D. Christopher Watts, Ph.D. D. Christopher Watts, Ph.D. Office of Pharmaceutical Office of Pharmaceutical Science, CDER, FDA Science, CDER, FDA ASQ/FDC ASQ/FDC October 22, 2004 October 22, 2004 Process Analytical Process Analytical Technology Technology (PAT) (PAT)
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D. Christopher Watts, Ph.D. Office of Pharmaceutical Science, CDER, FDA ASQ/FDC October 22, 2004 Process Analytical Technology (PAT)
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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
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)