The Third Annual Regulatory and Compliance Symposium Managing Risks

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The Third Annual Regulatory and Compliance
SymposiumManaging Risks From Pipeline to
Patient

• Meeting the Goals of the FDAs QbD Initiative
  Risk Management and Pharmaceutical Development

• Helen N. Winkle
• Director, Office of Pharmaceutical Science
• Center for Drug Evaluation and Research
• Food and Drug Administration

• Anjali R. Kataria
• Co-Founder and CMO, Conformia
• Principal Investigator,
• FDA-Conformia CRADA Study

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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

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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

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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

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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

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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

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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.
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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
• FDAs role is to do initial verification and
  subsequently audit

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Moving Toward the Desired State

• Philosophy Quality should be built into the
  product, and testing alone cannot be relied on to
  ensure product quality.

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Benefits of New Paradigm to FDA

• Enhances scientific foundation for review
• Better coordination across review, compliance and
  inspection
• Improvement in what is required for regulatory
  submissions
• Better consistency
• Improved quality in review (establishing a QMS
  for CMC)
• More flexibility in decision making
• Decisions made on science and not on empirical
  information
• Involves various disciplines in decision making
• Uses resources to address higher risks

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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!

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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

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FDA Conformia CRADAFindings from Part
1Opportunities, Priorities and Challenges in
Implementing FDAs Desired State

• August 23, 2007
• Anjali Kataria
• Principal Investigator
• FDA-Conformia CRADA

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CRADA Is Focused on Manufacturing Aspects Drug
Development
Conformia research focus
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Key Objectives Outputs of CRADA
Objective
Expected Output

• Analyze Root Cause Identify existing root causes
  of bottlenecks in drug development resulting in
  inefficiency
• Assess Guidelines Describe gaps, perceptions,
  and usefulness of existing guidance related to
  pharmaceutical development.
• Describe Current State Practices Summarize
  current state of pharmaceutical development,
  challenges, opportunities, and top of mind issues
  facing development organizations.
• Identify Potential Future State Define
  requirements needed for companies to implement
  Quality by Design (QbD) closed-loop, continuous
  improvement, process understanding approach to
  new drug development.
• Educate Increase familiarity of key initiatives,
  new technologies and future state possibilities

• Company Readout Identify current state practices
  / top of mind issues internal to participating
  companies.
• Final Report / Benchmarking Briefing Roll up
  results of all preliminary phase company
  participants ( Phase 1 )and loose comparison
• FDA Briefings Communicate to FDA current
  perceptions in understanding, expectations of
  future agency guidance opportunities for
  streamlining guidance.
• FDA Reaction Conformia to share FDAs feedback
  with participating companies.
• FDA Workshops Conduct Internal FDA Seminars to
  educate FDA on key areas Development Process,
  QbD, Design Space, PAT.

2/8/2014 FDA-Conformia CRADA Briefing
Confidential
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Research Agenda Was Split Into Two Parts

PRODUCT / PROCESS DEVELOPMENT
OPERATIONS
RESEARCH
Pre-Clinical
Prepare Submission
Lot release
Research
Clinical
Approval
Mfg
Distribution
CMC/Process development
Registration Phase
Part 1
Part 2
I. PAT / QbD / ICH Design Space
II. Information Management
VI. Communication / Decision Making
III. Regulatory Interaction
V. Collaboration Management
IV. Commercialization

• QbD Initiative
• Prior successes

• Adoption of QbD Concepts

Process Capabilities
Technology Capabilities

• Systems Tools
• Metrics

• Implementation Plans
• Perceived Benefit

• Skills and People Capabilities

Organization al Capabilities
Regulatory Perspective

• Feedback on current guidance/regulations
• Confidence in FDA Commitment

Topics completed ready for final report
2/8/2014 FDA-Conformia CRADA Briefing
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Participating Company Demographics
Relative Company Size
Smaller
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
2/8/2014 FDA-Conformia CRADA Briefing
Confidential
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Assessment Tool to Map Differences In Current
Practices
Related FDA Initiatives
Stages of Enablement
Ad-hoc processes
Exists, but in multiple silos
Limited harmonization across the enterprise some
systems adopted as standard
Single Process Frame for development integrated
with external partners Clear Technology strategy
Process Capabilities
Technology Capabilities
No formal initiative
Exists, but in multiple silos
Formalized Initiative spans cross-functional
groups
Stage 3 FTEs Assigned Initiatives integrated
into daily operations
Organizational Capabilities
Not very strong
Limited involvement or support by Senior mgmt
Top down Sr. mgmt support across the
organization
Executive Mgmt support translated into
formalized initiatives
Interaction with regulatory bodies limited to
regulatory and quality Some awareness and efforts
exist to adopt initiatives
Open dialogue across functions with regulatory
bodies recognizing the need for direction
setting and uniformity
Uniform definition of concepts clear plans
across the company Cross functional
bi-directional sharing of ideas and perspective
with FDA
Limited awareness of FDA initiative no clear
definitions and internal understanding of concepts
Regulatory Interactions
2/8/2014 FDA-Conformia CRADA Briefing
Confidential
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Findings Implementation of QbD Across Group is
Moving in the Direction of Integrated Enterprise
Wide
1. Ad-hoc / Not enabled
3. Partially Enabled
4. Integrated Enterprise-Wide
2. Emerging
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
2/8/2014 FDA-Conformia CRADA Briefing
Confidential
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QbD Initiatives in Place Coming
Source AMR
74 of manufacturers say they either already have
or will have in the next 12 months a QbD
initiative in place
of Responses. N95
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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

2/8/2014 CMC-IM Working Group
Confidential
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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

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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

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Top Obstacles cont..

• Lack of clear regulatory benefits / regulatory
  flexibility
• Need to showcase a compelling business case
• Difficulty accessing 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.

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Overall Observations

• Most companies had well documented development
  processes (roadmaps, technical briefs etc.)
• Though few companies had aligned these
  development process maps with the FDAs QbD
  approach such that key decision points
  encompassed/aligned with QbD goals
• Top obstacles include
• Poor information management supporting
  product/process lifecycle across development
• FDAs 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 FDAs implementation plans to support
  training of Reviewers and Inspectors in this new
  paradigm will help move QbD forward

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• Thank You