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1、Managing Pharmaceutical Quality: Risk or Uncertainty Management? Ajaz S. Hussain, Ph.D.Office of Pharmaceutical ScienceCDER, FDAPQRI Workshop February 1, 2005What is Quality?lWhat is pharmaceutical quality?lconsistent delivery of the label performance and lack of contamination.loperationalzed via a
2、set of pre-specified quality attributes (e.g., specifications, limits) and through the CGMP regulations.lFDA, in its quality definition, is standing in for the customerand it is apparent that health care practitioners and patients highly value an additional drug attribute: product availabilitylGood
3、pharmaceutical quality represents an acceptably low risk of failing to achieve the desired clinical attributes.Management GoalslImproving quality and ensuring availabilitylOptimal use of our resourceslA systems approach to CMC review and CGMP investigationslBased on knowledge and process understandi
4、nglAchieving “quality by design”lDemonstrating “science of design”lContinuous learning and improvement through “manufacturing science”An Approach for Quality Risk ConnectionlConcept of Quality by Design (QbD)lProduct and process performance characteristics are scientifically designed to meet specifi
5、c objectives, not merely empirically derived from performance of test batcheslCharacteristics important to desired performance must be derived from a combination of prior knowledge and experimental assessment during product development. lFrom this knowledge and data, a multivariate model linking pro
6、duct and process measurements and desired attributes may be constructed.lClinical study would then be viewed as confirmatory performance testing of the model.Woodcock, 2004A Systems ApproachScience of DesignManufacturing ScienceDeliverQuality by DesignState of Control &Continuous ImprovementQuality
7、can not be tested into a product; it has to be by design“Market Standards”Science of Design + Manufacturing Science = Quality by Design Risk/Benefit and QualityHarmAcceptableRisk/BenefitQualityLabelNo benefit (placebo effect)Managing Pharmaceutical QualitylQuality of a new molecular entity (a potent
8、ial drug)lIntrinsic pharmacological & toxicological attributeslIdentitylComplexitylA range of uncertainty with respect to identity of “active moiety”, purity and stability of materials used in evaluation of pharmacological and toxicological attributes (if a mixture; variability adds additional uncer
9、tainty)lVariability in the extent and rate of delivery of “active moiety” to the sites of action and variability in the pharmacological & toxicological response and measurement systems further adds uncertaintyManaging Pharmaceutical QualitylQuality of a drug productlFor establishing proposed therape
10、utic claim (label)lDrug product manufactured for clinical trials lAfter successful demonstration of therapeutic claim (acceptable risk-to-benefit ratio)lDrug product manufactured for commercial distribution lLife cycle of the product (shelf-life, exclusivity period, generic competition, post-approva
11、l changes,)lDrug product manufactured at many different facilities, changes in the process, different manufactures, Uncertainty, Variability and RisklQuality Clinical ConnectionlHow does a product formulation and its manufacturing process impact clinical performance?lWithout a clear understanding we
12、 are uncertain (lack of knowledge)lIn decision making there are many advantages in distinguishing between uncertainty, variability (random variation) and riskGoals and Characteristics of a Quality Decision System: Example Goal: expected to have the same clinical effect and safety profile when admini
13、stered to patients under the conditions specified in the labelingCharacteristicsUncertaintyVariabilityRiskPharmaceutical EquivalentSame active, identical amount, same dosage form, and route of administration.Identity, StrengthQuality, Purity.Compendial or other standardsPrior Knowledge (NDA)Post App
14、roval:Monitoring programSuch as MedWatchConsumer ComplaintsTherapeutic Inequivalence Coordinating CommitteeNeed for Bioequivalence AssessmentDo not present a known or potential bioequivalence problem. Acceptable in vitro standardCompendial Dissolution test methodPresent a known or potential bio -pro
15、blem. Appropriate bioequivalence standard90% Confidence Interval of Test/Ref ratio for rate and extent of absorption in 80 -125% rangeAdequately LabeledSimilarity with reference label, medication errors.,Certain differences due to changes in the manufacturer, distributor, pending exclusivity issues,
16、 or other characteristicsManufactured in conformance to CGMPsProcess Validation and Quality SystemDeviations, Out of Specifications,.ANDA Applications: Limited Information Content (e.g., IR Capsule)lGenerally 1bio-batchlBioequivalence goal post 80-125%l90 % Confidence Interval for the Test/Reference
17、 ratio for Cmax and AUC in between the goal postlNormal healthy subjects, cross-over design, fasting (and fed) conditionslCommon for all oral drugs i.e., procrusteanlTo cover “worst case” scenarioslIf mean is 100% and 90% CI is outside 80- 125 say 85 - 126.5?lExecuted batch record and master batch r
18、ecord (e.g., 10X) application commitmentlPost-approval process validation and stability commitmentlPost approval changes based on SUPAC-IRDemonstration of “quality by design”?lAnalytical data + Executed batch record + bio-study + process validationlIQ, OQ, PQ,.lPQ = 3 consecutive batches in conforma
19、ncelReduced testing e.g., compendial testslFor simple, conventional product designs works fine most of the time; quality by design is then the prior knowledge and what ever development data is generated (held at site)Uncertainty, Variability and RiskUncertainty?Variability?Risk?Uncertainty, Variabil
20、ity and RisklProcrustean standards have to address “worst case” scenarioslUncertainty is not risk, currently we have no choice but to force this equalitylUncertainty is reduced by improving knowledgelWe learn what to control and the degree of control necessary to minimize risklFor continuous quality
21、 improvement we should focus on improving uncertainty management process Example of a CMC Regulatory Decision: Acceptability of a Post Approval Manufacturing Process ChangelOriginal NDA or ANDA = CMC Quality & Performance (“Insurance”) ContractlFor example in ANDAs Regulatory commitments = Condition
22、s in executed batch recordslPrior Approval Supplement* (PAS) lProduct conforms with all established specificationslBut - “Specifications do not tell the whole story”lE.g., Shelf-life and/or bioavailability may have changed and/or a new impurity may be introduced that may not be detected with establi
23、shed analytical methods,sponsor may not adequately qualify changes (inspection frequency may not be sufficient),.*prior approval supplement for process optimization and continuous improvement effortsCompany X “Goes Lean”l“Cycle-time reduction subgroup members, for example, examine each process funct
24、ion, for example, dispensing, roller compaction and compression, to determine how to speed up changeover and get equipment to run faster and more efficiently.” l“The team solicits ideas at regular meetings and via email. The ideas are then rated from 1 to 10 based on bang for the buck to reduce cycl
25、e time, and on how difficult they would be to achieve-e.g., whether they will require validation or prior FDA approval.” PharmaM Post Approval Process Change (SUPAC Guidance)“Within”(ChangeTarget setting)“Outside”Current Uncertainty ManagementlAt the operational level the most efficient approach for
26、 managing uncertainty is “demand management” lStrict “checking the box” process using pre-specified requirements (recommendations) and procrustean standardslFDA guidance documents, 483 observations,.l90% CI 80-125%, in-process blend uniformity tests, . SOPs,.Current Demand Management: Characteristic
27、slFor conventional products and manufacturing processes - easy to implement, supervise, and mangelDecision responsibility is deferred to a set of “procrustean” standards - liability distributed to the entire pharmaceutical community (e.g., via USP, AAPS, etc.)lFor innovative and/or complex products
28、and processes no one is willing to take responsibility for decisions (e.g., develop guidance document) decision liability is then on the person willing to take a decision. Current Demand Management: CharacteristicslInnovation and continuous improvement slows down and inefficiency increaseslThe level
29、 of quality assurance achieved is difficult to measure and is buried in historical mindset and clinical variability lWith increasing complexity a major failure is necessary to signal inadequacies of the system such a failure is often the only approach to introduce new regulations or improved decisio
30、n criteria lChallenge to and alternate approaches to current procrustean standards difficult to prove and debates drain resourcesWithout Continuous (Community) Learning: Demand Management is “static” until a crisis is created, it then reacts to replace a current procrustean standard with another. Co
31、ntinuous Improvement: Enhancing Customer Satisfaction - Reducing Variability“Special Cause” or “Common Cause”Stable- Yes; Capable?UnstableCorrective ActionsEliminate “Special Cause”Reduce “Common Cause”VariabilityFrequent,MajorOOSMinor,OccasionalOOSStable & CapableOn the Continuous Improvement PathS
32、tate of ControlImproving Uncertainty ManagementlDemand managementlSpecified and procrustean standardslE.g., 90% CI 80-125%, in-process blend uniformity tests, . SOPs,.OpportunitieslPAT GuidancelPAT provides the pharmaceutical context for Lean, Six Sigma!lCPG 7132c.08lComparability ProtocollQuality S
33、ystems Approach to Pharmaceutical CGMPs lICH Q8, (9?), (10?)PAT GuidancelOpens the door to realize the benefits of connecting lFisher to- Shewart to- DeminglFocus on process understanding leading to control of process end-point!lResearch dataCTD-P2 Sec. QbDDrug Substanceor APIIntended UseRoute of ad
34、ministrationPatient population.Product DesignDesign Specifications(Customer requirements)P2.1 and 2.6P2.2, 2.4, 2.5, 2.6Drug ProductContainer Closure SystemMicrobiological AttributesCompatibility (e.g., recon)Manufacturing ProcessComponents of drug productP2.3Manufacturing Process Development“Design
35、 Space” = f (Intended Use * Design * Control)Quality SystemQuality SystemRisk ClassificationProcess Design & ControlSpecificationsProduct DesignIntended UseDesign RequirementsReliabilityTo DeliverDesignRequirementsAssessmentBased on ICH Q8Information/KnowledgeKnowledge Based Decisions: Require Scien
36、tific Generalizeable Knowledge the “SUPAC GAP”SUPAC Change Levels based onprior knowledge from the pharmaceutical community (AAPS SUPACWorkshops) + Research; Yet difficult to generalize because of multi factorial aspects + lot of subjectivityLimited information in NDA/ANDAPrior knowledge within a co
37、mpanyand a move towards mechanistic Understanding(ICH Q8 is intended to fill this gap)Gap = UncertaintyUncertainty Management: QbD & FlexibilityTime Scale & Mode of ResponseUncertainty ManagementSystem ModificationQbD FlexibilityOperationalRoot cause investigation, Efficiency, etc. Learning to R&DCo
38、ntrol of excipients and other sources of “common cause” variabilityReduce CGMP Risk Classification Continuous Improvement of Quality SystemTacticalOn-line controlDesign for Manufacturability Critical Control Points -Robust process end-pointRegulatory Specifications“Design Space”Real Time Release, Mo
39、dular ValidationReg. CMC ApprovalStrategicScience of Design Design to reduce “Uncertainty”Sci. & Tech. Integration Continuous Learning & ImprovementRegulatory CommunicationIntegrate Sci - Enabling Technology Platform “Plug & Play”“Time to Market” + “Production Efficiency” Science of DesignlOften des
40、ign and development activities are carried out based on experiential knowledge, intuition and rough guidelines difficult to communicate to individuals from different backgrounds (the “art” argument)lTo learn how to represent designs at a much higher level than the current descriptive “recipe” format
41、 (e.g., executed batch records, SOPs) while rigorously documenting key constrainsA Validated SystemlWe have begun updating our current thinking on validation lProcess Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval (CPG 7132c.08, Sec 490
42、.100). lRational experimental design and ongoing evaluation of data lAchieving and maintaining a state of control for a process begins at the process development phase and continues throughout the commercial phase of a products life-cyclelRisk-based approaches - inspectional scrutiny; use of advance
43、d technologies, and the role of conformance batches in the product life-cycle. lA focus on three full-scale production batches would fail to recognize the complete story on validation. Draft Guidance for IndustryQuality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulatio
44、ns Engineering a Quality System“Change Control” to “Continuous Improvement”PAT - ICH Q8“Design Space”Innovation& ContinuousImprovementOptionsManaged underThe CompanysQuality System;Subject toCGMP Inspections(no-change or variation)By Improving Uncertainty Management we have began a process of engine
45、ering a proactive decisions system for pharmaceutical qualitylReactive (examples)lTesting to document qualitylRepeating deviation and out of specification investigationslWaiting for FDA guidance to submit ANDA demonstrating therapeutic equivalence of generic productslPotential for multiple NDA CMC r
46、eview cycles lWaiting for FDA to approve a prior approval supplement for process optimization and continuous improvement effortslFear, apprehension lProactive (examples)lQuality by design and real time process controls to achieve real time release”lRight First TimelInnovative approaches for demonstrating therapeutic equivalence of genericslSingle NDA CMC review cyclelProcess optimization and continuous improvement efforts within a facilities quality systemlAbility to utilize prior knowledgelEmpowerment, recognition