Strategic Implantation of PAT :FDA Perspective
IFPAC 2008 Strategic Implantation of PAT
Baltimore, MDJanuary 27, 2008
Moheb M. Nasr, Ph.D. CDER, FDA
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Outline The Desired State - FDA Quality Initiatives Quality by Design (QbD) FDA view of Process Analytical Technology (PAT) How does PAT fit into Quality by Design (QbD)? Where are we with PAT today?
FDA progress Industry progress
Implementation of PAT What are barriers to expanding the use of PAT in the
pharmaceutical industry?
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The Desired State: A Mutual Goal ofIndustry, Society, and the Regulators
Janet Woodcock, M.D.October 5, 2005
A maximally efficient, agile, flexiblepharmaceutical manufacturingsector that reliably produces high-quality drug products withoutextensive regulatory oversight.
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The Desired State: A Mutual Goal ofIndustry, Society, and the Regulators
Driver EnhancedQuality and Efficiency
FDA Initiatives: A Quality Timeline
21st Century Initiative Report 9/04
Critical Path Initiative 3/04
ICH Q8 Finalized 11/05
ICH Q9 Finalized 11/05
ONDQA CMC
Pilot Program 7/05
PAT Guidance 9/04 2004 2005 2006
OGD QbR
Announced 1/06
Quality Systems
Guidance Finalized 9/062007 2008
ICH Q10 (Step 2) 5/07
ICH Q8R (Step 2) 11/07
Scope of Recent Guidances
ProductDesign
ManufacturingProcessDesign
ProcessMonitoring/ContinuousVerification
ICH Q8/Q8(R) - Pharmaceutical Development
PAT Guidance
ICH Q9 – Quality Risk Management
FDA Guidance on Quality Systems (9/06)/ICH Q10 – Pharmaceutical Quality Systems
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Quality by Design (QbD)
A systematic approach to developmentthat begins with predefined objectivesand emphasizes product and processunderstanding and process control,based on sound science and qualityrisk management (ICH Q8(R), step 2)
Qualityby
Design
QbD Approach (ICH Q8R)
Target the product profile Determine critical quality attributes (CQAs) Link raw material attributes and process
parameters to CQAs and perform riskassessment
Develop a design space Design and implement a control strategy Manage product lifecycle, including continual
improvement
Productprofile
CQAs
Riskassessment
Designspace
Controlstrategy
ContinualImprovement
Quality by Design (QbD) – A Systematic Approachto Pharmaceutical Development and Manufacturing
Risk-based; controls shiftedupstream; reducing productvariability; real-time release
Mainly by intermediate and endproduct testing
ControlStrategy
Continual improvement facilitatedReactive to problems & OOS;post-approval changes needed
LifecycleManagement
Part of the overall quality controlstrategy; based on desired productperformance (safety and efficacy)
Primary means of control; basedon batch data at time ofsubmission
ProductSpecification
PAT tools utilized for feedbackand feed forward controls
In-process testing for go/no-go;offline analysis
Process Control
Adjustable within designspace; opportunities forinnovation (PAT)
FixedManufacturingProcess
Systematic; multivariateexperiments
Empirical; typically univariateexperiments
PharmaceuticalDevelopment
QbDTraditionalAspects
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FDA’s View ofProcess Analytical Technologies
Process Analytical Technology (PAT) a system for designing, analyzing, and controlling
manufacturing through timely measurements of critical quality and
performance attributes of raw and in-process materials andprocesses
with the goal of ensuring final product quality PAT Fundamental Tenets
Quality cannot be tested into the product; it should be built-in or should be by design
PAT Goals Enhance understanding and control of processes
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PAT VS. QbD PAT and QbD share similar goals for pharmaceutical
manufacturing Process understanding Process control Risk based decisions
PAT tools facilitates the implementation of QbD Some elements of QbD (e.g., dosage form selection,
formulation development, design space) can beimplemented without implementation of PAT
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PAT Tools PAT tools can be categorized as:
Process analyzers Process control tools Multivariate tools for design, data acquisition
and analysis Continuous improvement and knowledge
management tools PAT is more than just an analyzer!
Process Analyzers vs. PAT
On-line Analyzer(real time measurement data)
Store data
Off-line analysis,used to develop process understanding
Evaluate data against criteria
End-producttesting
Decide Pass/FailOr Go/No Go
Adjust process based upon results
“True” PAT
Design Space & PAT
Process (or Process Step)
Design Space
Monitoring ofParameters
or Attributes
Process Controls/PAT
InputProcess
Parameters
Input Materials
Product(or Intermediate)
ProductVariability
ReducedProductVariability
ProcessVariability
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FDA Progress in PAT Implementation
Training 1st PAT Cadre – 15 investigators and reviewers
trained 2nd PAT Cadre – 45 investigators and reviewers
being trained Pharmaceutical Inspectorate – training
incorporates fundamentals of PAT Reviewer training – multiple sessions on many
aspects of PAT
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FDA Progress in PAT Implementation
CMC Review experience ONDQA CMC pilot program PAT Tools in all CMC pilots
PAT tools used in development In-process controls of manufacturing Process analyzers used for end-product release, including real time
release
CMC applications outside the pilot Model based feed-forward control PAT for product/batch release
Additional implementation for generic and veterinary drugs
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In-line laser light scattering analyzer to monitornucleation during crystallization
FTIR and FBRM (Focus Beam ReflectanceMeasurement) to understand crystal growth andnucleation
At-line DSC to monitor crystalline form At-line pressure test to force drug substance
degradation At-line particle size distribution monitoring NIR to understand & design blending process
Industry Progress: Examples ofPAT Tools in Development
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Industry Progress: Examples ofProcess Analyzers in Manufacturing
Monitoring only: Assay by on-line measurement Identity by on-line measurement On-line particle size monitoring
Monitoring and control: Table compression weight check and adjustment Endpoint determination of blending Weight check and adjustment of powder filling operation Adjustment of process parameters based on starting material
attributes
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Implementation of PAT Regulators/FDA Challenges
Training reviewers and investigators Developing new approaches for review and
inspection Integration of review and inspection
Communicating expectations to industry International harmonization Industry’s apprehension in adopting new
approaches and investing in new technologies Industry’s apprehension in sharing information
with FDA
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Implementation of PAT Industry Challenges
Lack of experience in developing and implementingPAT systems
Training of scientific, operational and regulatorypersonnel
Fear of change Perceived regulatory risks Investment - more resources needed initially
Management support crucial
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Questions to the Audience
What is do you see as themajor hurdles inimplementing PAT?
How can the FDA help lowerthose barriers?
THANK YOU