The Third Annual Regulatory and Compliance Symposium Managing

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					     The Third Annual Regulatory and
     Compliance Symposium
     Managing Risks – From Pipeline to Patient

           Meeting the Goals of the FDA’s
          QbD Initiative: Risk Management
          and Pharmaceutical Development
              Helen N. Winkle                        Anjali R. Kataria
Director, Office of Pharmaceutical Science   Co-Founder and CMO, Conformia
Center for Drug Evaluation and Research           Principal Investigator,
      Food and Drug Administration            FDA-Conformia CRADA Study
Actual Focus of Current Initiatives

   Implementing changes in how FDA regulates
    pharmaceutical products – or improvement in
    our business processes
   Necessity as move into 21st century
   Paradigm shift
   Evolution – not revolution
State of Pharmaceutical
Manufacturing
   In many cases, not state-of-art as compared to other
    industries
   Able to achieve reasonable product quality – but at a
    great effort and cost
   Little emphasis on manufacturing – mainly on
    development although manufacturing is
    approximately 25% of expenses
   Factory/equipment utilization rate about 15%
   For some products, waste as high as 50%
   Inability to predict effects of scale up on final product
   Inability to analyze or understand reasons for
    manufacturing failures
   Globally fragmented
Consequences
   High cost for products due to
       Low efficiencies in manufacturing
       Waste
       Manufacturing time requirements based on
        testing, etc.
   Drug shortages due to manufacturing
    problems
   Lack of improvements based on new
    technologies
   Slowed development/access for
    investigational drugs
   Need for intensive regulatory oversight
State of Regulatory Quality
Review Processes
   Oversight increased – reviewed every change made –
    increased number of application supplements
   Focused on chemistry but not on other important
    areas (e.g., engineering)
   Implemented numerous changes in process to
    facilitate increasing review requirements (SUPAC,
    BACPAC)
   Issued numerous “how to” guidances (prescriptive)
   All standards internally developed
   PDUFA requirements speed up review process
   More complex products along with new dosage forms
   Increased emphasis on focused issues such as
    counterterrorism, pandemic, counterfeiting
Consequences
   Too much work
   Not enough staff
   More and more information from sponsors
    required (not always relevant)
   No flexibility in regulatory process
   Impossible to ensure consistency
   Discouraged innovation on part of
    manufacturer because of need for
    supplements
   Assumed all responsibility for product quality
  The Desired State:
  A Mutual Goal of Industry,
  Society, and the Regulators

A maximally efficient, agile, flexible
pharmaceutical manufacturing sector that
reliably produces high quality drug products
without extensive regulatory oversight.

                           Janet Woodcock, M.D.
Characteristics of the
Desired State
   Quality is controlled by industry
   Manufacturers have extensive knowledge about
    critical product and process parameters and quality
    attributes
       Knowledge comes from product development, prior
        experience, studies, scientific and technical literature
       Use that knowledge to understand product risk and risk
        mitigation
       Use that knowledge to determine appropriateness to make
        manufacturing changes
   Manufacturers control process through quality
    systems over life cycle and strive for continuous
    improvement
   FDA’s role is to do initial verification and subsequently
    audit
Moving Toward the
Desired State
   Philosophy – “Quality should be built into the
    product, and testing alone cannot be relied
    on to ensure product quality.”
 Benefits of New Paradigm
 to FDA
1.   Enhances scientific foundation for review
2.   Better coordination across review, compliance and
     inspection
3.   Improvement in what is required for regulatory
     submissions
4.   Better consistency
5.   Improved quality in review (establishing a QMS for
     CMC)
6.   More flexibility in decision making
7.   Decisions made on science and not on empirical
     information
8.   Involves various disciplines in decision making
9.   Uses resources to address higher risks
Benefits to Industry
1.    Design better product with less problems in manufacturing
2.    Reduce number of manufacturing supplements required for
      post market changes – rely on process and risk understanding
      and risk mitigation
3.    Allow for implementation of new technology to improve
      manufacturing without regulatory scrutiny
4.    Possible reduction in overall costs of manufacturing – less
      waste
5.    Less hassle during review – reduced deficiencies – quicker
      approvals
6.    Better interaction with FDA – deal on a science level instead
      of on a process level
7.    Allow for continuous improvements in products
8.    Better understanding of how APIs and excipients affect
      manufacturing
9.    Relate manufacturing to clinical during design
10.   Better overall business model!
    Next Steps
   Evolution
   There are definitely obstacles to change and a lot to
    learn – gaps in science, knowledge, risk and risk
    mitigation
   Need to determine the applicability to risk
    management to manufacturing process
   What is appropriate information to submit in
    application based on current product development
    data?
   Need appropriate guidance to guide industry and FDA
    staff
   Training, training, training
   Will continue to work with industry and others to
    learn – CRADA with Conformia is a perfect example
    of how this is being done
         FDA – Conformia CRADA
          Findings from Part 1

Opportunities, Priorities and Challenges in
   Implementing FDA’s Desired State

                August 23, 2007
                 Anjali Kataria
             Principal Investigator
            FDA-Conformia CRADA
               Company Confidential to Conformia, Inc
CRADA Is Focused on Manufacturing Aspects Drug
Development




 Conformia research focus
                            Company Confidential to Conformia, Inc
    Key Objectives & Outputs of CRADA
                          Objective                                           Expected Output
        Analyze Root Cause: Identify existing root                 Company Readout: Identify current state
         causes of bottlenecks in drug development                   practices / top of mind issues internal to
         resulting in inefficiency                                   participating companies.

        Assess Guidelines: Describe gaps, perceptions,             Final Report / Benchmarking Briefing: Roll up
         and usefulness of existing guidance related to              results of all preliminary phase company
         pharmaceutical development.                                 participants ( Phase 1 )and loose comparison

        Describe Current State Practices: Summarize                FDA Briefings: Communicate to FDA current
         current state of pharmaceutical development,                perceptions in understanding, expectations of
         challenges, opportunities, and top of mind issues           future agency guidance; opportunities for
         facing development organizations.                           streamlining guidance.

        Identify Potential Future State: Define                    FDA Reaction: Conformia to share FDA’s
         requirements needed for companies to implement              feedback with participating companies.
         Quality by Design (QbD) closed-loop, continuous
         improvement, process understanding approach to             FDA Workshops: Conduct Internal FDA
         new drug development.                                       Seminars to educate FDA on key areas:
                                                                     Development Process, QbD, Design Space, PAT.
        Educate: Increase familiarity of key initiatives,
         new technologies and future state possibilities

                                                         Confidential
  FDA-Conformia CRADA CRADA
7/27/2011 FDA-ConformiaBriefing Briefing      15                          Confidential
   Research Agenda Was Split Into Two Parts

  RESEARCH                       PRODUCT / PROCESS DEVELOPMENT                                               OPERATIONS

                      Pre-                                   Prepare                                              Lot
         Research                  Clinical                                     Approval               Mfg                Distribution
                     Clinical                               Submission                                          release

                            CMC/Process development
                                                                     Registration Phase

                                Part 1                                                          Part 2

            I.                  II.                  III.                 IV.                         V.                  VI.
     PAT / QbD / ICH       Information          Regulatory          Commercialization           Collaboration      Communication /
      Design Space         Management           Interaction                                     Management         Decision Making

       Process Capabilities                                QbD Initiative                      Adoption of QbD Concepts
                                                           Prior successes

       Technology Capabilities                             Systems & Tools
                                                           Metrics


       Organization al Capabilities                        Implementation Plans                Skills and People
                                                           Perceived Benefit                    Capabilities


       Regulatory Perspective                              Feedback on current guidance/regulations
                                                           Confidence in FDA Commitment

                Topics completed; ready for final report         Confidential
  FDA-Conformia CRADA CRADA
7/27/2011 FDA-ConformiaBriefing Briefing           16                            Confidential
    Participating Company Demographics

                                           Relative Company
             Smaller                         Size*                             Larger


               9 Participating Companies


       At Present 9 participating companies. (Will expand to 25
        companies.)
       7 of these have a biotech division participating in the study or are
        a standalone biotech company. Designated by:
       Collectively:
            350+ commercial products to market
            Parallel and multi-site development activities occurring at all 9 companies
            All 9 companies using CMOs in Development process / tech transfer
              *Based on 2005 Annual Revenue, # of Employees, Number of Development Sites,
               Number of Commercial Sites
                                                 Confidential
  FDA-Conformia CRADA CRADA
7/27/2011 FDA-ConformiaBriefing Briefing   17                   Confidential
    Assessment Tool to Map Differences In Current Practices

 Related FDA Initiatives
                                                                                                                      4
                                                                                                            Integrated Enterprise-
                                                                                         3                           Wide
                                                                                Partially Enabled
                                                         2
                              1                       Emerging
                          Ad-hoc /
                         Not enabled



                    Ad-hoc processes             Exists, but in multiple       Limited harmonization         Single Process Frame for
Process                                          silos                         across the enterprise;        development integrated
                                                                               some systems adopted as       with external partners
Capabilities                                                                   standard
                                                                                                             Clear Technology strategy

Technology          No formal initiative         Exists, but in multiple       Formalized; Initiative        Stage 3 + FTE’s Assigned
                                                 silos                         spans cross-functional
Capabilities                                                                   groups                        Initiatives integrated into
                                                                                                             daily operations

Organizational      Not very strong              Limited involvement or        “Top down” Sr. mgmt           Executive Mgmt support
                                                 support by Senior mgmt        support across the            translated into formalized
Capabilities                                                                   organization                  initiatives

                     Limited awareness of FDA    Interaction with              Open dialogue across          Uniform definition of
Regulatory           initiative; no clear        regulatory bodies limited     functions with regulatory     concepts; clear plans
                     definitions and internal    to regulatory and quality     bodies; recognizing the       across the company
Interactions                                                                   need for direction setting
                     understanding of concepts   Some awareness and            and uniformity                Cross functional bi-
                                                 efforts exist to adopt                                      directional sharing of ideas
                                                 initiatives                                                 and perspective with FDA
                                                                Confidential
  FDA-Conformia CRADA CRADA
7/27/2011 FDA-ConformiaBriefing Briefing         18                            Confidential
    Findings: Implementation of QbD Across Group is Moving
    in the Direction of Integrated Enterprise Wide
                            1. Ad-hoc /           2. Emerging                            3. Partially    4. Integrated
                            Not enabled                                                  Enabled         Enterprise-Wide
Awareness & Understanding
 QbD Initiative
 QbD Definitions

 Prior Successes

Process & System Capabilities
 Use of Systems/ Tools

 Elements of QbD

 QbD approach applied
  consistently across
  development operations
Implementation
 Implementation Plans


 Perceived Benefit
Organizational
 Management Support

 Confidence in FDA
  Commitment

                                                Source: Qualitative Analysis based on CRADA interviews
                                                          Confidential
  FDA-Conformia CRADA CRADA
7/27/2011 FDA-ConformiaBriefing Briefing   19                                 Confidential
    QbD Initiatives in Place & Coming

                                                                                           Source: AMR

                                                  We have no
                                                 plans to have
                              No, but we will     one in place
                                                      7%                  Yes, we have
                               have one in
                                                                          one in place
                             place in 5 years
                                                                             today
                                    6%
                                                                              29%



                        No, but we will                                               74% of manufacturers
                         have one in
                       place in 3 years
                                                                                      say they either already
                             13%                                                      have or will have in the
                                                                                      next 12 months a QbD
                                                                                      initiative in place

                                                No, but we will
                                                 have one in
                                                place in 1 year
% of Responses. N=95                                 45%
                                                        Confidential
 FDA-Conformia CRADA Briefing                                          Confidential
    Top Priorities for Implementing QbD at Companies

     Design           Space
            Process, Formulation and Analytical Design Spaces
            Changes within Design Space / Notifications to agency
     Product            /Process Attributes
            Drug Substance and Drug Product attributes as determinants of
             process end points
     Risk       Assessment
            Establishing the methodology and information required to present risk
             assessment in a submission
            Linking risk assessment to control strategy
     Prior       Knowledge
            From previous submissions
            From internal information, successes, failures and learning's


                                           Confidential
  FDA-Conformia CRADA Briefing
7/27/2011 CMC-IM Working Group     21                     Confidential
  Top Priorities for Implementing QbD at Companies
  cont.

   Manufacturing              Principles / Commercial
     Direction
          Post Approval Changes
   Product/Process  Lifecycle Management –
     Continual Improvement
          Feedforward and Feedback
   On        the Horizon:
          The link between CMC specifications and clinical
           endpoints



                                     Confidential
FDA-Conformia CRADA Briefing                        Confidential
  Top Obstacles to Broader Implementation of QbD
  by Companies

     Perceived   commitment of QbD by FDA across
        Review, Field, and Policy Teams
     Lack  of harmonization of QbD across FDA,
        EMEA, PMDA
     Lack    of executive leadership within companies
        driving QbD “top down”
     Lack   of organized cross functional leadership
        across lines of business
            Formulation, API, Analytical, Quality, Regulatory, Commercial Manufacturing
             and Information Management all need to be involved

     Confusion                over core ICH Q8 / Q9 terminology
                                           Confidential
FDA-Conformia CRADA Briefing                              Confidential
  Top Obstacles cont..

   Lack   of clear regulatory benefits / regulatory
     flexibility
                  Need to showcase a compelling business case
   Difficultyaccessing prior knowledge despite
    significant investments in portals / online
    document management
   Underdeveloped business process strategies to
    support product / process lifecycle information
   No master formulation or master API repositories
    of product/process science information
                  Yet succeeding at QbD will require a master data management
                   strategy to support product/process attributes and prior knowledge
                   approaches.
                                          Confidential
FDA-Conformia CRADA Briefing                             Confidential
  Overall Observations

     Most companies had well documented development processes
      (roadmaps, technical briefs etc.)
            Though few companies had aligned these development process maps with
             the FDA’s QbD approach such that key decision points
             encompassed/aligned with QbD goals
     Top obstacles include:
            Poor information management supporting product/process lifecycle across
             development
            FDA’s perceived commitment to drive QbD across reviewers, inspectors and
             policy team
            Harmonization across PMDA, EMEA, FDA.
     Dialogue between industry and agency is helping companies
      translate concepts into practice / develop more case studies
            FDA-Conformia-PhRMA Workshops for Cross Functional Senior Leadership
            OPS Pilot Programs /Industry Meetings (ISPE, AAPS, PhRMA etc.)
     More communication between FDA and Industry regarding FDA’s
      implementation plans to support training of Reviewers and
      Inspectors in this new paradigm will help move QbD forward
                                           Confidential
FDA-Conformia CRADA Briefing                              Confidential
                               Thank You




                                  Confidential
FDA-Conformia CRADA Briefing                     Confidential

				
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