1. Process Understanding and 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: “Analytical“ includes:
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 D’Sa (CDER)
Mike Gavini (CDER)
William Bargo (CVM)
Brenda Uratani (CDER)
Reviewers:
Norman Schmuff (CDER)
Lorenzo Rocca (CDER)
Vibhakar Shah (CDER)
Rosario D’Costa (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 Team: Training & Certification
Completed Initial Training Program
“Lessons Learned”
Continuing Education
Involve in Next Training
Guidance Finalization
Team Approach /Inspection
Review
Inspection
Peer Review

8. 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

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

10. 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

11. Experimental Design: Establishing the “Critical Parameter(s)”
Disintegrant Level*
Parameter 3
Parameter 4
Active Particle Size*
Interaction 1
Interaction 2
Interaction 3
Interaction 4
Interaction 5
*Critical to Product Quality

12. PAT Approach: Particle Size
Raw Material Dispensing
Courtesy AstraZeneca
Understand Raw Material
Analyzer in Dispensing
What is the material?
What is Particle Size?
Predictive Models for Blend

13. 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
Blending
Courtesy AstraZeneca

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

15. Raw material Functionality & Dispensing
PAT Tablet Production
Raw material Functionality & Dispensing
Blending/Milling
Predictive Models
Compression
Control Blending Particle Size & Disintegrant Distribution
Functional Tests (Chemical and Physical)
Validate Process Control
Mitigate the Process Risk
Process Focused

16. How does PAT benefit? Efficiency Optimization Regulatory Burden
No “lab analysis” of blend or PSD
Blend to end-point
Mill only if necessary
Real Time Release
Optimization
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)

17. Summary: Process 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 on the Web: http://www.fda.gov/cder/OPS/PAT.htm
PAT on the Web:
Phone:
(301)