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

Science Seminar Series for the Office of Commissioner Science Seminar Series for the Office of Commissioner

April 9, 2004April 9, 2004

Process Analytical TechnologyProcess Analytical Technology(PAT):(PAT):

What’s in a name?What’s in a name?

The QuestionsThe Questions

• What is PAT?• Why is PAT necessary?• How will PAT help?

– Industry– Agency– Public Health

• How does PAT relate to other FDA Initiatives?

• Where are we going with PAT?

What is What is PATPAT??

• A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance

• 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

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

Doug Dean, FDA Science Board, Nov 16, 2001

Current Paradigm:• Utilisation levels - 15% or less• Scrap and rework - plan for 5-10% • Time to effectiveness - takes years• Hesitant to Innovate

– Incentive?• Manufacturing Costs: $90 Billion

Why Why PATPAT? ? IndustryIndustry PerspectivePerspective

Ray Scherzer, FDA Science Board, Apr 2, 2002

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)

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

One “Innovative” ApproachOne “Innovative” ApproachVisible ImageVisible Image NIR ImageNIR Image

Pure Active

Pure Excipient

Ideal Tablet

• “New Technology” in Manufacturing Process

• Analyze every tablet

““Innovative” Approach:Innovative” Approach:Still Testing to Document Still Testing to Document

QualityQuality• What is the Product Test?– Test every tablet (all 1,000,000)

• What process Information does this provide?– None. Testing is still Product focused.– Better estimate of Variability in Final Product

• Why the variability?– ?– Change acceptance criteria?

• Allow some outside 75%-125%

• 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?– Appropriate Instrumentation

• How do we control these parameters throughout the process?

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

• 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

Next Steps for Next Steps for PATPAT• First PAT Approval

• Finalize PAT Guidance• Continued Training of FDA Staff• Expand the Scope of PAT

– Office of Biotechnology Products

• ASTM Technical Committee• Research (Intra- and Extramural)

– Office of Testing and Research– Pfizer CRADA– NSF IAG– Support Policy Development and Training

Next StepsNext Steps

•FDA Science Forum– Quality by Design (QbD)

Breakout Session– Chair: Dr. Janet Woodcock

AcknowledgementsAcknowledgements• Office of the Commissioner• Committee for the Advancement of FDA

Science (CAFDAS)• Dr. Arifa Khan• Linda Huntington• Joanne Locke• Mrs. Helen Winkle• Dr. Ajaz Hussain• Dr. Ali Afnan• Dr. Rob Lyon• Dr. Pat Faustino

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