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2004 4052 b1-09_Hussain-Arden-UK-Presentation

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A useful repository- on the road to 'Process Understanding'. Starting in 1993 to the FIP Millennial Conference (2000) and onwards.

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2004 4052 b1-09_Hussain-Arden-UK-Presentation

  1. 1. Ajaz S. Hussain, Ph.D.Ajaz S. Hussain, Ph.D. Deputy DirectorDeputy Director Office of Pharmaceutical ScienceOffice of Pharmaceutical Science CDER, FDACDER, FDA On the Road toOn the Road to “Process“Process Understanding”Understanding” Arden House 2004, London
  2. 2. W. Edwards DemingW. Edwards Deming ““Learning is notLearning is not compulsory…. neither iscompulsory…. neither is survival”survival”
  3. 3. 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”
  4. 4. On the road to PATOn the road to PAT  AOAC International Special SymposiumAOAC 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 theChampions, conceptualization, charting the coursecourse  FIP’s Millennium CongressFIP’s Millennium Congress  New Technology Forum of the Royal PharmaceuticalNew Technology Forum of the Royal Pharmaceutical SocietySociety  [PhRMA Technical Conclave][PhRMA Technical Conclave]  The proposal - July 2001, Advisory CommitteeThe proposal - July 2001, Advisory Committee for Pharmaceutical Sciencefor Pharmaceutical Science
  5. 5. Advanced Quality Control of Pharmaceuticals: In-line Process Controls Ajaz S. Hussain and Thomas Layloff Division 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 regulatory acceptance of modern in-line controls The message has not changed! FIP Millennium Conference San Francisco
  6. 6. PAT Initiative: From a ReactivePAT 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 PharmaceuticalEmerging 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”“Don’t Use” or “Don’t Tell” approachapproach  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 facilitateScience Board support for FDA’s proposal to facilitate innovationinnovation http://www.fda.gov/cder/OPS/PAT.htm#scienceboard
  7. 7. 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)
  8. 8. Dimensions of the FDA’s Initiative onDimensions of the FDA’s Initiative on Pharmaceutical Quality for the 21Pharmaceutical Quality for the 21stst CenturyCentury 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
  9. 9. The Scientific OpportunityThe Scientific Opportunity  Pharmaceutical (development and)Pharmaceutical (development and) manufacturing is evolving from anmanufacturing is evolving from an artart form to oneform to one that is nowthat is now sciencescience and engineering based.and engineering based.  Effectively using thisEffectively using this knowledgeknowledge in regulatoryin regulatory decisions in establishing specifications anddecisions in establishing specifications and evaluating manufacturing processes canevaluating manufacturing processes can substantially improve thesubstantially improve the efficiencyefficiency of bothof both manufacturing and regulatory processes.manufacturing and regulatory processes. http://www.fda.gov/cder/gmp/21stcenturysummary.htm
  10. 10. The Risk Mitigation andThe 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 appliesReliability is a design engineering discipline which applies scientific knowledge to assure a product will perform itsscientific knowledge to assure a product will perform its intended function for the required duration within a givenintended function for the required duration within a given environment. This includes designing in the ability toenvironment. This includes designing in the ability to maintain, test, and support the product throughout its total lifemaintain, test, and support the product throughout its total life cycle. Reliability is best described as product performancecycle. Reliability is best described as product performance over time.”over time.” http://www.ewh.ieee.org/soc/rs/Reliability_Engineering/index.html
  11. 11. The Quality Systems OpportunityThe Quality Systems Opportunity A Historical Note on Quality: Milestones in QualityA 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 Pharmaceutical Quality System for the 21st Century
  12. 12. A Two Year Journey to TakeA Two Year Journey to Take Advantage of these OpportunitiesAdvantage of these Opportunities  This initiative is designed to leverage thisThis initiative is designed to leverage this opportunity through anopportunity through an integrated systemsintegrated systems approachapproach to product quality regulation foundedto product quality regulation founded onon sound science and engineering principlessound science and engineering principles forfor assessing and mitigating risks of poor productassessing and mitigating risks of poor product and process qualityand process quality in thein the context of thecontext of the intended useintended use of pharmaceutical products.of pharmaceutical products. http://www.fda.gov/cder/gmp/21stcenturysummary.htm
  13. 13. A Two Year Journey. What isA Two Year Journey. What is the Destination?the Destination?  ““Vision 2020 - I can seeVision 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
  14. 14. Desired StateDesired State • Product quality and performanceProduct quality and performance achieved andachieved and assured by designassured by design of effective and efficientof effective and efficient manufacturing processesmanufacturing processes • ProductProduct specifications based on mechanisticspecifications based on mechanistic understandingunderstanding of how formulation and processof how formulation and process factors impact product performancefactors impact product performance • Continuous "real time" assurance of qualityContinuous "real time" assurance of quality http://www.fda.gov/cder/gmp/21stcenturysummary.htm
  15. 15. Desired StateDesired State • Regulatory policies tailored to recognize theRegulatory policies tailored to recognize the level of scientificlevel of scientific knowledgeknowledge supporting productsupporting product applications, process validation, and processapplications, process validation, and process capabilitycapability • Risk based regulatory scrutiny relate to the:Risk based regulatory scrutiny relate to the: • level of scientific understandinglevel of scientific understanding of how formulationof how formulation and manufacturing process factors affect productand manufacturing process factors affect product quality and performance, andquality and performance, and • the capability ofthe capability of process control strategies to preventprocess control strategies to prevent or mitigate riskor mitigate risk of producing a poor quality productof producing a poor quality product http://www.fda.gov/cder/gmp/21stcenturysummary.htm
  16. 16. Directional VectorsDirectional Vectors  Ensure regulatory review and inspection policies areEnsure regulatory review and inspection policies are based on state-of-the-art pharmaceutical sciencebased on state-of-the-art pharmaceutical science  Encourage new technological advancesEncourage new technological advances  Encourage risk-based approaches that focus bothEncourage risk-based approaches that focus both industry and Agency attention on critical areasindustry and Agency attention on critical areas  Facilitate modern quality management techniques,Facilitate modern quality management techniques, including implementation of quality systemsincluding implementation of quality systems  Enhance the consistency and coordination of FDA's drugEnhance the consistency and coordination of FDA's drug quality regulatory programs, in part, by integratingquality regulatory programs, in part, by integrating enhanced quality systems approaches into the Agency'senhanced quality systems approaches into the Agency's business processes and regulatory policies concerningbusiness processes and regulatory policies concerning review and inspection activitiesreview and inspection activities Second Progress Report and Implementation Plan. http://www.fda.gov/cder/gmp/2ndProgressRept_Plan.htm (September 3, 2003)
  17. 17. Covering the Space Defined by theCovering 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/Integration ICH P2, QbD, & RiskICH P2, QbD, & Risk
  18. 18. Process UnderstandingProcess Understanding ∫∫∫= CAPABILITYLITY,PREDICTABIDESIGN,. INGUNDERSTANDPROCESS Intended Use 1st Principles Modeling Optimization Continuous Improvement (including CAPA) Risk based Regulatory Assessment DISCIPLINE Epidemiology Pharm. Engg. Clinical Clin.Pharm Pharm/Tox Pharmaceutics Chemistry Biology ORGANIZATION Marketing Information Technology Quality Assurance Manufacturing Regulatory Development Discovery TIME TIACC Generic AER/Complaints. Approval Phase III Phase II Phase I Discovery Moving forward towards a “shared vision”Moving forward towards a “shared vision” QbDQbD
  19. 19. What is Process AnalyticalWhat is Process Analytical Technology (PAT)?Technology (PAT)?  PATPAT is ais a systemsystem forfor designingdesigning,, analyzinganalyzing, and, and controllingcontrolling manufacturing throughmanufacturing through timelytimely measurementsmeasurements (i.e., during processing) of critical(i.e., during processing) of critical quality and performance attributes of raw and in-quality and performance attributes of raw and in- process materials and processes with the goal ofprocess materials and processes with the goal of ensuring final product qualityensuring final product quality  The termThe term analyticalanalytical in PAT is viewed broadly toin PAT is viewed broadly to include chemical, physical, microbiological,include chemical, physical, microbiological, mathematical, and risk analysis conducted in anmathematical, and risk analysis conducted in an integrated mannerintegrated manner
  20. 20. Draft Guidance for Industry PAT — A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance
  21. 21. PAT Framework ………...PAT Framework ………...  Two componentsTwo components  a set of scientific principles and toolsa set of scientific principles and tools supporting innovation, andsupporting innovation, and  a strategy for regulatory implementation thata strategy for regulatory implementation that will accommodate innovationwill accommodate innovation • creation of a PAT Team approach to CMC reviewcreation of a PAT Team approach to CMC review and CGMP inspections andand CGMP inspections and • joint training and certification of PAT review andjoint training and certification of PAT review and inspection staffinspection staff
  22. 22. Key PrinciplesKey Principles  Process understanding; quality by designProcess understanding; quality by design  Flexible, risk based regulatory scrutinyFlexible, risk based regulatory scrutiny  Reduce regulatory uncertaintyReduce regulatory uncertainty  Continuous improvementContinuous improvement • Research Data - “Safe Harbor”Research Data - “Safe Harbor”  Real time releaseReal time release  Integrated systems approachIntegrated systems approach  Opportunity for innovation; not aOpportunity for innovation; not a requirementrequirement
  23. 23. Process UnderstandingProcess Understanding  A process is generally considered wellA process is generally considered well understood whenunderstood when  all critical sources of variability are identifiedall critical sources of variability are identified and explained; (Level 1)and explained; (Level 1)  variability is managed by the process (Levelvariability is managed by the process (Level 2); and,2); and,  product quality attributes can be accuratelyproduct quality attributes can be accurately and reliably predicted over the ranges ofand reliably predicted over the ranges of acceptance criteria established for materialsacceptance criteria established for materials used, process parameters, and manufacturingused, process parameters, and manufacturing environmental and other conditions (Level 3)environmental and other conditions (Level 3)
  24. 24. Stages of KnowledgeStages of Knowledge  Production and operating knowledge canProduction and operating knowledge can be classified by the level of understandingbe classified by the level of understanding  LowestLowest • ““Art”: little is known other that characteristics of aArt”: 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 andAll aspects of production are known and understoodunderstood  All material and processing variation are articulated andAll material and processing variation are articulated and accounted for, with rules and procedures for everyaccounted for, with rules and procedures for every contingencycontingency D. A. Gravin. Building a learning organization. HBR. July 1993
  25. 25. Eight Levels of ProcessEight 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 whichAbility to define some conditions under which process gives good outputprocess gives good output  Discriminating among attributesDiscriminating among attributes  Which attributes are important? Experts mayWhich attributes are important? Experts may differ about relevance of patterns; newdiffer about relevance of patterns; new operators are often trained throughoperators are often trained through apprenticeshipsapprenticeships
  26. 26. Eight Levels of ProcessEight Levels of Process Understanding (#4-6)Understanding (#4-6)  Measuring attributesMeasuring attributes  Some key attributes are measured; measuresSome key attributes are measured; measures may be qualitative and relativemay be qualitative and relative  Locally controlling attributesLocally controlling attributes  Repeatable performance; process designedRepeatable performance; process designed by experts, but technicians can perform itby experts, but technicians can perform it  Recognizing and discriminating betweenRecognizing and discriminating between contingenciescontingencies  Production process can be mechanized andProduction process can be mechanized and monitored manuallymonitored manually
  27. 27. Eight Levels of ProcessEight Levels of Process Understanding (#7 & 8)Understanding (#7 & 8) Controlling contingenciesControlling contingencies  Process can be automatedProcess can be automated Understanding procedures andUnderstanding procedures and controlling contingenciescontrolling contingencies  Process is completelyProcess is completely understoodunderstood
  28. 28. Process Understanding -Process Understanding - InnovationInnovation  Provides a range of options for qualifyingProvides a range of options for qualifying and justifying new technologies and toand justifying new technologies and to achieveachieve real time releasereal time release  less burdensome approaches for validatingless burdensome approaches for validating new technologies for their intended usenew technologies for their intended use • in absence of process knowledge thein absence of process knowledge the test-to-testtest-to-test comparison between an on-line process analyzercomparison between an on-line process analyzer (e.g., NIR spectroscopy for content uniformity) and(e.g., NIR spectroscopy for content uniformity) and a conventional test method (e.g., a wet chemicala conventional test method (e.g., a wet chemical test) on collected samples may be the onlytest) on collected samples may be the only available optionavailable option
  29. 29. Process Understanding -Process Understanding - ValidationValidation  Can provide a high assurance of quality onCan provide a high assurance of quality on every batch and provide alternative,every batch and provide alternative, effective mechanisms to achieve validationeffective mechanisms to achieve validation  process validation can be enhanced andprocess validation can be enhanced and possibly consist of continuous qualitypossibly consist of continuous quality assurance where a process is continuallyassurance where a process is continually monitored, evaluated, and adjusted usingmonitored, evaluated, and adjusted using validated in-process measurements, tests,validated in-process measurements, tests, controls, and process endpointscontrols, and process endpoints
  30. 30. Process Understanding -Process Understanding - Justifying “Real Time Release”Justifying “Real Time Release”  Real time releaseReal time release is the ability to evaluate andis the ability to evaluate and ensure acceptable quality of in-process and/orensure acceptable quality of in-process and/or final product based on process analytical datafinal product based on process analytical data  Process understanding, control strategies, plusProcess understanding, control strategies, plus on-, in-, or at-line measurement of criticalon-, in-, or at-line measurement of critical attributes that relate to product quality canattributes that relate to product quality can provide a scientific risk-based approach to justifyprovide a scientific risk-based approach to justify howhow real timereal time quality assurance may bequality assurance may be equivalent to, or better than, laboratory-basedequivalent to, or better than, laboratory-based testing on collected samplestesting on collected samples
  31. 31. Process Understanding -Process Understanding - SpecificationsSpecifications  Ideally PAT principles and tools should beIdeally PAT principles and tools should be introduced during the development phaseintroduced during the development phase  Using PAT principles and tools duringUsing PAT principles and tools during development provides opportunities todevelopment provides opportunities to improve the mechanistic basis for establishingimprove the mechanistic basis for establishing regulatory specificationsregulatory specifications  Manufacturers are encouraged to developManufacturers are encouraged to develop and discuss approaches for establishingand discuss approaches for establishing mechanistic-based regulatory specificationsmechanistic-based regulatory specifications for their productsfor their products
  32. 32. Process Understanding - RiskProcess Understanding - Risk Based Regulatory ScrutinyBased Regulatory Scrutiny  Within a quality system and for a particularWithin a quality system and for a particular manufacturing process, an inversemanufacturing process, an inverse relationship between the level of processrelationship between the level of process understanding and the risk of producing aunderstanding and the risk of producing a poor quality product is expectedpoor quality product is expected  For processes that are well understood,For processes that are well understood, opportunities exist to develop lessopportunities exist to develop less restrictive regulatory approaches torestrictive regulatory approaches to manage changemanage change
  33. 33. Process Understanding - RiskProcess 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
  34. 34. Tools for ProcessTools for Process Understanding and ControlUnderstanding and Control  Multivariate data acquisition andMultivariate data acquisition and analysis toolsanalysis tools  Modern process analyzers or processModern process analyzers or process analytical chemistry toolsanalytical chemistry tools  Process and endpoint monitoring andProcess and endpoint monitoring and control toolscontrol tools  Continuous improvement andContinuous improvement and knowledge management toolsknowledge management tools
  35. 35. Multivariate Data Acquisition andMultivariate Data Acquisition and AnalysisAnalysis  Pharmaceutical products and processes arePharmaceutical products and processes are complex multi-factorial physical-chemical andcomplex multi-factorial physical-chemical and biological systemsbiological systems  Development knowledge base necessary toDevelopment knowledge base necessary to support and justify flexible regulatory paths forsupport and justify flexible regulatory paths for innovations in manufacturing and post-innovations in manufacturing and post- approval changesapproval changes  Opportunities need to be identified to improve theOpportunities need to be identified to improve the usefulness of available relevant product andusefulness of available relevant product and process knowledge during regulatory decisionprocess knowledge during regulatory decision making — without affecting a manufacturer'smaking — without affecting a manufacturer's development programdevelopment program
  36. 36. Knowledge BaseKnowledge Base  StructuredStructured  DOE based on statistical principles of orthogonality,DOE based on statistical principles of orthogonality, reference distribution, and randomization to identifyreference distribution, and randomization to identify and characterize formulation/process factors andand characterize formulation/process factors and interactioninteraction  Knowledge baseKnowledge base  Using DOE as the foundation as an institutionalUsing DOE as the foundation as an institutional knowledge base grows in coverage (range ofknowledge base grows in coverage (range of variables and scenarios) and data density, it can bevariables and scenarios) and data density, it can be mined to determine useful patterns for futuremined to determine useful patterns for future development projectsdevelopment projects  Focus on knowledge and not dataFocus on knowledge and not data  applicability and reliability of knowledge e.g., in theapplicability and reliability of knowledge e.g., in the form of mathematical relationships and models canform of mathematical relationships and models can be assessedbe assessed by statistical evaluation of modelby statistical evaluation of model predictionspredictions
  37. 37. Process Analyzers or ProcessProcess Analyzers or Process Analytical Chemistry ToolsAnalytical Chemistry Tools  Available tools have evolved from those thatAvailable tools have evolved from those that take simple process measurements, such as pH,take simple process measurements, such as pH, temperature, and pressure, to those thattemperature, and pressure, to those that measure chemical composition and physicalmeasure chemical composition and physical attributesattributes  Many recent innovations make real-time controlMany recent innovations make real-time control and quality assurance feasible duringand quality assurance feasible during manufacturingmanufacturing  ChemometricsChemometrics  Process signaturesProcess signatures  Correlations - causal linksCorrelations - causal links
  38. 38. Application of ProcessApplication of Process AnalyzersAnalyzers  Design and construction of the processDesign and construction of the process equipment, the analyzer, and their interfaceequipment, the analyzer, and their interface are critical to ensuring that collected data areare critical to ensuring that collected data are relevant and representative of process andrelevant and representative of process and product attributesproduct attributes  A review of current practice standards (e.g.,A review of current practice standards (e.g., ASTM) for process analyzers in otherASTM) for process analyzers in other industries can provide useful information andindustries can provide useful information and facilitate discussions with the Agencyfacilitate discussions with the Agency
  39. 39. Process Monitoring, Control, andProcess Monitoring, Control, and End PointsEnd Points  Design a process withDesign a process with  measurement system to allow real time or near-real timemeasurement system to allow real time or near-real time monitoring of all critical attributesmonitoring of all critical attributes  process controls that provide adjustments (based non feed-process controls that provide adjustments (based non feed- forward or feed-back information) to ensure control of all criticalforward or feed-back information) to ensure control of all critical attributesattributes  A processA process endpointendpoint need not be a fixed time, but can be theneed not be a fixed time, but can be the achievement of the desired material attributesachievement of the desired material attributes  Design strategies should accommodateDesign strategies should accommodate  the attributes of input materialsthe attributes of input materials  the ability and reliability of process analyzers to measure criticalthe ability and reliability of process analyzers to measure critical attributes, andattributes, and  the achievement of pre-established process endpoints to ensurethe achievement of pre-established process endpoints to ensure consistent quality of the output materials and the final product.consistent quality of the output materials and the final product.
  40. 40. 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 purpose 2. Applying a common process, and 3. Sharing a common destiny Quality ofQuality of RelationshipRelationship Quality ofQuality of ThinkingThinking Quality ofQuality of ActionAction Quality ofQuality of ResultsResults
  41. 41. Organizational EngineeringOrganizational Engineering “Conservators” “Performers”“Changers” “Perfectors” Steering Committee Review-Inspection Team
  42. 42. Examples of “Strengths”Examples of “Strengths”  Steering CommitteeSteering Committee  ideally suited to situations thatideally suited to situations that require people who arerequire people who are responsive to new andresponsive to new and creative solutionscreative solutions  able to generate a continuingable to generate a continuing stream of new, sometimesstream of new, sometimes unorthodox ideasunorthodox ideas  may wander a bit under amay wander a bit under a relatively constant stream ofrelatively constant stream of new ideasnew ideas  tends to resolve issues bytends to resolve issues by using analysis, assessmentusing analysis, assessment and planningand planning  Review-Inspection TeamReview-Inspection Team  Capable of handling complexCapable of handling complex situations that require carefulsituations that require careful assessment and preciseassessment and precise execution.execution.  The group is unlikely to missThe group is unlikely to miss anything of significance inanything of significance in their reviewtheir review  When given detailed andWhen given detailed and exhaustive operationalexhaustive operational specification, the team willspecification, the team will probably produce highlyprobably produce highly reliable results of consistentreliable results of consistent qualityquality
  43. 43. Progress?Progress?  PAT now a part for the 21PAT now a part for the 21stst Century Initiative andCentury Initiative and FDA’s Strategic PlanFDA’s Strategic Plan  ASTM Committee E55: PharmaceuticalASTM 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 aCRADA with Pfizer on Chemical Imaging as a PAT toolPAT tool  Academic and industry champions world wide –Academic and industry champions world wide – to ensure steady progress towards the desiredto ensure steady progress towards the desired statestate  Communication and cooperation with otherCommunication and cooperation with other regulatory agenciesregulatory agencies
  44. 44. Next StepsNext Steps  Final GuidanceFinal Guidance  Discussions to expand the scope of the guidance toDiscussions to expand the scope of the guidance to include CBER and CDER/OPS’s Office of Biotechnologyinclude CBER and CDER/OPS’s Office of Biotechnology ProductsProducts  April 13, 2004 Advisory Committee for Pharmaceutical ScienceApril 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 onNew and improved training program with sufficient focus on BiotechBiotech  22ndnd team and its trainingteam and its training  PATRIOT a model for Product Specialist on InspectionPATRIOT a model for Product Specialist on Inspection program in CDER?program in CDER?
  45. 45. 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 willThis afternoon Jon Clark and Ken Morris will discuss this furtherdiscuss this further
  46. 46. What do we wish to accomplishWhat do we wish to accomplish with ICH Q8with ICH Q8  Ensure Q8 facilitates movement towards the “desiredEnsure Q8 facilitates movement towards the “desired state” we have articulatedstate” we have articulated  This willThis will  Help us better understand the proposedHelp us better understand the proposed product and processproduct and process designdesign and its relation to the intended useand its relation to the intended use • improve process of establishing regulatory specificationsimprove process of establishing regulatory specifications  Improve our ability to identify and understandImprove our ability to identify and understand critical product andcritical product and process factorsprocess factors • improve our understanding and confidence in risk mitigationimprove our understanding and confidence in risk mitigation strategiesstrategies  Allow us to utilize risk based approaches and recognize goodAllow us to utilize risk based approaches and recognize good science and facilitate continuous improvementscience 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
  47. 47. CTD-P2 Sec. QbD and RiskCTD-P2 Sec. QbD and Risk Drug Substance or API Intended Use Route of administration Patient population ….. Product Design Design Specifications (Customer requirements) P2.1 and 2.6 P2.2, 2.4, 2.5, 2.6 Drug Product Container Closure System Microbiological Attributes Compatibility (e.g., recon) Manufacturing Process Components of drug product P2.3 Manufacturing 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.
  48. 48. ““Learning Before Doing” aLearning Before Doing” a prerequisite to “Building Quality In”prerequisite to “Building Quality In”  Identify and develop most promising NME’sIdentify and develop most promising NME’s  Accurate prediction of clinical performance using prior informationAccurate prediction of clinical performance using prior information and pre-clinical dataand pre-clinical data  Drug Delivery system attributes optimized for therapeuticDrug Delivery system attributes optimized for therapeutic objectives and manufacturing processes designed to ensureobjectives and manufacturing processes designed to ensure consistent drug delivery objectivesconsistent drug delivery objectives  Clinical trials designed using all available knowledge to documentClinical trials designed using all available knowledge to document clear safety and efficacy profile in the target or intended patientclear safety and efficacy profile in the target or intended patient populationpopulation  How can we (FDA) help?How can we (FDA) help?  Ask theAsk the “right”“right” questionquestion and insist on theand insist on the “right” answer“right” answer
  49. 49. Systems Approach: Integration acrossSystems Approach: Integration across disciplines, organization, and over timedisciplines, organization, and over time Appropriate labeling and risk managementAppropriate 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 InBuilding Quality In ? ? ? Safety & Efficacy ?
  50. 50. Product and Process QualityProduct and Process Quality KnowledgeKnowledge:: Science-Risk Based cGMP’sScience-Risk Based cGMP’s Quality by Design Process Design Yes, Limited to the Experimental Design Space Maybe, Difficult to Assess GMP/CMC FOCUS Design qualification Focused; Critical Process Control Points (PAT) Extensive; Every Step (CURRENT)DATA DERIVED FROM TRIAL-N-ERROR EXPERIMENTATION DECISIONS BASED ON UNIVARIATE APPROACH CAUSAL LINKS PREDICT PERFORMANCE MECHANISTIC UNDERSTANDING 1st Principles
  51. 51. ““I Can See Clearly Now”:I Can See Clearly Now”: Targeting for MaximumTargeting for Maximum ProtectionProtection “amoral” “incompetent” “political citizen” “Good Citizens” Kagan and Scholz. Perspectives on Regulation: Law, Discretion, and Bureaucratic behavior, May 1980. Science is the only fair and transparent means to recognize FDA Focus on High Risk Low Risk

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