上海CMC培训EnsuringDrugQualityforPublicHealthTheImplementation课件

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1、Ensuring Drug Quality for Public Health The ImplementationBrenda Uratani,Ph.D.Assistant Country DirectorFDA China Office,Beijing1上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationOverviewChallenges to Globalization of Drug Manufacturing FDAs Work in ChinaGMP Principles:Issues of the

2、most concern2上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationChallengesSignificant demand in resources for inspectionsConsequences of globalization,including more foreign manufacturing and clinical trials sitesGreater complexity associated with manufacturingFDA concern about the st

3、ate of industry compliance and insufficient investment in manufacturing and quality systems3上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationFDA International Efforts4上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationFDA Overseas EffortsLong-Term GoalProducts coming

4、to the U.S.meet U.S.requirements.Strengthened Regulatory CounterpartsIndustry Responsibility:Supply Chain Management at Point of Manufacture,Point of Export,and When Presented for Importation5上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationFDA Overseas Presence Current LocationsChi

5、naIndiaLatin America EuropeMiddle East(2010)6上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationFDAs Work in China7上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationFDA China OfficeIn-Country StaffBeijingChris Hickey,Office DirectorMike Kravchuk,Deputy(device)Brenda Ur

6、atani(drug)Irene Chan(food)ShanghaiCharles Ahn(drug inspection)BJ Marciante(device inspection)GuangzhouDennis Doupnik(food inspection)Dennis Hudson(food inspection)8上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationFDA/SFDA Agreement:Key ProvisionsKey Provisions:Registration of desig

7、nated drugs and devicesJoint Training/Capacity BuildingGreater/More Rapid Information SharingGreater Access to FacilitiesProduct Integrity/Anti-counterfeitingStrengthened FDA,SFDA Collaboration Under Multilateral Auspices9上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationDrugs in Chi

8、na:What Has FDA Done?FDA-SFDA CollaborationInspectionsEngagement of IndustryCapacity-Building10上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationWhat Is China Doing?Updating Standards,MethodsRevision of China CGMPWorking to Improve Drug Adverse Event ReportingTraining Elite Group of

9、Inspectors Re:International StandardsAttempting to Strengthen Drug Application Review ProcessTaking More Active Role in International Standard-SettingShifting Focus to Conduct More Pre-Approval InspectionsUtilizing Tools to Detect Counterfeiting Supply Chain:Developing Tools and Standards for Tracki

10、ng/Tracing11上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationChinas Role in Drug Development:Challenges for ChinaNeed for Regulatory ReformUniformity of implementation of CGMP across all provincesRegulatory Authorities Working to Strengthen Capacity,Authority,Streamline Reporting St

11、ructuresCounterfeits Economically-Motivated Adulteration“Show”and Shadow FactoriesSupply Chain IntegrityBulk ChemicalsExcipient QualityRaw Material Processing Where There is no OversightAdverse Drug Reaction ReportingDifferent Standards for Domestic,Exported ProductsData IntegrityProcess Inspects Fi

12、rms Generally,Not Capacity to Produce Specific Products12上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationCGMP Requirements&PrinciplesIssues of Most Concern13上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationCGMPC”=currentdynamic and evolve over time“GMP”=Good Manufa

13、cturing PracticesMinimal standardsNot“best”practices unless“best”is,in fact,current minimal.14上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationPotential Problems from Non-Compliance with CGMPSuper-potency or SubpotencyImpuritiesContaminationSafety and Efficacy effects15上海CMC培训 Ensur

14、ing Drug Quality for Public Health The ImplementationSome Issues of most concernDay-to-day implementation of CGMP Understanding the product and the processCant“test”quality into the productQuality system managementMaterial managementEquipment qualification and useSupply chain management16上海CMC培训 Ens

15、uring Drug Quality for Public Health The ImplementationDay-to-day Implementation of CGMPEliminate variabilityAchieving Process Consistency is of utmost importance to ensure quality of each batch17上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationProcess UnderstandingInadequate Develo

16、pment WorkReaction parameters are often too wide and not supported by development workEither extremity of an executed range of parameters is often selected as optimal conditionGaps in knowledge management in progressing from one stage to another stageLack of formalized structure for process developm

17、ent18上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationQuality System19上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationFundamental Quality Management PrinciplesStrong commitment to drug quality and patient safety Strong“believer”in the value of CGMPUnderstand the im

18、portance and impact of quality management,control,and implementation20上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationFirms should not work only to pass an FDA inspectionFirm should operate the facility under quality system21上海CMC培训 Ensuring Drug Quality for Public Health The Imple

19、mentationPharmaceutical Quality SystemThe Quality System is the foundation for the drug manufacturing systemsQuality system model integrates manufacturing systems22上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationQuality SystemCritical Commitment from Top ManagementUnderstand&recogn

20、ize the value of quality systemStrong commitment on producing safe and effective product-decision to release or reject of batch justified by data and science(responsibility of QA)Clear communication and promotion from top management on importance of quality to all employees and units of operationImp

21、lementation and enforcement on quality system23上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationPharmaceutical Quality System Lifecycle Approach Process performance and product quality monitoring system;Corrective action and preventive action(CAPA)system;Change management system;Man

22、agement review of process performance and product quality.24上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationLifecycle ApproachValidation,maintenance,and continuous improvement of product quality5%pre-approval95%Post-approval25上海CMC培训 Ensuring Drug Quality for Public Health The Impl

23、ementationFormal Formal ExperimentalExperimentalDesign Design(DOE)(DOE)Conformance/Validation StudiesPost-ApprovalProposeProduct Life CycleEvaluationIdentifyIdentify(Critical/Key(Critical/Key Attributes/Attributes/Parameters)Parameters)Confirm(Control/Predict)(Control/Predict)MonitorMonitor(CAPACAPA

24、ContinuousContinuousImprovementImprovementInnovation)Innovation)RiskRisk Assessment/Assessment/MitigationMitigationComparabilityComparabilityProtocolProtocolRiskRisk Assessment/Assessment/MitigationMitigationCGMPCGMPAdherenceAdherencePATPATPATPAT26上海CMC培训 Ensuring Drug Quality for Public Health The

25、ImplementationQuality System ICH Q10 Concepts3.1.3 Commercial Manufacturing“The pharmaceutical quality system should assure that the desired product quality is routinely met,suitable process performance is achieved,the set of controls are appropriate,improvement opportunities are identified and eval

26、uated,and the body of knowledge is continually expanded”27上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationQuality SystemDeviations&investigationsChange controlTrainingAudit/reviewAnnual product reviewContract agreementDocument control28上海CMC培训 Ensuring Drug Quality for Public Healt

27、h The ImplementationInvestigation&DeviationsAdd Value&Impact QualityLearn from mistakesPrevent recurrences:corrective action&preventive action(CAPA)Build knowledge:variability reduction,continuous improvement in product quality29上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationWhat

28、is Change Control?Changes are managed by the firm:Evaluates everyday changes to the manufacturing facility,equipment,personnel,improvements,and minor adjustments to the process.All changes must always be done with a written protocol under the change control system including approval by QAHave proced

29、ures in place for the execution of the change in an orderly mannerEvaluate the impact of the change Document the change and resultsAdequacy of changes are evaluated by FDA during inspection30上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationTrainingQualified employee to perform the a

30、ssigned task Strict implementation of the established proceduresSupervision Periodic re-evaluationContinuing education in training31上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationAudit/Review Annual Product ReviewRegular trending reviews and evaluation of process and product Evalu

31、ation of stability,recalls,OOS,product complaints,returnsRisk assessment,mitigation before occurrence of serious consequencesEnsure operation is maintained in an ongoing state of controlKnowledge gained for continuous improvement in product life cycle32上海CMC培训 Ensuring Drug Quality for Public Health

32、 The ImplementationContract AgreementClear contractual agreements on:Responsibilities of each partyEffective communication on all issues that potentially impact drug qualityAdequate qualification,auditing and regular periodic evaluations of contractorsNotification to FDA for changes in contractors33

33、上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationDocument ControlsA most critical element to support acceptability of a production batch and GMP complianceNot just a bureaucratic exercise to satisfy FDA REQUIRE ORIGINAL RECORDS as the task(operation)is being performed,not a re-copyi

34、ng of the original.Data must not be alteredProduction:batch recordsQC:testing recordsViolations:Serious Consequences 34上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationDocumentation All SOP(especially production batch record)should be in sufficient detail for the operator to carry o

35、ut the task in a consistent mannerChanges in SOP must be reviewed and approved by QA35上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationMaterial Management36上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationMaterial ControlsRaw materialsIntermediatesComponentsAPIManuf

36、acturing materialse.g.,sterilizing filtersFacility materialse.g.,HEPA filters37上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationICH Q7A:Materials ManagementManufacturers of intermediates and/or API should have a system for evaluating the suppliers of critical materialMaterials shoul

37、d be purchased against an agreed specification,from a suppliers,approved by the quality unit(s)If the supplier of a critical material is not the manufacturer of that material,the name and address of that manufacturer should be known by the intermediate and/or API manufacturer.Changing the source of

38、supply of critical raw materials should be treated according to Section 13,Change Control.38上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationEquipment Management39上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationQualification of EquipmentIssues especially pertain to

39、:Adequate IQ,OQ,PQ Instruction and training of operation for use of equipmentEstablish regular maintenance,calibration and maintain documentation of these activities40上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationSupply Chain Management41上海CMC培训 Ensuring Drug Quality for Public H

40、ealth The ImplementationSupply Chain ManagementIdentify critical control points(areas)and implement adequate controls to ensure integrity of the supply of raw materials,component,excipients,API,drug product through procurement,manufacturing and distribution.Tamper resistantSerializationtesting42上海CM

41、C培训 Ensuring Drug Quality for Public Health The ImplementationRegulatory Actions for non-GMP compliant firmsWarning LettersWithholding ApprovalImport Detentions and AlertsSeizuresInjunctionsProsecutionsIMPACT:Product NOT suitable for use.43上海CMC培训 Ensuring Drug Quality for Public Health The ImplementationThank YouBrenda UrataniBrenda.44上海CMC培训 Ensuring Drug Quality for Public Health The Implementation