Parimal R' Desai, Ph'D' Vice President

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Case Study Approach for Filing with PAT

• Parimal R. Desai, Ph.D.Vice President
• Analytical and Quality Sciences
• Wyeth Research

AAPS Fall Workshop September 11-12, 2006
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Process Analytical Technology (PAT)

• Key Drivers
• FDAs Final Guidance on PAT (September 2004)
• EU PAT Initiative (Openness to parametric
  release)
• USP PAT Initiative (Expand the use of PAT in
  USP-NF)
• ICH Q8 Guidance (Design Space)
• ICH Q9 Guide on Quality Risk Management
• Use of Comparability Protocols as a viable
  regulatory pathway
• CMC Pilot Program Discussions with FDA

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Design Space

• Multi-dimensional space that encompasses
  combinations of product design, manufacturing
  process design, critical manufacturing process
  parameters and component attributes that provide
  assurance of suitable product quality and
  performance

4
Control Space

• Multi-dimensional space that encompasses
  process operating parameters and component
  quality measurements that assure process or
  product quality. It is a subset of the design
  space

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Control Strategy

• Strategy/Methodology to mitigate risks
  associated with the batch failure when the
  critical and non-critical process parameters fall
  outside the control space but within the design
  space

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Robust Manufacturing Processes

• The QbD Approach
• Gives certainty of process operation within the
  design space
• Allows greater process understanding prior to
  technology transfer
• Builds the framework for continuous process
  improvement
• Elucidates the strategy for process control
• The development of the design space must start
  early in development
• Transitioning to the to-be-marketed formulation
• IVIVR/C must be defined early in development
• Critical Process Parameters should be risk-based
  defined

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Case History Extended Release Dosage Form

• Biopharmaceutical Properties
• relatively high dose
• highly water soluble salt
• high permeability
• t ½ (human) 10 hours
• Formulation strategy
• ER formulation for once-a-day dosing
• HPMC matrix tablet
• Densification
• fluid-bed granulation
• wet granulation
• roller compaction

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Level A IVIVC Established
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HPMC Attributes that Affect Dissolution Rate

• Viscosity
• Measure of polymer average molecular weight
• Ratio of methoxy to hydroxypropoxy groups
• Controls rate of hydration
• Water content
• USP Specification inadequate
• Design of Experiment on excipient attributes

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Hypromellose Quality Attributes Control Strategy

• Control Space Experience Space
• Response surfaces observed in DOEs are
  relatively flat
• Therefore, Design space USP Specifications
• If HPMC received is outside of control space but
  within design space, extensive dissolution study
  (multi-point) will be used to justify expansion
  of control space, without a regulatory filing.
• Within Control Space for Hypromellose and
  manufacturing, single point dissolution is
  justified (reduced testing)

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PAT Pyramid
All raw materials are released and dispensed
against established specifications to verify
identity and quality.
Control of Manufacturing Ingredients
NIR Monitoring Blend Uniformity of API and HPMC ?
     
   
   

QbD
Compression
Initial Blend
? Fette Control Loops Monitoring Weight and NIR
Monitoring Identity and Assay of API and HPMC
 
Roller Compactor Milling
Laser Diffraction Monitoring Particle Size ?
Process Stage Quality Control or PAT
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Quality by Design PATNIR Spectroscopy for
Identity and Assay

• NIR is used to assess tablet assay of API and
  HPMC in real time
• Active drug assay surrogate
• Active/HPMC ratio in combination with tablet
  weight will be a surrogate for dissolution
• Extensive DOEs indicate no effect of
  manufacturing variables on dissolution performance

Bruker Optics Model MPA FT-NIR
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Quality by Design PAT Implementation
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QbD and PAT Realized Benefits

• Robust Processes
• API Manufacture
• Product Manufacture
• Analytical Methods
• Continuous Improvement
• Regulatory Relief
• Freedom to move around in a control space
• Reduced testing possible within control space
  (with appropriate PAT controls, real-time release
  is feasible)
• Manufacture outside of approved control space
  (but within design space) would require full
  testing and is managed within plant quality
  systems
• Change to control space (within approved design
  space) could be annual reportable
• Design space exceptions or expansion (proposed
  regulatory strategy)
• Critical parameters would require regulatory
  filing
• Non-critical parameters would not require
  regulatory filing

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PAT Implementation at Wyeth Key Success Factors

• Integrated Team Approach
• Empowered cross-functional team with a true
  sense-of-urgency
• Involve Engineering, Quality, Manufacturing,
  Development, IT, Facilities and Regulatory
• Application of good science and good rationale
• Early identification of technology equipment
• Early identification of manufacturing site
• Thorough Process Understanding (CPPs and CQAs)
• Engagement with the regulatory agencies (FDA,
  EMEA)
• Risk Management (decisions based on clinical
  milestones and alignment of RD/Commercial
  objectives)