Regulatory Opportunities and Challenges on the Use of Pharmaceutical Development Information: An Ind

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Regulatory Opportunities and Challenges on the
Use of Pharmaceutical Development InformationAn
Industry Perspective

• Robert G. Baum, Ph.D.
• Arden House 2004
• Pfizer Global RD
• January 26, 2004

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Background Information

• How many have some responsibility for CMC or PAI?
• Familiarity with Common Technical Document? E.U.
  Development Pharmaceutics?
• Knowledge of FDA 21st Century Drug Quality
  Initiative?
• Empowered to represent the single voice of your
  firm on matters relating to regulatory policy?

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Pharmaceutical Development

• Rationale for Pharmaceutical Development
• ICH CTD P2 - history
• What is P2 all about?
• Issues and questions
• Opportunities
• Where we stand and where we may go?
• Feedback

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Pharmaceutical DevelopmentBack to the Future.
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A Baby with Many Names

• Development Pharmaceutics
• Pharmaceutical Development Report
• Pharmaceutical Development
• CTD-Q Section 3.2.P.2
• P2
• Development Pharmaceutics and Manufacturing
  Science
• Quality by Design
• ICH Q8

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Pharmaceutical Development History

• Industry appraisal of current requirements
• Generation of green, yellow, red evaluation
• Development Pharmaceutics identified as red
• Expert Report and Gaiyo listed as regional
  requirements and not in scope of CTD

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Pharmaceutical Development History

• Initial discussions on the value of Development
  Pharmaceutics to the E.U. reviewers
• Proposal from E.U. to include Development
  Pharmaceutics in CTD
• PhRMA agreement to consider proposal
• FDA and MHLW neutral to proposal

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Pharmaceutical Development History

• Some firms submit Development Pharmaceutics in
  the U.S.
• U.S. industry generally against including
  Development Pharmaceutics in CTD
• Discussed industry concerns of including
  development data in the CTD
• Evening meeting at Restaurant Vincent (FDA, E.U.,
  PhRMA)

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Agenda for E.U. seminar
Pharmaceutical Development History

• How files are reviewed in the E.U.
• Role of Development Pharmaceutics in the E.U.
  review process
• Role of Expert Report in the E.U. review process

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Outcome of E.U. PhRMA meeting
Pharmaceutical Development History

• Consensus on including Pharmaceutical Development
  in CTD
• Development data generally limited to studies
  on commercial formulation (not a comprehensive
  development history)
• Most information common to both FDA and E.U.
• Agreement that Expert Report was probably not
  needed

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Consensus Agreements
Pharmaceutical Development History

• Consensus on including P2 in CTD-Q
• E.U. to develop new guideline to replace
  Development Pharmaceutics
• FDA to include information on content of P2 in
  Draft Drug Product Guidance
• MHLW technical guidance for CTD content would be
  developed

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Pharmaceutical Development History

• Step 4 sign off on CTD
• IWG discussions on new CTD-Q topics
• Presentation of P2 Concept Paper to ICH Steering
  Committee to harmonize content (Feb. 2003)
• Pharmaceutical Development approved as a new
  topic by ICH Steering Committee (Oct. 2003)

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Pharmaceutical Development in CTD (P2)
Development Report for PAI
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Opportunities and Challenges

• Opportunities and challenges for what?
• How related is this to the FDAs 21st Century
  Initiative?
• Opportunities to change the current U.S.
  regulatory system (CMC review and inspection)?
• Regulatory relief or additional requirements?
• Incremental vs. transformational?
• What problem(s) are we trying to solve?

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What is the problem?

• Quality of drugs?
• Manufacturing practices? Costs?
• Regulatory review and inspection?
• Overall assessment and approval system?
• Too many mfg supplements?
• Information on quality by design lacking?
• Too many batch failures?
• Not widespread use of PAT?

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What is the problem?

• Lack of meaningful specifications?
• Value of current approach to validation?
• Disconnect between review and field?
• Should we only consider registration?
• What about IND Phases II/III?
• Current regulatory system does not facilitate
  continuous improvement?

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Questions

• Is there a significant problem with the quality
  of pharmaceuticals today?
• Does industry fully understand their
  manufacturing processes?
• How well are manufacturing processes optimized?
• Should regulators be concerned with manufacturing
  efficiency?
• What is Quality by Design? Is it new?
• How many firms () are using PAT?
• Drug Quality System for the 21st Century?

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Drug Quality System for the 21st Century

• Where are we now? What has changed?
• Where will (should) we be in 2 yrs? 5 yrs? 10
  yrs?
• Recommendations from April PQRI?
• Incremental or transformational change?

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Long-term vision?
5 Years
3 - 5 Years
1 - 2 Years
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Quality Improvements

• The biggest opportunities lie in improving the
  overall system
• Identify and remove barriers
• A system without aim is not a system

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What is the primary goal?

• Bring important, life-saving medicines to
  patients faster
• Improved efficiency allow everyone to do more
  with the same resources
• Optimization and better understanding of
  manufacturing processes
• Reduced manufacturing variation and failures

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What does CTD-Q require for P2?

• Nothing!
• CTD-Q is a format document
• But, CTD-Q does provide illustrative examples of
  what data and information might be included in
  this section
• Current EU FDA Guidance
• Results of studies to establish that the dosage
  form, formulation, manufacturing process,
  container closure, microbiological attributes are
  appropriate for the purpose specified in the
  application
• Focus on formulation and process attributes that
  can influence batch reproducibility, product
  performance, and product quality

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P2 Content per CTD-Q

• Drug substance
• Key physicochemical characteristics
• Compatibility
• Excipients
• Drug product
• Rationale for type of product
• Formulation development
• Overages
• Physicochemical and biological properties
• Performance testing
• Manufacturing Development
• Container closure system (and delivery devices)
• Microbiological attributes
• Compatibility

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What does a P2 section look like?

• or

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The Future of Q8?

• What could P2 look like as part of an Integrated
  Drug Quality System for the 21st Century?
• How could P2 be positioned as a strategic
  document within CTD-Q?

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Rationale for Pharmaceutical Development

• Not a consistent approach for providing and
  evaluating development information across the
  three regions
• Help reviewers gain a better understanding of key
  product and process attributes
• Help route field investigators through the
  inspection process
• Increased knowledge of manufacturing science and
  technology should lead to greater flexibility in
  regulatory requirements (e.g., fewer supplements)

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Future Possibilities for Q8 in CTD-Q?
Risk Analysis
Dev Info Key Quality Attributes
DP Critical Steps/Controls
Q8
Interim Specs
DS Critical Steps/Controls
Post-approval Changes
Continuous Improvement
Innovative Technology
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Quality by Design

• Quality by Design a systematic process of
  achieving desirable quality by a careful and
  methodical scrutiny of all the attributes that go
  into characterizing quality, from the inception
  of a product to its end use, involving all
  stakeholders (the patient, the manufacturer, the
  physician and the regulator)

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The Vision Quality by Design

• Product quality and performance achieved and
  assured by design of a robust product produced by
  effective and efficient manufacturing processes

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New CMC Review Process?
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Future Possibilities for Q8 in CTD-Q?

• Opportunity for the applicant to tell a short
  story on what has been learned about the product
  and manufacturing processes
• Discussion on how development data have been
  transformed into knowledge of the manufacturing
  science and technology
• Starting point for many of the risk-based Drug
  Quality discussions
• Drive the shift from data-based to knowledge
  and science-based approach to the overall
  (review inspection) registration and approval
  process

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The Proposed Pharmaceutical Quality System
ICH topic / Osaka 2003
ICH / non-ICH topics Includes Submission, review
and inspection
The Regulatory Quality System
ICH topic / Brussels
Risk Management
Pharmaceutical Development Q8
(Product Process Knowledge)
Proposed topic for ICH topic
Drug Quality System GMP Q7B
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Issues to be resolved

• What is required vs. what is optional?
• Why would anyone want to do this (ROI)?
• Need to define a tiered or flexible
  regulatory process for review and inspections
• How will information in P2 be reviewed? Concept
  of safe harbor?
• Level of detail to be included?
• One-time submission or living document?
• Consider a phased development and implementation
  of P2

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Pharmaceutical Development Current Status

• Osaka November 2003
• First ICH EWG on Q8

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Pharmaceutical Development Concepts

• WHAT to do
• High level (not overly prescriptive)
• How it is used in the CTD (review)
• How it is updated during the life cycle
• Use in change management
• Not HOW to do it

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Pharmaceutical Development Concepts

• What could be in Q8
• Development story
• Quality by design
• Risk management
• Continous improvement
• Post approval changes
• Manufacturing experience (post approval)
• What should not be in Q8
• Failed historic formulations (not a thesis)
• DQ/PQ/IQ/OQ of equipement
• Other GMP elements

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Importance of Design
Some Typical Failure Modes for Pharma

• Potency mass balance of material
• Degradation impurities (new or greater extent),
  color, on stability
• Uniformity Poor content uniformity, performance
• Release dissolution variable or changing
• Quality (Characterization) of raw materials
• Performance or purity concerns
• Variability of intermediates/raw material
• Economic performance/productivity issues/ cost of
  investigations

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Pharmaceutical Development Expectations

• Appropriate amount of development history
• Manufacturing Science in the dossier
• Quality by Design
• Document useful over life cycle of the product
• Road Map for
• Registration and Review
• Inspections
• Post Approval Changes

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Where to start whats available?

• EU Note for Guidance
• Plus annexes
• Plus NfG on validation ( draft NfG on validation
  of non-standard processes)
• FDA Draft Drug Product Guideline
• CTD Section P2
• Draft P2 guideline from 1999
• From a blank piece of paper..

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P2 Content per CTD-Q

• Drug substance
• Key physicochemical characteristics
• Compatibility
• Excipients functionality, critical
  physicochemical characteristics,
  interchangeability
• Drug product
• Rationale for type of product
• Formulation development
• Overages
• Physicochemical and biological properties
• Performance testing
• Manufacturing Development
• Container closure system (and delivery devices)
• Microbiological attributes
• Compatibility

• Where to put information on
• Quality by design
• Science technology
• Continous improvement
• Risk Management

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Q8 More Issues Questions

• How much information is Industry prepared to put
  into the P2 report?
• Impact upon post-approval changes?
• Is the amount of information to be provided
  mandatory or optional and open to the
  applicant to decide?
• New guideline should indicate the expectations
• More information - greater flexibility around
  post approval changes?
• History of failures?
• where relevant as part of assessment of critical
  factors
• Facilitate Continuous Improvement?
• Include Biotech products

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Data Balance Submission vs Post Approval
Amount of data in PAC
Amount of data in P2
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Expected Outcome of Pharmaceutical Development
Q8

• An evolving report which communicates knowledge
  to enable a science based assessment of the
  dossier and which provides the foundation for
  manufacturing life cycle development, risk
  management and assessment, and also provides
  support to inspection processes

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Advantages of a Risk-Based Regulatory Assessment

• Less burdensome change management systems based
  on pharmaceutical development and risk-assessment
  information provided.
• Use pharmaceutical development information to
  assist in management and assessment of
  post-approval changes and as a basis for
  continuous improvement

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