Manufacturing Subcommittee of the Advisory Committee for Pharmaceutical Science July 20-21, 2004

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Manufacturing Subcommitteeof the Advisory
Committee for Pharmaceutical ScienceJuly 20-21,
2004

• Ajaz S. Hussain, Ph.D.
• Deputy Director
• Office of Pharmaceutical Science
• CDER, FDA

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(No Transcript)
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Dimensions of the FDAs Initiative on
Pharmaceutical Quality for the 21st Century
FDA Unveils New Initiative To Enhance
Pharmaceutical Good Manufacturing Practices
http//www.fda.gov/bbs/topics/NEWS/2002/NEW00829.
html (August 21, 2002 )
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Directional Vectors

• Ensure regulatory review and inspection policies
  are based on state-of-the-art pharmaceutical
  science
• Encourage new technological advances
• Encourage risk-based approaches that focus both
  industry and Agency attention on critical areas
• Facilitate modern quality management techniques,
  including implementation of quality systems
• Enhance the consistency and coordination of FDA's
  drug quality regulatory programs, in part, by
  integrating enhanced quality systems approaches
  into the Agency's business processes and
  regulatory policies concerning review and
  inspection activities

Second Progress Report and Implementation Plan.
http//www.fda.gov/cder/gmp/2ndProgressRept_Plan.
htm (September 3, 2003)
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Covering the Space Defined by the Directional
Vectors
Preapproval Inspection Compliance Program
Dispute Resolution Process
Risk
Pharmaceutical Inspectorate
Product Specialists on Inspection Process
Systems/Integration
Guidance on CFR Part 11
Aseptic Processing
Comparability Protocol
ICH P2, QbD, Risk
PAT
Science
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The Scientific Opportunity

• Pharmaceutical (development and) manufacturing is
  evolving from an art form to one that is now
  science and engineering based.
• Effectively using this knowledge in regulatory
  decisions in establishing specifications and
  evaluating manufacturing processes can
  substantially improve the efficiency of both
  manufacturing and regulatory processes.

http//www.fda.gov/cder/gmp/21stcenturysummary.htm
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The Risk Mitigation and Communication Opportunity

• Intuitive/Subjective to Quantitative
• HCCP
• FMEA
• Quality by Design
• Reliability is a design engineering discipline
  which applies scientific knowledge to assure a
  product will perform its intended function for
  the required duration within a given environment.
  This includes designing in the ability to
  maintain, test, and support the product
  throughout its total life cycle. Reliability is
  best described as product performance over time.
  

http//www.ewh.ieee.org/soc/rs/Reliability_Enginee
ring/index.html
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The Quality Systems Opportunity A Historical
Note on Quality Milestones in Quality Journey or
Lurching from Fad to Fad?

• Sampling Plans (50s)
• Zero-Defect Movement (60s)
• ISO-9000 (80s)
• QS-9000
• Malcolm Baldrige Award
• European Quality Award
• Total Quality Management
• Six Sigma
• The Ultimate Six Sigma - The Big Q

Pharmaceutical Quality System for the
21st Century
K. R. Bhote and A. K. Bhote. World Class Quality
(2000) ISBN 0-8144-0427
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A Two Year Journey? What is the Destination?

• Vision 2020 - I can see clearly now
• The Desired State

http//www.fda.gov/ohrms/dockets/ac/01/slides/3804
s1_02_hussain.ppt
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Desired State
http//www.fda.gov/cder/gmp/21stcenturysummary.htm

• Product quality and performance achieved and
  assured by design of effective and efficient
  manufacturing processes
• Product specifications based on mechanistic
  understanding of how formulation and process
  factors impact product performance
• Continuous "real time" assurance of quality

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Desired State
http//www.fda.gov/cder/gmp/21stcenturysummary.htm

• Regulatory policies tailored to recognize the
  level of scientific knowledge supporting product
  applications, process validation, and process
  capability
• Risk based regulatory scrutiny relate to the
• level of scientific understanding of how
  formulation and manufacturing process factors
  affect product quality and performance, and
• the capability of process control strategies to
  prevent or mitigate risk of producing a poor
  quality product

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Meeting Objectives

• Seek input and advise on charting the most
  efficient path towards the desired state
• Review assessment of Chemistry, Manufacturing,
  and Controls (CMC) sections of submissions
• Risk based cGMP Inspections Selection of
  Manufacturing sites for inspections

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What do we wish to accomplish with ICH Q8

• Ensure Q8 facilitates movement towards the
  desired state we have articulated
• This will
• Help us better understand the proposed product
  and process design and its relation to the
  intended use
• improve process of establishing regulatory
  specifications
• Improve our ability to identify and understand
  critical product and process factors
• improve our understanding and confidence in risk
  mitigation strategies
• Allow us to utilize risk based approaches and
  recognize good science and facilitate continuous
  improvement
• Improve communication and systems thinking
• More efficient review and inspection process
• Be a win win win for public health, regulators
  and industry

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ICH Q8 Integrating QbD and Risk Mitigation
Dimensions
Illustrative Examples of points to consider
Development Objectives
Risks to Quality Risk of incorrect identity Poor
product process Changes in clinical trial
product (Bridging studies) Inadequate Design
Specifications (e.g., TDS adhesive
attribute) Critical to quality and
performance? Risk of unqualified impurities Risk
of poor bioavailability Risk of incorrect expiry
date Risk of inadequate controls Risks After
Approval Risk of SUPAC,.. Risk of
unrepresentative test samples Risk of
Inadequate Facility and QS
Tests Controls -Risk Mitigation
ICH Q9
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Continuous Improvement Emerging ICH Q8 Design
Space Concept

• Multi-dimensional space defined by critical
  vectors of product quality and performance
• Examples of critical vectors
• Robust manufacturing process consistent,
  reproducible delivery of product meeting its
  specifications
• Manufacturing options
• Stability (shelf-life) and
• Bioavailability

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Data based decisions No Generalization
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Knowledge based decisions Improved Ability to
Generalize
Pharmaceutical Development Knowledge
raw material properties
process conditions
environmental
Robust process Stable and Bioavailable product
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cGMP regulatory oversight
ICH Q8
Companys Quality system
Risk
Process Understanding
Post approval change
CMC regulatory oversight
ICH Q89
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ICH Q8 Q9
Proposed ICH Q 10
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Moving towards the Desired StateDay 1

• Update on Current Efforts
• ICH Q8, Q9 and proposed Q10
• ASTM
• Awareness topic Filling the gaps Research
  planning
• Bayesian approaches in CMC?
• Critical Path Initiative
• Implementing the concepts developed in ONDC and
  OGD
• Manufacturing Science
• Quality by Design

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Moving towards the Desired StateDay 2

• Risk based CGMP Inspections
• Update on research study on pharmaceutical
  industry practices
• Pilot model for prioritizing selection of
  manufacturing sites for inspections
• CGMPs for the Production of Phase I INDs
• Efforts on facilitating continuous improvement
  through reduction in the need for Prior Approval
  Supplements
• PAT Example
• Comparability protocol concept