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

Office of Pharmaceutical ScienceOffice of Pharmaceutical ScienceCDER, FDACDER, FDA

On the Road to On the Road to “Process “Process

Understanding”Understanding”

Arden House 2004, London

W. Edwards DemingW. Edwards Deming

““Learning is not Learning is not compulsory…. neither is compulsory…. neither is

survival”survival”

Contributions of the PAT Initiative in Developing a Shared Vision

for Pharmaceutical Product Development and Manufacturing in the 21st Century

Vision 2020: “I Can See Clearly Now”

On the road to PATOn the road to PAT AOAC International Special Symposium AOAC International Special Symposium

“ “ Pharmaceutical Process Control and Quality Assessment by Non-Pharmaceutical Process Control and Quality Assessment by Non-Traditional Means,” October 1993, St. Louis, MissouriTraditional Means,” October 1993, St. Louis, Missouri

Champions, conceptualization, charting the Champions, conceptualization, charting the coursecourse FIP’s Millennium Congress FIP’s Millennium Congress New Technology Forum of the Royal Pharmaceutical New Technology Forum of the Royal Pharmaceutical

SocietySociety [PhRMA Technical Conclave][PhRMA Technical Conclave]

The proposal - July 2001, Advisory Committee for The proposal - July 2001, Advisory Committee for Pharmaceutical SciencePharmaceutical Science

Advanced Quality Control ofPharmaceuticals: In-line Process

Controls

Ajaz S. Hussain and Thomas LayloffDivision of Product Quality Research, CDER, FDA

and The United States Pharmacopoeia

Outline• Pharmaceutical product development and

manufacture: “Building Quality In”– Formulation/process design and specifications

• Modern in-line controls– Potential advantages over traditional controls– A better approach for “building quality in”

• Accelerating industry and regulatoryacceptance of modern in-line controls

The message has notchanged!

FIP Millennium ConferenceSan Francisco

PAT Initiative: From a Reactive PAT Initiative: From a Reactive to Proactive Initiativeto Proactive Initiative

FDA Science Board Meetings (11/01, 4/02)FDA Science Board Meetings (11/01, 4/02) Emerging Science Issues in Pharmaceutical Emerging Science Issues in Pharmaceutical

ManufacturingManufacturing• Current state of Pharmaceutical ManufacturingCurrent state of Pharmaceutical Manufacturing

G. K. Raju (M.I.T) and Doug Dean (PriceWaterHouseCoopers)G. K. Raju (M.I.T) and Doug Dean (PriceWaterHouseCoopers)• Opportunities for improvementsOpportunities for improvements

Norman Winskill and Steve Hammond (Pfizer)Norman Winskill and Steve Hammond (Pfizer)• New Technology - New Technology - “Don’t Use” or “Don’t Tell” approach“Don’t Use” or “Don’t Tell” approach

Ray Scherzer (CAMP/GlaxoSmithKline)Ray Scherzer (CAMP/GlaxoSmithKline)• Challenge to Phrama Industry - Challenge to Phrama Industry - Quality By DesignQuality By Design

Science Board support for FDA’s proposal to facilitate Science Board support for FDA’s proposal to facilitate innovationinnovation

http://www.fda.gov/cder/OPS/PAT.htm#scienceboard

Main points from this:

• High tech in R & D

• Relatively low tech in Manufacturing

• It mattersBig Pharma manufacturing costs are $ 90 BnSignificantly more than R&D

Quality by Design: A Challenge to the Pharma Industry

(CAMP, R. Scherzer. FDA Sci. Board. 4/9/02)

Dimensions of the FDA’s Initiative on Dimensions of the FDA’s Initiative on Pharmaceutical Quality for the 21Pharmaceutical Quality for the 21stst Century Century

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

The Scientific OpportunityThe Scientific Opportunity

Pharmaceutical (development and) Pharmaceutical (development and) manufacturing is evolving from an manufacturing is evolving from an artart form to one form to one that is now that is now sciencescience and engineering based. and engineering based.

Effectively using this Effectively using this knowledgeknowledge in regulatory in regulatory decisions in establishing specifications and decisions in establishing specifications and evaluating manufacturing processes can evaluating manufacturing processes can substantially improve the substantially improve the efficiencyefficiency of both of both manufacturing and regulatory processes. manufacturing and regulatory processes.

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

The Risk Mitigation and The Risk Mitigation and Communication OpportunityCommunication Opportunity

Intuitive/Subjective to QuantitativeIntuitive/Subjective to Quantitative HCCPHCCP FMEAFMEA Quality by DesignQuality by Design

• ““Reliability is a design engineering discipline which applies Reliability is a design engineering discipline which applies scientific knowledge to assure a product will perform its scientific knowledge to assure a product will perform its intended function for the required duration within a given intended function for the required duration within a given environment. This includes designing in the ability to environment. This includes designing in the ability to maintain, test, and support the product throughout its total life maintain, test, and support the product throughout its total life cycle. Reliability is best described as product performance cycle. Reliability is best described as product performance over time.” over time.”

http://www.ewh.ieee.org/soc/rs/Reliability_Engineering/index.html

The Quality Systems Opportunity The Quality Systems Opportunity

A Historical Note on Quality: Milestones in Quality A Historical Note on Quality: Milestones in Quality Journey or Lurching from Fad to Fad?Journey or Lurching from Fad to Fad?

Sampling Plans (‘50s)Sampling Plans (‘50s) Zero-Defect Movement (‘60s)Zero-Defect Movement (‘60s) ISO-9000 (‘80s)ISO-9000 (‘80s) QS-9000QS-9000 Malcolm Baldrige AwardMalcolm Baldrige Award European Quality AwardEuropean Quality Award Total Quality ManagementTotal Quality Management Six SigmaSix Sigma

The Ultimate Six Sigma - “The Big Q”The Ultimate Six Sigma - “The Big Q”

cGMPs

K. R. Bhote and A. K. Bhote. World Class Quality (2000) ISBN 0-8144-0427

PharmaceuticalQualitySystem

for the 21st

Century

A Two Year Journey to Take A Two Year Journey to Take Advantage of these OpportunitiesAdvantage of these Opportunities

This initiative is designed to leverage this This initiative is designed to leverage this opportunity through an opportunity through an integrated systems integrated systems approachapproach to product quality regulation founded to product quality regulation founded on on sound science and engineering principlessound science and engineering principles for for assessing and mitigating risks of poor product assessing and mitigating risks of poor product and process qualityand process quality in the in the context of the context of the intended useintended use of pharmaceutical products. of pharmaceutical products.

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

A Two Year Journey. What is A Two Year Journey. What is the Destination? the Destination?

““Vision 2020 - I can see Vision 2020 - I can see clearly now”clearly now”

The “Desired State” The “Desired State”

http://www.fda.gov/ohrms/dockets/ac/01/slides/3804s1_02_hussain.ppt

Desired StateDesired State Product quality and performance Product quality and performance achieved and achieved and

assured by designassured by design of effective and efficient of effective and efficient manufacturing processesmanufacturing processes

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

Continuous "real time" assurance of quality Continuous "real time" assurance of quality

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

Desired StateDesired State Regulatory policies tailored to recognize the level of Regulatory policies tailored to recognize the level of

scientific scientific knowledgeknowledge supporting product supporting product applications, process validation, and process applications, process validation, and process capability capability

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

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

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

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

Directional VectorsDirectional Vectors Ensure regulatory review and inspection policies are based Ensure regulatory review and inspection policies are based

on state-of-the-art pharmaceutical science on state-of-the-art pharmaceutical science Encourage new technological advancesEncourage new technological advances Encourage risk-based approaches that focus both industry Encourage risk-based approaches that focus both industry

and Agency attention on critical areas and Agency attention on critical areas Facilitate modern quality management techniques, including Facilitate modern quality management techniques, including

implementation of quality systems implementation of quality systems Enhance the consistency and coordination of FDA's drug Enhance the consistency and coordination of FDA's drug

quality regulatory programs, in part, by integrating enhanced quality regulatory programs, in part, by integrating enhanced quality systems approaches into the Agency's business quality systems approaches into the Agency's business processes and regulatory policies concerning review and processes and regulatory policies concerning review and inspection activities inspection activities

Second Progress Report and Implementation Plan. http://www.fda.gov/cder/gmp/2ndProgressRept_Plan.htm (September 3, 2003)

Covering the Space Defined by the Covering the Space Defined by the Directional VectorsDirectional Vectors

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

Process Process UnderstandingUnderstanding

CAPABILITYLITY,PREDICTABIDESIGN,. INGUNDERSTANDPROCESS

Intended Use 1st PrinciplesModeling

OptimizationContinuous

Improvement(including CAPA)

Risk based Regulatory Assessment

DISCIPLINEEpidemiologyPharm. Engg.ClinicalClin.PharmPharm/ToxPharmaceuticsChemistryBiology

ORGANIZATIONMarketingInformation TechnologyQuality AssuranceManufacturingRegulatoryDevelopmentDiscovery

TIMETIACCGenericAER/Complaints.ApprovalPhase IIIPhase IIPhase IDiscovery

Moving forward towards a “shared vision”Moving forward towards a “shared vision”

QbDQbD

What is Process Analytical What is Process Analytical Technology (PAT)?Technology (PAT)?

PAT PAT is a is a systemsystem for for designingdesigning, , analyzinganalyzing, , and and controllingcontrolling manufacturing through manufacturing through timely measurementstimely measurements (i.e., during (i.e., during processing) of critical quality and processing) of critical quality and performance attributes of raw and in-performance attributes of raw and in-process materials and processes with the process materials and processes with the goal of ensuring final product qualitygoal of ensuring final product quality

The term The term analyticalanalytical in PAT is viewed in PAT is viewed

broadly to include chemical, physical, broadly to include chemical, physical, microbiological, mathematical, and risk microbiological, mathematical, and risk analysis conducted in an integrated manner analysis conducted in an integrated manner

Draft Guidance for IndustryPAT — A Framework forInnovative PharmaceuticalManufacturing and Quality

Assurance

PAT Framework ………...PAT Framework ………... Two componentsTwo components

a set of scientific principles and tools a set of scientific principles and tools supporting innovation, and supporting innovation, and

a strategy for regulatory implementation a strategy for regulatory implementation that will accommodate innovation that will accommodate innovation • creation of a PAT Team approach to CMC creation of a PAT Team approach to CMC

review and CGMP inspections and review and CGMP inspections and • joint training and certification of PAT review joint training and certification of PAT review

and inspection staff and inspection staff

Key PrinciplesKey Principles

Process understanding; quality by design Process understanding; quality by design Flexible, risk based regulatory scrutinyFlexible, risk based regulatory scrutiny Reduce regulatory uncertaintyReduce regulatory uncertainty Continuous improvement Continuous improvement

• Research Data - “Safe Harbor”Research Data - “Safe Harbor” Real time releaseReal time release

Integrated systems approach Integrated systems approach Opportunity for innovation; not a requirementOpportunity for innovation; not a requirement

Process UnderstandingProcess Understanding

A process is generally considered well A process is generally considered well understood whenunderstood when all critical sources of variability are all critical sources of variability are

identified and explained; (Level 1)identified and explained; (Level 1) variability is managed by the process variability is managed by the process

(Level 2); and, (Level 2); and, product quality attributes can be product quality attributes can be

accurately and reliably predicted over the accurately and reliably predicted over the ranges of acceptance criteria established ranges of acceptance criteria established for materials used, process parameters, for materials used, process parameters, and manufacturing environmental and and manufacturing environmental and other conditions (Level 3)other conditions (Level 3)

Stages of KnowledgeStages of Knowledge Production and operating knowledge can be Production and operating knowledge can be

classified by the level of understandingclassified by the level of understanding LowestLowest

• ““Art”: little is known other that characteristics of a Art”: little is known other that characteristics of a “good” product“good” product

few clearly articulated standardsfew clearly articulated standards HighestHighest

• All aspects of production are known and understoodAll aspects of production are known and understood All material and processing variation are articulated and All material and processing variation are articulated and

accounted for, with rules and procedures for every accounted for, with rules and procedures for every contingency contingency

D. A. Gravin. Building a learning organization. HBR. July 1993

Eight Levels of Process Eight Levels of Process Understanding (#1-3)Understanding (#1-3)

Recognizing prototypesRecognizing prototypes What is a good product?What is a good product?

Recognizing attributes within prototypesRecognizing attributes within prototypes Ability to define some conditions under which Ability to define some conditions under which

process gives good outputprocess gives good output Discriminating among attributesDiscriminating among attributes

Which attributes are important? Experts may Which attributes are important? Experts may differ about relevance of patterns; new operators differ about relevance of patterns; new operators are often trained through apprenticeshipsare often trained through apprenticeships

Eight Levels of Process Eight Levels of Process Understanding (#4-6)Understanding (#4-6)

Measuring attributesMeasuring attributes Some key attributes are measured; measures may Some key attributes are measured; measures may

be qualitative and relativebe qualitative and relative Locally controlling attributesLocally controlling attributes

Repeatable performance; process designed by Repeatable performance; process designed by experts, but technicians can perform itexperts, but technicians can perform it

Recognizing and discriminating between Recognizing and discriminating between contingenciescontingencies Production process can be mechanized and Production process can be mechanized and

monitored manually monitored manually

Eight Levels of Process Eight Levels of Process Understanding (#7 & 8)Understanding (#7 & 8)

Controlling contingenciesControlling contingenciesProcess can be automatedProcess can be automated

Understanding procedures and Understanding procedures and controlling contingenciescontrolling contingenciesProcess is completely Process is completely

understoodunderstood

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

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

Process Understanding - Process Understanding - Justifying “Real Time Release”Justifying “Real Time 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 - SpecificationsSpecifications

Ideally PAT principles and tools Ideally PAT principles and tools should be introduced during the should be introduced during the development phasedevelopment phase Using PAT principles and tools during Using PAT principles and tools during

development provides opportunities to development provides opportunities to improve the mechanistic basis for improve the mechanistic basis for establishing regulatory specifications establishing regulatory specifications

Manufacturers are encouraged to Manufacturers are encouraged to develop and discuss approaches for develop and discuss approaches for establishing mechanistic-based establishing mechanistic-based regulatory specifications for their regulatory specifications for their productsproducts

Process Understanding - Risk Process Understanding - Risk Based Regulatory ScrutinyBased Regulatory Scrutiny

Within a quality system and for a Within a quality system and for a particular manufacturing process, an particular manufacturing process, an inverse relationship between the inverse relationship between the level of process understanding and level of process understanding and the risk of producing a poor quality the risk of producing a poor quality product is expectedproduct is expected

For processes that are well For processes that are well understood, opportunities exist to understood, opportunities exist to develop less restrictive regulatory develop less restrictive regulatory approaches to manage changeapproaches to manage change

Process Understanding - Risk Process Understanding - Risk FMEAFMEA

HarmHarm Understand factors and failure modesUnderstand factors and failure modes

ProbabilityProbability Reduce through designReduce through design ““Detection ability”Detection ability”

• Control/PreventionControl/Prevention Risk based CMC Review & InspectionsRisk based CMC Review & Inspections

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

Multivariate Data Acquisition and Multivariate Data Acquisition and Analysis Analysis

Pharmaceutical products and processes are Pharmaceutical products and processes are complex multi-factorial physical-chemical complex multi-factorial physical-chemical and biological systemsand biological systems

Development knowledge base necessary to Development knowledge base necessary to

support and justify flexible regulatory paths support and justify flexible regulatory paths for innovations in manufacturing and post-for innovations in manufacturing and post-approval changes approval changes Opportunities need to be identified to improve Opportunities need to be identified to improve

the usefulness of available relevant product and the usefulness of available relevant product and process knowledge during regulatory decision process knowledge during regulatory decision making — without affecting a manufacturer's making — without affecting a manufacturer's development program development program

Knowledge BaseKnowledge Base StructuredStructured

DOE based on statistical principles of orthogonality, DOE based on statistical principles of orthogonality, reference distribution, and randomization to identify and reference distribution, and randomization to identify and characterize formulation/process factors and interactioncharacterize formulation/process factors and interaction

Knowledge baseKnowledge base Using DOE as the foundation as an institutional Using DOE as the foundation as an institutional

knowledge base grows in coverage (range of variables knowledge base grows in coverage (range of variables and scenarios) and data density, it can be mined to and scenarios) and data density, it can be mined to determine useful patterns for future development determine useful patterns for future development projectsprojects

Focus on knowledge and not dataFocus on knowledge and not data applicability and reliability of knowledge e.g., in the form applicability and reliability of knowledge e.g., in the form

of mathematical relationships and models can be of mathematical relationships and models can be assessedassessed by statistical evaluation of model predictions by statistical evaluation of model predictions

Process Analyzers or Process Process Analyzers or Process Analytical Chemistry ToolsAnalytical Chemistry Tools

Available tools have evolved from those Available tools have evolved from those that take simple process measurements, that take simple process measurements, such as pH, temperature, and pressure, to such as pH, temperature, and pressure, to those that measure chemical composition those that measure chemical composition and physical attributesand physical attributes

Many recent innovations make real-time Many recent innovations make real-time control and quality assurance feasible control and quality assurance feasible during manufacturingduring manufacturing ChemometricsChemometrics Process signaturesProcess signatures Correlations - causal linksCorrelations - causal links

Application of Process Application of Process AnalyzersAnalyzers

Design and construction of the process Design and construction of the process equipment, the analyzer, and their equipment, the analyzer, and their interface are critical to ensuring that interface are critical to ensuring that collected data are relevant and collected data are relevant and representative of process and product representative of process and product attributesattributes

A review of current practice standards A review of current practice standards (e.g., ASTM) for process analyzers in other (e.g., ASTM) for process analyzers in other industries can provide useful information industries can provide useful information and facilitate discussions with the Agencyand facilitate discussions with the Agency

Process Monitoring, Control, and Process Monitoring, Control, and End Points End Points

Design a process withDesign a process with measurement system to allow real time or near-real time measurement system to allow real time or near-real time

monitoring of all critical attributes monitoring of all critical attributes process controls that provide adjustments (based non process controls that provide adjustments (based non

feed-forward or feed-back information) to ensure control feed-forward or feed-back information) to ensure control of all critical attributesof all critical attributes

A process A process endpoint endpoint need not be a fixed time, but can be need not be a fixed time, but can be the achievement of the desired material attributes the achievement of the desired material attributes

Design strategies should accommodate Design strategies should accommodate the attributes of input materials the attributes of input materials the ability and reliability of process analyzers to measure the ability and reliability of process analyzers to measure

critical attributes, and critical attributes, and the achievement of pre-established process endpoints to the achievement of pre-established process endpoints to

ensure consistent quality of the output materials and the ensure consistent quality of the output materials and the final product. final product.

The PAT Team: The PAT Team: The Engine of SuccessThe Engine of Success

A team is a group of interdependent individuals with complimentary skills who are organized and committed to: 1. Achieving a common purpose2. Applying a common process, and 3. Sharing a common destiny

Quality of Quality of RelationshipRelationship

Quality ofQuality ofThinkingThinking

Quality of Quality of ActionAction

Quality ofQuality ofResultsResults

Organizational EngineeringOrganizational Engineering

“Conservators”

“Performers”“Changers”

“Perfectors”

SteeringCommittee

Review-InspectionTeam

Examples of “Strengths”Examples of “Strengths” Steering CommitteeSteering Committee

ideally suited to situations that ideally suited to situations that require people who are require people who are responsive to new and creative responsive to new and creative solutionssolutions

able to generate a continuing able to generate a continuing stream of new, sometimes stream of new, sometimes unorthodox ideasunorthodox ideas

may wander a bit under a may wander a bit under a relatively constant stream of relatively constant stream of new ideasnew ideas

tends to resolve issues by using tends to resolve issues by using analysis, assessment and analysis, assessment and planningplanning

Review-Inspection TeamReview-Inspection Team Capable of handling complex Capable of handling complex

situations that require careful situations that require careful assessment and precise assessment and precise execution. execution.

The group is unlikely to miss The group is unlikely to miss anything of significance in anything of significance in their reviewtheir review

When given detailed and When given detailed and exhaustive operational exhaustive operational specification, the team will specification, the team will probably produce highly probably produce highly reliable results of consistent reliable results of consistent qualityquality

Progress?Progress? PAT now a part for the 21PAT now a part for the 21stst Century Initiative and Century Initiative and

FDA’s Strategic Plan FDA’s Strategic Plan 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 a CRADA with Pfizer on Chemical Imaging as a

PAT toolPAT tool Academic and industry champions world wide – to Academic and industry champions world wide – to

ensure steady progress towards the desired stateensure steady progress towards the desired state Communication and cooperation with other Communication and cooperation with other

regulatory agenciesregulatory agencies

Next StepsNext Steps Final Guidance Final Guidance Discussions to expand the scope of the guidance to Discussions to expand the scope of the guidance to

include CBER and CDER/OPS’s Office of Biotechnology include CBER and CDER/OPS’s Office of Biotechnology ProductsProducts

April 13, 2004 Advisory Committee for Pharmaceutical Science April 13, 2004 Advisory Committee for Pharmaceutical Science MeetingMeeting

Training and certification programTraining and certification program Lessons learned exerciseLessons learned exercise New and improved training program with sufficient focus on New and improved training program with sufficient focus on

BiotechBiotech 22ndnd team and its training team and its training

PATRIOT a model for Product Specialist on Inspection PATRIOT a model for Product Specialist on Inspection program in CDER?program in CDER?

Next StepsNext Steps

Quality System for CMC ReviewQuality System for CMC Review Starting with New DrugsStarting with New Drugs Peer reviewPeer review Customer focusCustomer focus Team approach to reviewTeam approach to review Asking the “right” questionsAsking the “right” questions

• This afternoon Jon Clark and Ken Morris will This afternoon Jon Clark and Ken Morris will discuss this further discuss this further

What do we wish to accomplish What do we wish to accomplish with ICH Q8with ICH Q8

Ensure Q8 facilitates movement towards the “desired Ensure Q8 facilitates movement towards the “desired state” we have articulatedstate” we have articulated

This will This will Help us better understand the proposed Help us better understand the proposed product and process product and process

designdesign and its relation to the intended use and its relation to the intended use • improve process of establishing regulatory specificationsimprove process of establishing regulatory specifications

Improve our ability to identify and understand Improve our ability to identify and understand critical product and critical product and process factorsprocess factors

• improve our understanding and confidence in risk mitigation improve our understanding and confidence in risk mitigation strategiesstrategies

Allow us to utilize risk based approaches and recognize good Allow us to utilize risk based approaches and recognize good science and facilitate continuous improvement science and facilitate continuous improvement

Improve communication and systems thinkingImprove communication and systems thinking• More efficient review and inspection processMore efficient review and inspection process

Be a “win win” for public health and industryBe a “win win” for public health and industry

CTD-P2 Sec. QbD and RiskCTD-P2 Sec. QbD and Risk

Drug Substanceor API Intended Use

Route of administrationPatient population

…..Product Design

Design Specifications(Customer requirements)

P2.1 and 2.6

P2.2, 2.4, 2.5, 2.6Drug ProductContainer Closure SystemMicrobiological AttributesCompatibility (e.g., recon)

Manufacturing Process

Components of drug product

P2.3Manufacturing Process Development

FDA comments (2/4/04) on draft 1.1 reflect an attempt to integrate "quality by design," and aspects of the "risk assessment, mitigation and communication," objectives within the CTD-Q P2 format.

““Learning Before Doing” a Learning Before Doing” a prerequisite to “Building Quality In” prerequisite to “Building Quality In”

Identify and develop most promising NME’s Identify and develop most promising NME’s Accurate prediction of clinical performance using prior information Accurate prediction of clinical performance using prior information

and pre-clinical dataand pre-clinical data Drug Delivery system attributes optimized for therapeutic Drug Delivery system attributes optimized for therapeutic

objectives and manufacturing processes designed to ensure objectives and manufacturing processes designed to ensure consistent drug delivery objectivesconsistent drug delivery objectives

Clinical trials designed using all available knowledge to document Clinical trials designed using all available knowledge to document clear safety and efficacy profile in the target or intended patient clear safety and efficacy profile in the target or intended patient populationpopulation

How can we (FDA) help?How can we (FDA) help? Ask the Ask the “right”“right” questionquestion and insist on the and insist on the “right” answer“right” answer

Systems Approach: Integration across Systems Approach: Integration across disciplines, organization, and over timedisciplines, organization, and over time

Appropriate labeling and risk management

Discovery Development Review Marketing

Pre-clinical Clinical I, II, III Approval IV AER’s

Pre-formulation Formulation (Clinical) (Optimization)

Optimization Scale-Up Manufac. Changes

Appropriate Controls & Specifications Building Quality In ? ?

?Safety

&Efficacy

?

Product and Process Quality Product and Process Quality KnowledgeKnowledge: : Science-Risk Based cGMP’sScience-Risk Based cGMP’s

Quality by DesignProcess Design

Yes, Limited to theExperimentalDesign Space

Maybe, Difficult toAssess

GMP/CMC FOCUS Design qualification

Focused; Critical Process Control Points (PAT)

Extensive; EveryStep (CURRENT)

DATA DERIVED FROM

TRIAL-N-ERROR EXPERIMENTATION

DECISIONS BASED ONUNIVARIATE APPROACH

CAUSAL LINKSPREDICT PERFORMANCE

MECHANISTICUNDERSTANDING

1st Principles

““I Can See Clearly Now”: I Can See Clearly Now”: Targeting for Maximum Targeting for Maximum

ProtectionProtection

“amoral”

“incompetent”

“political citizen”

“GoodCitizens”

Kagan and Scholz. Perspectives on Regulation: Law, Discretion, and Bureaucratic behavior, May 1980.

Science isthe only

fair and transparentmeans to recognize

FDA Focus onHigh Risk

Low Risk