Ajaz S. Hussain, Ph.D. Deputy Director Office of Pharmaceutical Science CDER, FDA The Process...

Ajaz S. Hussain, Ph.D.Ajaz S. Hussain, Ph.D.Deputy DirectorDeputy Director

Office of Pharmaceutical ScienceOffice of Pharmaceutical Science

CDER, FDACDER, FDA

The Process Analytical The Process Analytical Technology Initiative: PAT Technology Initiative: PAT and the Pharmacopeiasand the Pharmacopeias

EDQM Spring Conference, Cannes, 3-4 May 2004EDQM Spring Conference, Cannes, 3-4 May 2004

Presentation OutlinePresentation Outline

The PAT InitiativeThe PAT Initiative A part of the Pharmaceutical Quality for A part of the Pharmaceutical Quality for

the 21the 21stst Century Initiative Century Initiative PAT and the USPPAT and the USP

Opportunities for the USP to support the Opportunities for the USP to support the PAT Framework PAT Framework

Current StateCurrent State Transition StateTransition State Desired StateDesired State Desired StateDesired State

Anchoring the changeAnchoring the changeAnchoring the changeAnchoring the change

Leading changeLeading changeLeading changeLeading changeArticulating a Shared NeedArticulating a Shared Need

Shaping a Shared VisionShaping a Shared Vision

Mobilizing Mobilizing commitmentcommitment

Monitoring ProgressMonitoring Progress

Finishing the JobFinishing the Job

Change Model, adapted for the purpose of outlining this presentation, from Quality Progress, April 2004

US Drug products are of high US Drug products are of high quality, But..quality, But.. Increasing trend toward Increasing trend toward

manufacturing-related problemsmanufacturing-related problems Low manufacturing process Low manufacturing process

efficiency--cost implicationsefficiency--cost implications Innovation, modernization and Innovation, modernization and

adoption of new technologies slowedadoption of new technologies slowed High burden on FDA resourcesHigh burden on FDA resources

Dr. Janet Woodcock, FDA Science Board, 2001 &2002Dr. Janet Woodcock, FDA Science Board, 2001 &2002

Articulating a Shared NeedArticulating a Shared Need

Analysis of Industry FactorsAnalysis of Industry Factors Reluctance to innovate/invest in Reluctance to innovate/invest in

manufacturing sector - manufacturing sector - poor poor stepchild compared to R&D?stepchild compared to R&D?

Emphasis on getting product out Emphasis on getting product out discourages early work on process discourages early work on process and changes after marketingand changes after marketing

Possible role of regulatory Possible role of regulatory oversight--unintended consequencesoversight--unintended consequences



Analysis of Regulatory RoleAnalysis of Regulatory Role Thirty years ago--FDA’s emphasis Thirty years ago--FDA’s emphasis

was on institution of basic was on institution of basic procedures and recordkeeping--procedures and recordkeeping--evolved to cGMPevolved to cGMP

Currently: FDA attempting to drive Currently: FDA attempting to drive innovation and investment in innovation and investment in manufacturing sector via manufacturing sector via compliance/enforcement actionscompliance/enforcement actions



OpportunityOpportunity Empirical methods are probably Empirical methods are probably

approaching their theoretical approaching their theoretical maximum effectivenessmaximum effectiveness

New scientific understanding & new New scientific understanding & new technologies can provide science-technologies can provide science-based approachesbased approaches

Plan: Use PAT as modelPlan: Use PAT as model



PAT Steering CommitteeDoug Ellsworth, ORA/FDA

Dennis Bensley, CVM/FDA Mike Olson, ORA/FDA

Joe Famulare, CDER/FDAKeith Webber, CDER/FDA

Frank Holcomb, CDER/FDAMoheb Nasr, CDER/FDA

Ajaz Hussain Chair, CDER/FDA

PAT Review - Inspection TeamInvestigators:

Robert Coleman (ORA/ATL-DO)Rebeca Rodriguez (ORA/SJN-DO)

Erin McCaffery (ORA/NWJ-DO)George Pyramides (PHI-DO)

Dennis Guilfoyle (ORA/NERL)Compliance Officers:

Albinus D’Sa (CDER)Mike Gavini (CDER)William Bargo (CVM)

Brenda Uratani (CDER)Reviewers:

Norman Schmuff (CDER)Lorenzo Rocca (CDER) Vibhakar Shah (CDER)

Rosario D’Costa (CDER)Raafat Fahmy (CVM)Brian Riley (CDER)

PAT Policy, Consultant, Support TeamRaj Uppoor, OPS/CDERChris Watts, OPS/CDERHuiquan Wu, OPS/CDER

Ali Afnan, OPS/CDER

PAT Training CoordinatorsJohn Simmons, Karen Bernard

and See Lam

Shaping a Shared Vision:Shaping a Shared Vision: Team Team Approach to CMC Review and CGMP InspectionApproach to CMC Review and CGMP Inspection

FDA Unveils New Initiative To Enhance Pharmaceutical Good Manufacturing Practices http://www.fda.gov/bbs/topics/NEWS/2002/NEW00829.html (August 21, 2002 )

Strong Public Health

Protection

Integrated quality systems orientation

Science-based policies and standards

Risk-based orientation

International cooperation

Time

Shaping a Shared Vision: Dimensions of Shaping a Shared Vision: Dimensions of the 21the 21stst Century Initiative Century Initiative

Scientific Scientific Pharmaceutical development and Pharmaceutical development and

manufacturing is evolving from an manufacturing is evolving from an artart form to form to one that is now one that is now sciencescience and engineering based and engineering based

Risk mitigation and communicationRisk mitigation and communication Ability to move from intuitive/subjective Ability to move from intuitive/subjective

approaches to more quantitative approachesapproaches to more quantitative approaches Quality systems thinkingQuality systems thinking

Milestones in quality journey provide a way Milestones in quality journey provide a way forward to bring a systems perspective to forward to bring a systems perspective to pharmaceutical quality assessment and pharmaceutical quality assessment and assurance assurance

Shaping a Shared Vision: Shaping a Shared Vision: OpportunitiesOpportunities

http://www.fda.gov/cder/gmp/21stcenturysummary.htm

Public meetings, conferences and Public meetings, conferences and workshopsworkshops FDA’s Advisory Committee, FDA Science FDA’s Advisory Committee, FDA Science

Board, PAT-Sub-committee, Board, PAT-Sub-committee, Manufacturing Sub-committeeManufacturing Sub-committee

Arden House Conferences in US and Arden House Conferences in US and Europe, Discussions at several ISPE and Europe, Discussions at several ISPE and PDA Conferences in US, Europe and Japan, PDA Conferences in US, Europe and Japan, IFPAC Conferences, PQRI, FIP Workshops,..IFPAC Conferences, PQRI, FIP Workshops,..

ICH Meetings in Brussels, Japan, and ICH Meetings in Brussels, Japan, and London London


Product quality and performance Product quality and performance achieved and assured by designachieved and assured by design of of effective and efficient manufacturing effective and efficient manufacturing processesprocesses

Product Product specifications based on specifications based on mechanisticmechanistic understandingunderstanding of how of how formulation and process factors formulation and process factors impact product performanceimpact product performance

Continuous "real time" assurance of Continuous "real time" assurance of qualityquality

Shaping a Shared Vision: Shaping a Shared Vision: Defining the Desired StateDefining the Desired State


Regulatory policies tailored to recognize the Regulatory policies tailored to recognize the level of scientific level of scientific knowledgeknowledge supporting supporting product applications, process validation, and product applications, process validation, and process capability process capability

Risk based regulatory scrutiny relate to the:Risk based regulatory scrutiny relate to the: level of scientific understandinglevel of scientific understanding of how of how

formulation and manufacturing process factors formulation and manufacturing process factors affect product quality and performance, and affect product quality and performance, and

the capability of the capability of process control strategies to process control strategies to prevent or mitigate riskprevent or mitigate risk of producing a poor of producing a poor quality product quality product

Shaping a Shared Vision: Shaping a Shared Vision: Defining the Desired StateDefining the Desired State


Mobilizing CommitmentMobilizing CommitmentMobilizing CommitmentMobilizing Commitment

Risk

Science

Preapproval Inspection Compliance Program

Dispute Resolution Process

Comparability Protocol

PATPAT

Pharmaceutical Inspectorate

Product Specialists on Inspection Process

Aseptic Processing

Guidance on CFR Part 11

Systems/

Integrat

ionICH P2, QbD, & RiskICH P2, QbD, & Risk

Mobilizing CommitmentMobilizing CommitmentMobilizing CommitmentMobilizing Commitment

Draft Guidance for IndustryPAT — A Framework forInnovative PharmaceuticalManufacturing and Quality

Assurance

Commitment to support innovationCommitment to support innovation Framework approach to PAT; not a “how to” Framework approach to PAT; not a “how to”

guidance, applicable to any new technology guidance, applicable to any new technology Team approach to review and inspection with Team approach to review and inspection with

supportive training, certification, expert supportive training, certification, expert consultant and research support consultant and research support

A systems approach to provide flexibility in A systems approach to provide flexibility in validation of new technology for its indented validation of new technology for its indented application, and a very flexible regulatory application, and a very flexible regulatory process by taking advantage of our team process by taking advantage of our team approachapproach

Address areas of regulatory uncertainty and fearAddress areas of regulatory uncertainty and fear

Mobilizing Commitment: Mobilizing Commitment: PAT ProcessPAT Process


PAT Framework and ProcessPAT Framework and Process

PAT is a PAT is a systemsystem for: for: designing, analyzing, and controlling designing, analyzing, and controlling

manufacturingmanufacturing timely measurements (i.e., during timely measurements (i.e., during

processing)processing) critical quality and performance attributes critical quality and performance attributes raw and in-process materialsraw and in-process materials processesprocesses

““Analytical“ Analytical“ includes:includes: chemical, physical, microbiological, chemical, physical, microbiological,

mathematical, and risk analysis mathematical, and risk analysis conducted in an integrated mannerconducted in an integrated manner

PAT = Process PAT = Process UnderstandingUnderstanding

A process is well understood when:A process is well understood when: all critical sources of variability are all critical sources of variability are

identified and explainedidentified and explained variability is managed by the processvariability is managed by the process

product quality attributes can be accurately product quality attributes can be accurately and reliably predictedand reliably predicted

Accurate and Reliable predictions reflect Accurate and Reliable predictions reflect process understandingprocess understanding

Process understanding inversely Process understanding inversely proportional to risk proportional to risk

Process Understanding - Process Understanding - InnovationInnovation

Provides a range of options for Provides a range of options for qualifying and justifying new qualifying and justifying new technologies and to achieve technologies and to achieve real time real time releaserelease less burdensome approaches for less burdensome approaches for

validating new technologies for their validating new technologies for their intended use intended use • in absence of process knowledge the in absence of process knowledge the test-to-test-to-

testtest comparison between an on-line process comparison between an on-line process analyzer (e.g., NIR spectroscopy for content analyzer (e.g., NIR spectroscopy for content uniformity) and a conventional test method uniformity) and a conventional test method (e.g., a wet chemical test) on collected (e.g., a wet chemical test) on collected samples may be the only available optionsamples may be the only available option

Tools for Process Tools for Process Understanding and ControlUnderstanding and Control

Multivariate data acquisition and Multivariate data acquisition and analysis tools analysis tools

Modern process analyzers or Modern process analyzers or process analytical chemistry tools process analytical chemistry tools

Process and endpoint monitoring Process and endpoint monitoring and control toolsand control tools

Continuous improvement and Continuous improvement and knowledge management toolsknowledge management tools

Process Understanding - Process Understanding - Justifying “Real Time Justifying “Real Time

Release”Release” Real time releaseReal time release is the ability to evaluate and is the ability to evaluate and

ensure acceptable quality of in-process and/or ensure acceptable quality of in-process and/or final product based on process analytical datafinal product based on process analytical data

Process understanding, control strategies, plus Process understanding, control strategies, plus on-, in-, or at-line measurement of critical on-, in-, or at-line measurement of critical attributes that relate to product quality can attributes that relate to product quality can provide a scientific risk-based approach to justify provide a scientific risk-based approach to justify how how real timereal time quality assurance may be quality assurance may be equivalent to, or better than, laboratory-based equivalent to, or better than, laboratory-based testing on collected samplestesting on collected samples

Process Understanding - Process Understanding - ValidationValidation

Can provide a high assurance of Can provide a high assurance of quality on every batch and provide quality on every batch and provide alternative, effective mechanisms to alternative, effective mechanisms to achieve validationachieve validation process validation can be enhanced and process validation can be enhanced and

possibly consist of continuous quality possibly consist of continuous quality assurance where a process is continually assurance where a process is continually monitored, evaluated, and adjusted monitored, evaluated, and adjusted using validated in-process using validated in-process measurements, tests, controls, and measurements, tests, controls, and process endpoints process endpoints

ASTM Committee E55: Pharmaceutical ASTM Committee E55: Pharmaceutical Applications of PATApplications of PAT

http://www.astm.orghttp://www.astm.org Interagency Agreement with NSFInteragency Agreement with NSF CRADA with Pfizer on Chemical Imaging as CRADA with Pfizer on Chemical Imaging as

a PAT toola PAT tool Academic and industry champions world Academic and industry champions world

wide – to ensure steady progress towards wide – to ensure steady progress towards the desired statethe desired state

Communication and cooperation with Communication and cooperation with other regulatory agenciesother regulatory agencies



Several PAT proposals, one approvalSeveral PAT proposals, one approval Expect several application a year from nowExpect several application a year from now

Training of first PAT Team completedTraining of first PAT Team completed Under developmentUnder development

Quality System for PAT ProcessQuality System for PAT Process Training program for the next PAT teamTraining program for the next PAT team Final PAT Guidance and expansion of its scope to Office Final PAT Guidance and expansion of its scope to Office

of Biotechnology Products of Biotechnology Products Increasing Increasing

ASTM membership and activitiesASTM membership and activities Schools (US, Europe and Japan) incorporating PAT in Schools (US, Europe and Japan) incorporating PAT in

their curriculum their curriculum Peer-reviewed PAT publicationsPeer-reviewed PAT publications PAT technology and support companiesPAT technology and support companies

Monitoring ProgressMonitoring Progress

FDA Strategic PlanFDA Strategic Plan CFR Part 11CFR Part 11 Warning Letter – Center Review (signifying a Team Warning Letter – Center Review (signifying a Team

Approach)Approach) Work in progress (examples)Work in progress (examples)

Final Guidance on PAT, Aseptic processing, Comparability Final Guidance on PAT, Aseptic processing, Comparability Protocols, Dispute resolution process, etc., Protocols, Dispute resolution process, etc.,

Quality System for CMC ReviewQuality System for CMC Review Dispute resolution processDispute resolution process Pharmaceutical InspectoratePharmaceutical Inspectorate Product Specialist on InspectionProduct Specialist on Inspection Other guidance documents plannedOther guidance documents planned ICH Q8 and ICH Q9ICH Q8 and ICH Q9

Innovation in Medical Technology and the Critical Innovation in Medical Technology and the Critical Path InitiativesPath Initiatives

Anchoring the changeAnchoring the changeAnchoring the changeAnchoring the change

Opportunities for the USP to Opportunities for the USP to support the PAT Frameworksupport the PAT Framework(Note: The author selected to focus on (Note: The author selected to focus on the interrelationship between PAT and the interrelationship between PAT and the USP and did not wish to generalize the USP and did not wish to generalize

the comments to follow to all other the comments to follow to all other Pharmacopeias)Pharmacopeias)

The USP recognizes that assuring The USP recognizes that assuring quality by design may provide greater quality by design may provide greater assurance than testing to document assurance than testing to document

quality..quality.. ““Data derived from manufacturing Data derived from manufacturing

process validationprocess validation studies and from studies and from in-process controlsin-process controls may provide may provide greater assurance that a batch greater assurance that a batch meets a particular monograph meets a particular monograph requirement than analytical data requirement than analytical data derived from an examination of derived from an examination of finished units drawn from that finished units drawn from that batch.” (General Notices, USP 27)batch.” (General Notices, USP 27)

PAT is Consistent with USP PAT is Consistent with USP PhilosophyPhilosophy

PAT based measurements, controls, and PAT based measurements, controls, and “real time” release based on PAT are “real time” release based on PAT are expected/likely to beexpected/likely to be “private” or “private” or company standards (alternate company standards (alternate analytical procedure)analytical procedure) ““Every compendial article in commerce shall Every compendial article in commerce shall

be so constituted that when examined in be so constituted that when examined in accordance with these assay and test accordance with these assay and test procedures, it meets all of the requirements in procedures, it meets all of the requirements in the monograph defining it.” (General Notices, the monograph defining it.” (General Notices, USP 27)USP 27)

PAT is Consistent with USP PAT is Consistent with USP PhilosophyPhilosophy

““However, it is not to be inferred that However, it is not to be inferred that application of every analytical application of every analytical procedure in the monograph to procedure in the monograph to sample from every production batch sample from every production batch is necessarily a prerequisite for is necessarily a prerequisite for assuring compliance with assuring compliance with Pharmacopeial standards before the Pharmacopeial standards before the batch is released for distribution.” batch is released for distribution.” (General Notices, USP 27)(General Notices, USP 27)

PAT FrameworkPAT Framework Provides an opportunity to utilize Provides an opportunity to utilize

novel/modern process analyzers along with novel/modern process analyzers along with other tools (e.g., multivariate data analysis, other tools (e.g., multivariate data analysis, feed-back and feed-forward process feed-back and feed-forward process controls) to:controls) to: Improve Improve process process understandingunderstanding to improve to improve confidence in confidence in process process validationvalidation

PAT FrameworkPAT Framework Ensure appropriate control of all relevant Ensure appropriate control of all relevant

critical attributes of in-process materials (e.g., critical attributes of in-process materials (e.g., using process endpoints)using process endpoints) to allow the to allow the process to manage the inherent process to manage the inherent variability in variability in physicalphysical attributes of attributes of Pharmacopieal materialsPharmacopieal materials (e.g., API and (e.g., API and excipients) that can impact their excipients) that can impact their process-abilityprocess-ability

Improve manufacturing efficiency and provide Improve manufacturing efficiency and provide a means for a means for “greater assurance”“greater assurance” of quality of quality “than analytical data derived from an “than analytical data derived from an examination of finished units drawn from that examination of finished units drawn from that batch” (“text” from General Notices, USP 27)batch” (“text” from General Notices, USP 27)

PAT: USP Compliance PAT: USP Compliance Uncertainty?Uncertainty?

Concepts in the PAT Framework are well Concepts in the PAT Framework are well established (over last ~30 years or established (over last ~30 years or longer) and are also recognized in, and longer) and are also recognized in, and supported by, the concepts articulated supported by, the concepts articulated in the General Notices chapter of the in the General Notices chapter of the USPUSP However, a perception or view of some in However, a perception or view of some in

industry is that PAT Framework is not industry is that PAT Framework is not compatible with USP compliancecompatible with USP compliance

USP can help to remove this misperception! USP can help to remove this misperception!


PAT Framework provides for higher level PAT Framework provides for higher level of material scrutiny (e.g., possibility of of material scrutiny (e.g., possibility of 100% or a large % of in-process and 100% or a large % of in-process and final product evaluated final product evaluated nondestructively)nondestructively) This unfortunately is perceived as This unfortunately is perceived as

increasing the risk that a large number of increasing the risk that a large number of batches may be judged to be non-compliant batches may be judged to be non-compliant with certain USP monograph requirementswith certain USP monograph requirements• E.g., Content Uniformity Test E.g., Content Uniformity Test

Numbers of tablets found outside Numbers of tablets found outside range 75-125% among a batch of range 75-125% among a batch of

1,000,000 tablets for different 1,000,000 tablets for different means, sigma’smeans, sigma’s

MeanMean

SigmaSigma 95%95%100%100% 105%105%

6%6% 430430 3030 430430

7%7% 21502150 360360 21502150

7.8%7.8% 52325232 13501350 52325232

Dr. Janet Woodcock, April 9, 2002


Optimal application of the PAT Framework can Optimal application of the PAT Framework can assure quality is built into the product and assure quality is built into the product and process by designprocess by design Therefore, companies utilizing this framework will Therefore, companies utilizing this framework will

not have to worry about non-conformance to not have to worry about non-conformance to compendial monographs (since such risks would be compendial monographs (since such risks would be mitigated by design and the risk level expected to mitigated by design and the risk level expected to be lower than the corresponding current risk level)be lower than the corresponding current risk level)

However, this aspect is not widely appreciated and However, this aspect is not widely appreciated and some companies seek further clarification on issues some companies seek further clarification on issues with compliance to pharmacopieal monographs for with compliance to pharmacopieal monographs for situations with larger sample size for analysis situations with larger sample size for analysis

USP Compliance Uncertainty: How USP Compliance Uncertainty: How USP Can Support PAT Framework?USP Can Support PAT Framework?

The pharmacopoeias establish marketplace legal standards The pharmacopoeias establish marketplace legal standards which help to assure practitioners and patients that which help to assure practitioners and patients that products meet their quality requirementsproducts meet their quality requirements

The marketplace standard must be met regardless of how The marketplace standard must be met regardless of how products are produced (from compounding to PAT based products are produced (from compounding to PAT based manufacturing process) manufacturing process)

The pharmacopoeias, correctly, do not dictate or define The pharmacopoeias, correctly, do not dictate or define how to achieve the established marketplace standardshow to achieve the established marketplace standards

Any attempt to do so by a pharmacopoeia or a regulatory Any attempt to do so by a pharmacopoeia or a regulatory authority will impede innovation and continuous improvementauthority will impede innovation and continuous improvement

USP can support the PAT Framework USP can support the PAT Framework by providing clear communication on by providing clear communication on issues identified as “compendial issues identified as “compendial uncertainty”uncertainty”

SummarySummary

PAT is defined as a system based on a set of PAT is defined as a system based on a set of principles and a tool box for process designprinciples and a tool box for process design The FDA draft Guidance is a framework that The FDA draft Guidance is a framework that

provides a flexible approach for innovation – it is provides a flexible approach for innovation – it is by design not a “how to” guidance by design not a “how to” guidance

PAT Framework is a directional vector in the PAT Framework is a directional vector in the broader FDA’s 21broader FDA’s 21stst Century Initiative Century Initiative

USP can support PAT by: USP can support PAT by: Providing clear communication that PAT based Providing clear communication that PAT based

QC/QA is an acceptable alternate approach QC/QA is an acceptable alternate approach

Ajaz S. Hussain, Ph.D. Deputy Director Office of Pharmaceutical Science CDER, FDA The Process...

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