D. Christopher Watts, Ph.D.D. Christopher Watts, Ph.D.Office of Pharmaceutical Science, CDER, FDAOffice of Pharmaceutical Science, CDER, FDA

ACPS, Manufacturing SubcommitteeACPS, Manufacturing Subcommittee

July 21, 2004July 21, 2004

Process UnderstandingProcess Understandingand PATand PAT

The QuestionsThe 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?

What is What is PATPAT??

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

PATPAT = Process = Process UnderstandingUnderstanding

• 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

The The FDA PAT TeamFDA PAT Team (ORA, CDER, CVM) (ORA, CDER, CVM)

PAT Steering CommitteeDoug Ellsworth, ORA/FDADennis Bensley, CVM/FDA Patricia Lefler, ORA/FDAJoe Famulare, CDER/FDAKeith Webber, CDER/FDA

Frank Holcomb, CDER/FDAMoheb Nasr, CDER/FDA

Ajaz Hussain, Chair, CDER/FDA

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 Policy TeamChris Watts, OPS/CDER

Ali Afnan, OPS/CDERHuiquan Wu, OPS/CDER

PAT Training CoordinatorsJohn Simmons, Karen Bernard

and See Lam

The The FDA PAT TeamFDA PAT Team: : Training & Training &

CertificationCertification• 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)

The The FDA PAT TeamFDA PAT Team::Training & Training &

CertificationCertification• Completed Initial Training Program

– “Lessons Learned”– Continuing Education– Involve in Next Training– Guidance Finalization

• Team Approach /Inspection– Review– Inspection– Peer Review

TeamTeam Approach to Approach to Review/Inspection: Implementation Review/Inspection: Implementation

OptionsOptions• 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

How does How does PATPAT benefit? benefit?Example: Current Tablet Example: Current Tablet

ProductionProduction

Raw Material

Dispensing

Blending Milling

Identification Tests (Chemical Only or

Certificate of Analysis)

Test Product Quality (Active

Only)

(Time Based)

End-Product Focused Testing to Document

Quality

Blending

Compression

PATPAT Approach: Quality by Design Approach: Quality by DesignFocus 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

Experimental Design: Experimental Design: Establishing the “Establishing the “Critical Critical

Parameter(s)Parameter(s)””

*Critical to Product Quality

Parameter 1Disintegrant

Level*Parameter 3Parameter 4

Active Particle Size*

Interaction 1Interaction 2Interaction 3Interaction 4Interaction 5

PAT PAT Approach: Approach: Particle SizeParticle Size

Raw Material DispensingCourtesy AstraZeneca

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

PATPAT: : AnalyzeAnalyze and and ControlControl

BlendingCourtesy AstraZeneca

• Analyzer on Blender• Particle Size?• Disintegrant mixed?

• Stop blend with desired mix (not time based)• Mill?• No lab-based Uniformity or PSD Test

Understand and Control Blend

How does How does PATPAT benefit? benefit?Example: Current Tablet Example: Current Tablet

ProductionProduction

Raw Material

Dispensing

Blending Milling

Identification Tests (Chemical Only or

Certificate of Analysis)

Test Product Quality (Active

Only)

(Time Based)

End-Product Focused Testing to Document

Quality

Blending

Compression

PATPAT Tablet Production Tablet Production

Compression

Functional Tests (Chemical and

Physical)

Validate Process Control

Control Blending Particle Size &

Disintegrant Distribution

Process Focused

Mitigate the Process Risk

Raw material Functionality &

Dispensing

Blending/Milling

Predictive Models

• 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)

How does How does PATPAT benefit? benefit?

Summary:Summary:Process Understanding Process Understanding and and PATPAT

• 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

Next Steps for Next Steps for PATPAT

• 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

ContactContact

• Email:– PAT@cder.fda.gov– wattsc@cder.fda.gov

• PAT on the Web:– http://www.fda.gov/cder/OPS/

PAT.htm• Phone:

– (301)-443-5197