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

ASQ/FDCASQ/FDCOctober 22, 2004October 22, 2004

Process Analytical TechnologyProcess Analytical Technology(PAT)(PAT)

The QuestionsThe Questions

• What is PAT?• Why is PAT necessary?• What does PAT mean to me?

– Industry– Regulator– Consumer

• How does PAT relate to other FDA Initiatives?

• Where are we going with PAT?

PAT PAT GuidanceGuidance

• Released September 29, 2004

• Scientific principles and tools supporting innovation– PAT Tools– Process Understanding – Risk-Based Approach– Integrated Approach

• Regulatory Strategy accommodating innovation – PAT Team approach to Review

and Inspection – Joint training and certification

of staff

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

Why PAT? Why PAT? FDAFDA Perspective Perspective

An increasing burden on FDA resources:•~ 4,000 manufacturing supplements

annually•Unable to meet statutory biennial GMP

inspection requirement•Lower scrutiny of non-domestic

industry

Cost implications for the industry from:• Low manufacturing and QA efficiency

Dr. Janet Woodcock,FDA Science Board

Why PAT? Why PAT? Public HealthPublic Health PerspectivePerspective

US Drug products are of high quality, BUT:• Increasing trend toward manufacturing-related

problems• Recalls - 176 in 1998 rising to 354 in 2002• Loss of availability of essential drugs• Disruption of manufacturing operations• Negative impact on new drug approvals

• Efficient pharmaceutical development and manufacturing are vital components of the “Critical Path” leading to an effective U.S. health care system Dr. Janet Woodcock,FDA Science Board

Main points from this:

• High tech in R & D

• Relatively low tech in Manufacturing

• It matters

Big Pharma manufacturing costs are $ 90 Bn

Significantly more than R&D

Quality by Design: A Challenge to the Pharma Industry

(CAMP, R. Scherzer. FDA Sci. Board. 4/9/02)

The Genesis of The Genesis of PATPAT: A : A ProactiveProactive

InitiativeInitiative

• Began at ACPS Discussions in July, 2001• FDA Science Board Meetings (11/01, 4/02)

– Current state of Pharmaceutical Manufacturing• Industrial Practice• FDA Regulation

– Science Board support for FDA’s proposal to facilitate innovation

http://www.fda.gov/cder/OPS/PAT.htm#scienceboard

How can How can PATPAT help? help?Example: Current Tablet Example: Current Tablet

ProductionProduction

Raw Material

Dispensing

Blending Compression

Identification Tests (Chemical

Only)

Test Product Quality for

Release (Active Only)

No Tests (Time Based)

End-Product Focused Testing to Document

Quality

Process at Risk

Current Tablet Production: Current Tablet Production: Testing to Document QualityTesting to Document Quality

• What is the Product Test?– Typically 30 Tablets/batch (1,000,000)

• What process Information does this provide?– None. Testing is Product focused.

• Will we see “failures”?– Expect number of “failing” tablets/batch, even

though 30 tablets/batch “pass”– 4% of batches may fail, even though not

different from a “passing” batch

• Does this facilitate process understanding and control?– No

PATPAT Approach: Quality by Design Approach: Quality by DesignFocus on Process Understanding

• What parameters are critical to Product Quality?– Experimental Design

• How do we analyze these parameters?– K.I.S.

• How do we control these parameters throughout the process?– Feed-back/-forward

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 Dispensing

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

PATPAT: : AnalyzeAnalyze and and ControlControl

Blending

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

• Stop blend with desired particle size and mix (not time based)

Understand and Control Blend

Example: Current Tablet Example: Current Tablet ProductionProduction

Raw Material

Dispensing

Blending Compression

Identification Tests (Chemical

Only)

Test Product Quality for

Release (Active Only)

No Tests (Time Based)

End-Product Focused Testing to Document

Quality

Process at Risk

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

Predictive Models

PATPAT:: Risk-Managed Risk-Managed Approach to Approach to Regulatory ScrutinyRegulatory Scrutiny

• Expect an 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

Implementation OptionsImplementation Options• Under the facility's own quality system

– Inspections by the PAT Team or PAT certified Investigator can precede or follow PAT implementation.

• A supplement (PAS, CBE, etc) can be submitted prior to implementation– if necessary, an inspection can be performed by a PAT Team

or PAT certified Investigator before implementation.• A comparability protocol can be submitted

– Following approval of this comparability protocol by the Agency, one or a combination of the above regulatory pathways can be adopted for implementation

• To facilitate adoption or approval of a PAT process, manufacturers may request a preoperational review of a PAT manufacturing facility and process

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

PAT Review - Inspection Team

Investigators:Robert Coleman (ORA/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 Development TeamAli Afnan, OPS/CDER

Chris Watts, OPS/CDERHuiquan Wu, OPS/CDER

PAT Training CoordinatorsJohn Simmons, Karen Bernard

and See Lam

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

CertificationCertification• Summary

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

• Team Approach– Review– Inspection– Peer Review

• FDA CGMP Initiative– Risk-based regulation– “Non-impeding” regulation– Consistent regulation

• Success based on Broad Cooperation– Industry– Academia– FDA

http://www.fda.gov/bbs/topics/NEWS/2002/NEW00829.html

PAT PAT and and CGMPCGMP Initiative Initiative

PATPAT and The and The “Critical Path”“Critical Path”

http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.pdf

PATPAT and The and The “Critical Path”“Critical Path”

http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.pdf

PAT, CGMP, and The Critical PAT, CGMP, and The Critical PathPath

Process Analytical

Technology

Encourage Innovation

New TechnologiesCGMP’s for

the 21st Century

The Critical Path

Risk-Management

Broad Cooperation:

Industry, Academia, FDA

International International CollaborationCollaboration

• ASTM Technical Committee E55

• International Regulators forming PAT Teams– Canada, Europe, Japan

• Invitation to Participate in Training

Guidance WorkshopsGuidance Workshops• Co-sponsored Public Workshops on PAT

Guidance– AAPS, ISPE, RPS

• US (Arlington, VA)– November 16, 2004

• Tokyo, Japan– December 8, 2004

• London, UK– December 14, 2004

• Brussels, Belgium– February 22, 2005

• Mumbai, India – February 25, 2005

SummarySummary• Finalized PAT Guidance

– Guidance Workshops• Expanded the Scope of PAT

– Office of Biotechnology Products• Continue Training of FDA Staff• Various Workshops (Global)

– AAPS, AIChE, IFPAC, ISPE• ASTM Technical Committee E55 on the

Pharmaceutical Application of PAT• Research (Intra- and Extramural)

– 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