D. Christopher Watts, Ph.D.

1
Process Understandingand PAT

• D. Christopher Watts, Ph.D.
• Office of Pharmaceutical Science, CDER, FDA
• ACPS, Manufacturing Subcommittee
• July 21, 2004

2
The Questions

• What is PAT?
• Who is involved with PAT?
• Engine for Success
• How will PAT benefit?
• Industry
• Agency
• Public Health
• Where are we going with PAT?

3
What is PAT?

• A system for
• designing, analyzing, and controlling
  manufacturing
• timely measurements (i.e., during processing)
• critical quality and performance attributes
• raw and in-process materials
• processes
• Analytical includes
• chemical, physical, microbiological,
  mathematical, and risk analysis
• conducted in an integrated manner

4
PAT Process Understanding

• A process is well understood when
• all critical sources of variability are
  identified and explained
• variability is managed by the process
• product quality attributes can be accurately and
  reliably predicted
• Accurate and Reliable predictions reflect process
  understanding
• Process Understanding inversely proportional to
  risk

5
The FDA PAT Team (ORA, CDER, CVM)
Review - Inspection Investigators Robert
Coleman (ATL-DO) Rebeca Rodriguez (SJN-DO) Erin
McCaffery (NWJ-DO) George Pyramides
(PHI-DO) Dennis Guilfoyle (NELD) Compliance
Officers Albinus DSa (CDER) Mike Gavini
(CDER) William Bargo (CVM) Brenda Uratani
(CDER) Reviewers Norman Schmuff (CDER) Lorenzo
Rocca (CDER) Vibhakar Shah (CDER) Rosario
DCosta (CDER) Raafat Fahmy (CVM) Bryan Riley
(CDER)
PAT Steering Committee Doug Ellsworth,
ORA/FDA Dennis Bensley, CVM/FDA Patricia Lefler,
ORA/FDA Joe Famulare, CDER/FDA Keith Webber,
CDER/FDA Frank Holcomb, CDER/FDA Moheb Nasr,
CDER/FDA Ajaz Hussain, Chair, CDER/FDA
PAT Policy Team Chris Watts, OPS/CDER Ali Afnan,
OPS/CDER Huiquan Wu, OPS/CDER
PAT Training Coordinators John Simmons, Karen
Bernard and See Lam
6
The FDA PAT Team Training Certification

• Team Building
• FDA PAT Team (CDER, ORA, CVM)
• Two Didactic Sessions
• FDA
• Three Practica
• University of Washington (CPAC)
• Purdue University (CPPR)
• The University of Tennessee (MCEC)

7
The FDA PAT TeamTraining Certification

• Completed Initial Training Program
• Lessons Learned
• Continuing Education
• Involve in Next Training
• Guidance Finalization
• Team Approach /Inspection
• Review
• Inspection
• Peer Review

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Team Approach to Review/Inspection
Implementation Options

• Supplement (CBE, CBE-30, or PAS) can be
  submitted
• if necessary, an inspection can be performed
• Implemented under the facility's own quality
  system
• CGMP inspections by the PAT Team or PAT
  certified Investigator may follow
• Implemented following an inspection
• by the FDA PAT Team or a PAT certified
  Investigator
• recommendations in the inspection report serve
  as a summary basis of final approval
• Comparability Protocol can be submitted
• one or a combination of the above regulatory
  pathways can be adopted for implementation

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How does PAT benefit?Example Current Tablet
Production
Raw Material Dispensing
Blending
Milling
Blending
(Time Based)
Identification Tests (Chemical Only or
Certificate of Analysis)
Test Product Quality (Active Only)
Compression
End-Product Focused Testing to Document Quality
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PAT Approach Quality by Design

• Focus on Process Understanding
• What parameters are critical to Product Quality?
  (How? Why?)
• Experimental Design
• How do we analyze these parameters?
• Appropriate Instrumentation
• How do we control these parameters throughout the
  process?
• Control Strategy

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Experimental Design Establishing the Critical
Parameter(s)
Parameter 1 Disintegrant Level Parameter
3 Parameter 4 Active Particle Size Interaction
1 Interaction 2 Interaction 3 Interaction
4 Interaction 5
Critical to Product Quality
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PAT Approach Particle Size

• Understand Raw Material
• Analyzer in Dispensing
• What is the material?
• What is Particle Size?
• Predictive Models for Blend

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PAT Analyze and Control
Understand and Control Blend

• Analyzer on Blender
• Particle Size?
• Disintegrant mixed?
• Stop blend with desired mix
  (not time based)
• Mill?
• No lab-based Uniformity or PSD Test

14
How does PAT benefit?Example Current Tablet
Production
Raw Material Dispensing
Blending
Milling
Blending
(Time Based)
Identification Tests (Chemical Only or
Certificate of Analysis)
Test Product Quality (Active Only)
Compression
End-Product Focused Testing to Document Quality
15
PAT Tablet Production
Predictive Models
Compression
Control Blending Particle Size
Disintegrant Distribution
Functional Tests (Chemical and Physical)
Validate Process Control
Mitigate the Process Risk
Process Focused
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How does PAT benefit?

• Efficiency
• No lab analysis of blend or PSD
• Blend to end-point
• Mill only if necessary
• Real Time Release
• Optimization
• Blend to end-point
• Feed-forward from Raw Material Characterization
• Feed-forward from Blending
• Mill?
• Regulatory Burden
• Process no longer frozen in time
• No supplement for process change
• Team Approach (if Review/Inspection necessary)

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SummaryProcess Understanding and PAT

• Inverse relationship between the level of process
  understanding and the risk of producing a poor
  quality product
• Well understood process ? less restrictive
  regulatory approaches to manage change
• Focus on process understanding can facilitate
  risk-managed regulatory decisions and innovation
• Team Approach to Review/Inspection
• Several Options for Implementation

18
Next Steps for PAT

• Finalize PAT Guidance
• Expand the Scope of PAT
• Office of Biotechnology Products
• Continued Training of FDA Staff
• ASTM Technical Committee
• Research (Intra- and Extramural)
• Office of Testing and Research
• Pfizer CRADA
• NSF IAG
• Support Policy Development and Training

19
Contact

• Email
• PAT_at_cder.fda.gov
• wattsc_at_cder.fda.gov
• PAT on the Web
• http//www.fda.gov/cder/OPS/PAT.htm
• Phone
• (301)-443-5197