Ajaz S. Hussain, Ph.D.

1
PAT Initiative Next Steps

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

2
PAT Initiative

• FDA Science Board Meetings (11/01, 4/02)
• Emerging Science Issues in Pharmaceutical
  Manufacturing
• Current state of Pharmaceutical Manufacturing
• G. K. Raju (M.I.T) and Doug Dean
  (PriceWaterHouseCoopers)
• Opportunities for improvements
• Norman Winskill and Steve Hammond (Pfizer)
• New Technology - Dont Use or Dont Tell
  approach
• Ray Scherzer (CAMP/GlaxoSmithKline)
• Challenge to Phrama Industry - Quality By Design
• Science Board support for FDAs proposal to
  facilitate innovation

http//www.fda.gov/cder/OPS/PAT.htmscienceboard
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PAT Progress

• Advisory Committee for Pharmaceutical Science
  (PAT Subcommittee) deliberations
• Definitions, benefits, and scope
• Perceive/real regulatory hurdles
• Internal (with-in company) hurdles
• Need for across discipline communication
• PharmacyChemistryEngineering Pharmaceutical
  Engineering
• Approaches for removing these hurdles
• Case studies
• General approaches for validation
• PAT Training curriculum for FDA staff

4
PAT Teams ORA, CDER CVM
PAT Steering Committee Doug Ellsworth,
ORA/FDA Dennis Bensley, CVM/FDA Mike Olson,
ORA/FDA Joe Famulare, CDER/FDA Yuan-yuan Chiu,
CDER/FDA Frank Holcomb, CDER/FDA Moheb Nasr,
CDER/FDA Ajaz Hussain Chair, CDER/FDA
PAT Review - Inspection Team Investigators Rober
t Coleman (ORA/ATL-DO) Rebecca Rodriguez
(ORA/SJN-DO) Erin McCaffery (ORA/NWJ-DO) George
Pyramides (PHI-DO) Compliance Officers Albinus
DSa (CDER) Mike Gavini (CDER) William Bargo
(CVM) Reviewers Norman Schmuff (CDER) Lorenzo
Rocca (CDER) Vibhakar Shah (CDER) Rosario
DCosta (CDER) Raafat Fahmy (CVM)
PAT Policy Development Team Raj Uppoor,
OPS/CDER Chris Watts, OPS/CDER Huiquan Wu,
OPS/CDER (Ali Afnan, OPS/CDER)
PAT Training Coordinators John Simmons, Karen
Bernard and Kathy Jordan
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Why Process Analytical Technologies?

• PAT provides an opportunity to move from the
  current testing to document quality paradigm to
  a Continuous Quality Assurance paradigm that
  can improve our ability to ensure quality was
  built-in or was by design - ultimate
  realization of the true spirit of cGMP!
• Greater insight and understating of processes
• At/On/In-line measurement of performance
  attributes
• Real-time or rapid feedback controls (focus on
  prevention)
• Potential for significant reduction in production
  and development cycle time
• Minimize risks of poor process quality and reduce
  (regulatory) concerns

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PAT Conceptual Framework for Regulatory Policy
Development
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Product and Process Quality Knowledge
Science-Risk Based cGMPs
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Regulatory Framework

• PAT tools not a requirement
• Research exemption
• Continuous improvement without the fear of being
  considered non-compliant
• Regulatory support and flexibility during
  development implementation
• Eliminate the fear of delayed approval
• Dispute avoidance/resolution
• Science Risk based regulatory approach
• Low risk categorization based on a higher level
  of process understanding

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Strategy for Moving Forward

• Scientific Workshops
• Several FDA co-sponsored and other workshops
  conducted (US and Europe)
• Scientific discussion and debate
• across disciplines (pharmacy, chemistry, chemical
  engineering)
• organizational units (development, manufacturing,
  quality control, and regulatory departments)
• General guidance on PAT to be released
• Training workshop
• Bring together different Associations
  (disciplines)

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Strategy for Moving Forward

• Champions to drive this initiative towards a
  shared vision or desired state
• Industry Pfizer, GSK, BMS, Aventis, Lilly,
  Novartis,...
• Academia MIT, Purdue, Washington, Tennessee,
  Michigan, Rutgers, Maryland, Minnesota,
  Connecticut, Puerto Rico, Duquesne.., London,
  Bradford, Basel, (planned - Gifu and other
  universities in Japan)
• PAT introduced in Pharmaceutical Engineering
  programs at Purdue, Michigan and Rutgers
• (Instrument vendors - moving towards an
  association to address common issues)

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Strategy Moving forward

• Improving the FDA knowledge base for technical
  policy development
• Several experts recruited
• Intramural research refocused to address
  technical needs and for in-house training
• Significant increase in peer reviewed
  contributions
• Learn from other industries (e.g., link with
  ASTM)
• CRADA with Pfizer developed, awaiting final FDA
  approval (focus on chemical imaging)
• Collaborate with NSF (Center for Pharmaceutical
  Processing Research)

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Strategy Moving forward

• PAT Initiative a part of the broader cGMP
  Initiative for the 21st Century (announced 12
  August 2002)
• An example of science and risk-based systems
  approach to product quality regulations

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Strategy for Moving Forward

• Post approval implementation of PAT
• PAT-Comparability protocols proposed by several
  companies
• systems thinking, process understanding, risk
  mitigation strategies - Manufacturing Science
• PAT Review Inspection team
• training and certification
• science and risk based review and inspection
• Product Specialist on inspection concept
• Expertise Industrial pharmacists, chemical
  engineers, chemometric, process analytical
  chemistry

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Move from testing to document quality to
quality by design

• What does this mean?
• Effective methods for managing/controlling
  (particle size) variability to provide consistent
  performance
• Establishing causal links between material
  attribute (particle size) variability and
  performance
• Reduce reliance on lab-based test methods
• Improve focus on process understanding as
  compared to test to test comparisons

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Risk ?

• Change Risk(?)
• Section 116 of the Modernization Act section 506A
  (21 U.S.C. 356a) the Food, Drug, and Cosmetic Act
  (the Act)
• .potential to have an adverse effect on the
  identity, strength, quality, purity, or potency
  of a product as they may relate to the safety or
  effectiveness of the product (506A(c)(2)).
• Substantial Potential - PAS
• Moderate potential - CBE-30 Days or CBE
• Minimal potential -AR

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Risk Based Review

• Review - minimizes intolerable risk to patient
  safety
• Process
• Identify risk scenarios
• Assess likelihood of fault condition
• Assess severity of impact
• Assign risk grade
• Assess probability of detecting fault condition
• Determine mitigation strategy

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Quality Risk Scenarios

• Risk of unacceptable quality (examples)
• Releasing a unacceptable quality product
• Inadequate controls/specifications
• New impurities
• Bio-in-equivalence
• Inadequate process validation
• sampling not representative
• Stability failure
• Bio-in-equivalence
• Poor Process quality
• Others

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Risk of Bio-in-equivalence

• Risk factors
• Manufacturing changes pre/post approval
• minor - moderate - major changes
• Poor process capability
• high between and within batch variability
• Reliance on in vitro dissolution tests
• single point specification - sampling -
  predictability
• Other factors
• deficiencies in BE study design - Type II error

Bioequivalence - one of the critical links
between quality and SE
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BCS a tool for risk management

• Assessment of risk
• What is the risk of bio-in-equivalence between
  two pharmaceutical equivalent products when in
  vitro dissolution test comparisons are used for
  regulatory decisions?
• Likelihood of occurrence and the severity of the
  consequences?
• Regulatory Decision
• whether or not the risks are such that the
  project can be persued with or without additional
  arrangements to mitigate the risk
• Acceptability of the Decision
• is the decision acceptable to society?

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Quality Risk Classification (based on SUPAC and
GAMP-4)
Quality by design Systems approach
Risk Likelihood
Level 3
Level 2
Impact on Quality
Level 1
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Quality Risk Priority
Quality by design Systems approach
Probability of Detection
Low
Medium
High
High
3
Medium
Risk Classification
2
Low
1
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A Perspective on PAT One piece of the puzzle

• Vision 2020 - I can see clearly now
• Quality performance by design Continuous
  real time monitoring of quality
• Specifications based on mechanistic understanding
  of how formulation and process factors impact
  product performance
• High efficiency and capacity utilization
• Science based regulatory decisions focused on
  product and process quality

http//www.fda.gov/ohrms/dockets/ac/01/slides/3804
s1_02_hussain.ppt
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PAT Process Understanding