D. Christopher Watts, Ph.D. Office of Pharmaceutical Science, CDER, FDA Science Seminar Series for...
-
Upload
shanna-hunt -
Category
Documents
-
view
216 -
download
1
Transcript of D. Christopher Watts, Ph.D. Office of Pharmaceutical Science, CDER, FDA Science Seminar Series for...
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:– [email protected]
– [email protected]• PAT on the Web:
– http://www.fda.gov/cder/OPS/PAT.htm• Phone:
– (301)-443-5197