             CMC Pilot - Benefits

   Pilot enables industry and FDA to
       Explore ways to implement Q8, Q9, PAT, and PQAS
   Pilot enables FDA to
       Better define what constitutes a QbD-based submission
       Better establish what constitutes a science-based risk
        assessment
       Use experience gained to develop a guidance on QbD
        and PQAS
   Good science leads to better quality product,
    fewer product rejects/recalls, and enhanced
    public health protection
                                                                 15
         CMC Pilot - Challenges

   Level of detail in submission demonstrating product
    knowledge and process understanding
   Expectations for a QbD-based submission while
    addressing traditional requirements
   Providing regulatory flexibility while assuring
    product quality
   Industry’s continuous apprehension in sharing
    information, including failed experiments, with FDA
   Cultural changes needed in industry and FDA
   More resources needed initially for industry & FDA

                                                          16
        CMC Pilot - Summary

   Pilot Program got off to a good start in meeting
    its initial goal for industry participation
   Aspects of QbD were included in Pilot NDAs,
    and expanded PD is useful
   CQOS needs further development
   Scientific approaches to CQAs, CPPs, & design
    space need further development
   Regulatory flexibility is being proposed
   CMC Regulatory Agreement is being explored
   Program benefits FDA in developing guidance
    to implement QbD and PQAS
   Challenges remain for industry and FDA
                                                       17
               Public Meetings

   CMC Workshop, October 2005
   ACPS, October 2005
   CMC-GMP Track, DIA Meeting, June 2006
   PDA-FDA Meeting, September 2006
   ACPS, October 2006
   AAPS Meeting, October 2006
   ISPE/PDA Q8/Q9 Workshop, December 2006
   FDA Quality Initiatives Workshop, February 2007

                                                      18
               Internal Trainings

   Hands-on training through team review
   NDA Peer Review Forum twice a month
   ONDQA Focus Groups
       Biotech; Dissolution; Drug Eluting Devices;
        Excipients; Fermentation Products;
        Inhalation Products; Manufacturing Science;
        Oral Dosage Form Formulation; Quality by Design;
        Topical Products; Transdermal Delivery System
   ONDQA Science Forum once a year
   ONDQA Seminar Series by outside experts
   Other subject matter trainings on an ad hoc basis
                                                           19
                  Next Steps

   Sharing of lessons learned with each
    applicant under CMC Pilot Program
   Sharing of lessons learned from CMC Pilot
    Program within FDA and with industry
   Evaluate need for new guidances on
       PQAS
       QbD
       CQOS
       CMC Regulatory Agreement
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