Strategic Implantation of PAT :FDA Perspective

IFPAC 2008 Strategic Implantation of PAT

Baltimore, MDJanuary 27, 2008

Moheb M. Nasr, Ph.D. CDER, FDA

MOHEB.NASR@FDA.HHS.GOV

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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