cGMP培训.ppt

SimonRusminMarch17and18,2006SIX SYSTEM APPROACH TO GMP IN MANUFACTURINGOF SOLID DOSAGE FORM固体制剂的六大体系Presented bysFDA&Alliance Pharmon浙江省药监局&美国洲际药业17,18 March 2006Hangzhou,ChinaSpeakerSimon Rusmin,Ph.D.SimonRusminMarch17and18,2006SEMINARCONTENTS研讨会内容QualitySystemApproachtoGMPMicrobesinnon-sterilemanufacturingValidationPrinciplesandPracticesPreparingforregulatoryinspectionSimonRusminMarch17and18,2006QUALITYSYSTEMAPPROACHTOGMPGMP的质量系统SimonRusminMarch17and18,2006nThe FDA experts studied all quality systems includingthose of non-pharmaceutical.nFDA认证专家研究了所有的包括非制药的质量系统认证专家研究了所有的包括非制药的质量系统nIn August 2002 the USA-FDA initiatedscience-based&risk-base quality systemapproach to CGMP.n2002年八月，美国年八月，美国FDA成立了以科学和风险为基础的成立了以科学和风险为基础的CGMP质量系统质量系统nTo be in compliance with USA CGMP&EU GMP,we need to understand the approaches&to know how to implement them.n为了达到美国为了达到美国CGMP&欧盟欧盟GMP要求，我们需要知道方法及如何执行要求，我们需要知道方法及如何执行。nFirst we need to understand the concept and science of QUALITY and the present day QUALITY SYSTEMS.n首先我们需要了解质量理念和知识及现行的质量系统首先我们需要了解质量理念和知识及现行的质量系统1.1WhyQualitySystemApproach为什么使用质量系统法?SimonRusminMarch17and18,2006nUnlike adult wild animals,human beings need products(goods and services)provided by others.不同于成年的野生动物，人类需要由别人提供的产品（不同于成年的野生动物，人类需要由别人提供的产品（物品和服务）物品和服务）nQUALITY is the characteristicsof Goods and Services that the users LIKE.质量是使用者对物品和服务喜欢的特征质量是使用者对物品和服务喜欢的特征nIn the science of manufacturingQuality is documented as measurable SPEFICIATIONSn生产质量知识已被当作可测量的规格写成了文件生产质量知识已被当作可测量的规格写成了文件1.2WhatisQuality什么是质量?SimonRusminMarch17and18,20061.3HistoryofQuality质量的历史1850snBefore the INDUSTRIAL REVOLUTION在工业革命在工业革命以前以前nProduct is UNIQUE(one of a kind).n产品是唯一的（一种一个）产品是唯一的（一种一个）nPersonal skills&pridemake QUALITYn人类的技能和自尊心造就了质量人类的技能和自尊心造就了质量nHigh variability.可变化性高可变化性高nAfter工业革命后工业革命后 nProduct is UNIFORMn产品是统一的产品是统一的nScientific controlsmake QUALITYn科学控制造就了质量科学控制造就了质量nLow variability 可变化性低可变化性低SimonRusminMarch17and18,20061.4StatisticalQualityControl统计质量控制1920snNature is inherently non-UNIFORM.Its variability is of Normally Distribution.n本质上不再统一，其可变性有了正态分布本质上不再统一，其可变性有了正态分布nIn 1920s Schewart pioneered the science of statistical quality controls:n在二十年代，休哈特倡导了统计质量控制在二十年代，休哈特倡导了统计质量控制nStatistical Sampling统计抽样统计抽样nStatistical Process control统计工艺控制统计工艺控制nProcess Capability加工能力加工能力nDesign of Experiment实验设计实验设计World War II 二次世界大战二次世界大战(1945)-the PEAK of Industrial Revolution,and the subsequent flood of consumer goods afterward.工业革命的鼎盛时期，出现了后来的生活工业革命的鼎盛时期，出现了后来的生活消费品潮消费品潮SimonRusminMarch17and18,20061.5TheRaceofQuality质量的赛跑1970snAfter WWII,Deming taught Japanese industry methodsand techniques of qualitymanagement&improvement.n第二次世界大战后，戴明教给了日本人工业方法和质量管理第二次世界大战后，戴明教给了日本人工业方法和质量管理n及改进方法及改进方法nJapan perfected quality into Total Quality Management日本把质量完善为总的质量管理日本把质量完善为总的质量管理:nTop management commits to qualityn主管管理质量主管管理质量nEveryone participate in qualityn人人参与质量人人参与质量nProcesses are continuously improvedn工艺不断改进工艺不断改进nIn 1976 the USA-FDA issued Good Manufacturing Practices.n1976年美国年美国FDA发布了质量生产规范发布了质量生产规范GMPSimonRusminMarch17and18,2006nIn the 1980s the USA industry learned the Japanese ways of manufacturing and caught up in quality.n在八十年代，美国工业学习了日本的生产方式并且引发了质量在八十年代，美国工业学习了日本的生产方式并且引发了质量nMotorola&General Electric initiatedthe Six-Sigma Manufacturingquality system,followedby Lean-Manufacturing.摩托罗拉及通用电气根据精益生产，发起了六西格码质量系统摩托罗拉及通用电气根据精益生产，发起了六西格码质量系统Six sigma六西格码六西格码=defect of 3/106 3/106的缺陷的缺陷Lean精益精益=highest value at lowest cost 以最小的成本得到最大的价值以最小的成本得到最大的价值Current quality system concepts are the baseof FDAs Quality System Approach to CGMP.当前的质量系统理念是FDA的CGMP质量系统的基础1.6Qualityinthe21thCentury21世纪的质量SimonRusminMarch17and18,2006 QUALITY IS 质量是质量是n What the CustomersLike 消费者喜欢什么消费者喜欢什么n measured by Specificationsn根据规格进行测量根据规格进行测量n got by Reducing Variability of manufacturing通过减少生产可变通过减少生产可变性得到性得到1.6a QUICK SUMMARY快速总结SimonRusminMarch17and18,20061.7WhatisaProcess什么是过程?Changinglow-valueINPUTintohigh-valueOUTPUT把低价值的输入变成高价值的输出SimonRusminMarch17and18,20061.8KnowledgeisPower知识就是力量ProcessKnowledgeisthepowertocontroltheprocess工艺知识是控制过程的力量AlvinToffler托夫勒TheTHIRDWAVE第三次浪潮-1980SimonRusminMarch17and18,20061.9ProcessThreeFactors过程的三个因素FactorscontributetoProcessvariability影响过程可变性的因素SimonRusminMarch17and18,20061.10TheBusinessProcessFlow商业的工艺流程Businessisachangeofprocessestheoutputofoneprocessistheinputofthenextprocess商业是过程的变更一个过程的输出是下一个过程的输入SimonRusminMarch17and18,2006qProductDevelopmentleadstoManufacturingAuthorization(NDA,ANDA,DMFprocess/productspecs)Facility,Utility,Equipmentmapping,qualificationandvalidation.产品的发展导致了生产核准（NDA,ANDA,DMF工艺/产品规格），设备，公共设施的系统图，确认和验证qEstablishmaintenance/calibration.建立维护/校准qProcess-mapping,Risk-analysis(FMEA,HACCP),&establishProcess-controls.q工艺描述，风险分析(FMEA,HACCP),&建立工艺控制qEstablishMaterial-testingandProcess-monitoring,In-process,intermediate,andfinishedproducttesting.Set-upTesting-laboratories.q建立材料检验和工艺监测，内控标准，中间体和成品检验，建立测试实验室qDocumentationandKnowledge-transfertooperators&managersthroughcontinuoustraining.q不断的对操作者&管理者进行文件建立及知识培训qChange-control&Problem-solving(Deviation,OOS,&conformance),andestablishCAPA.q变更控制&问题解决（偏差，超标&一致性），建立CAPAqAudit(self-inspection)&AnnualQualityReview(health-check).q审核（自我检查）&年度质量审阅（健康检查）1.11CreatingProcessKnowledge创造性的工艺知识SimonRusminMarch17and18,20061.12FDASixQualitySystemsApproachFDA的六个质量系统方法SimonRusminMarch17and18,2006 QUALITY SYSTEM 质量系统是质量系统是n is the MEANS to control process variability,n by Mapping&Analyzing the Process,andn Establishing Six Control Pointsn是通过工艺描述、分析及建立六个控制点来控制过程变化的方法是通过工艺描述、分析及建立六个控制点来控制过程变化的方法1.12a QUICK SUMMARY快速总结SimonRusminMarch17and18,20061.13DocumentPyramid文件金字塔SimonRusminMarch17and18,2006qAsaSHOWCASEtointroducethequalityoperationsofqthecompany.把企业的质量操作当作一种优势介绍qTheQUALITYPOLICYstatementisthecommitmentofthehighestmanagementtoQUALITY质量方针陈述是质量的最高管理承诺qDisplaysthesitesofmanufacturingandtheproductsmanufacturedinthesites.把生产的位置和所在位置生产的产品显示出来qDefinetheorganizationandpersonnelinvolvedinquality,andeachfunctionresponsibilities(Quality Unit(Qualified PersonofEU)isindependentofManufacturing.q定义包含在质量中的组织和人员，及每种职责（质量单位（EU有资格的人）和生产无关）qAppendedwithListofothermanuals(Manufacturing/AnalyticalLabs),SOPs,andotherdocumentsasaGATEWAYtoviewthecompletequalitysystems.q附加的有：其它手册（生产/分析实验室），SOPs，及其它可以浏览到全部质量系统的文件1.14QualityPolicy质量方针SimonRusminMarch17and18,2006qTheveryfirstSOPdescribinghowtowriteanSOPandmanageGMPdocuments.q第一份SOP描述的是如何编写SOP和管理GMP文件qFORMAT格式Softwaretouseandtemplate使用的软件和模版;Numberingsystem编号系统-Example例如:JS1013:J=co.code;S=SOP(F=form构成,L=logbook日志,T=testmethod检验方法,P=protocol方案);1=qualityassurance质量保证(2=qualitycontrollab质量控制实验室,3=manufacturing生产,4=engineering工程);013=Serialnumber序号.qCONTENTS内容Purpose目的;Scope范围;(Background背景);Responsibilities职责;Procedure规程;Appendix附录;Approval批准;Revisionhistory修订记录qPROCESS工艺Creation制造,Approval批准,Distribution分布,Change变更,Periodicreview定期审阅,Absolution无限制,Archiving存档.qCONTROL控制TheDocument ControllerfunctionsinSOPs&Records.SOPs&记录中的文件管理者作用1.15QualitySystemDocumentation质量系统文件SimonRusminMarch17and18,2006qMajorSYSTEM SOPscreatedbyQUinclude：qQU创造的主要SOPS系统包括:1Qualitysystemdocumentation(grand-fatherSOP)质量系统文件（起始SOP）1Personnel&contactors人员&承包商2Facility,utility,andequipment设施，公用设备，设备3Incomingmaterialsandsuppliers来料和供应商4,5Manufacturingandcontrols生产和控制5Distribution,complaints,&recalls分发，投诉和召回6Qualitycontrol&testinglaboratories质量控制&测试实验室Processvalidationandimprovement工艺验证和改进qCreationofINSTRUCTION SOPsarebytheusersofeachorganizationalfunctions(beginwithflowcharting).q指令是由行为组织者创造的（从流程图开始）qHandlingofRECORDSisdescribedingrand-fatherSOP.q有关记录的处理在起始中有描述1.16SOPsandRecordsSOPs和记录SimonRusminMarch17and18,2006qSOP:“ManufacturingandControlPersonnel&Responsibilities生产和控制人员&职责”,containing包括:Sufficientpersonneltodothetaskswitheducation(knowledge),skills,andexperience用足够的有文化（知识），技能及经验的人员来执行任务Clearauthoritiesandresponsibilities明确权利和职责ResponsibilitiesofQA/QP(releaseproduct),QC,&ManufacturingunitsQA/QP(产品放行），QC,&生产单位的职责qSOP:“WorkplaceAttire工作场所服装&OperatingRules操作规则”(safeguardsofproductqualityandpersonalsafety产品质量和人员安全保障)qSOP:“TrainingProgram培训计划&documentation文件”qSOP:“ConsultantsandContractedWorks顾问和签约工作”,containing包括:Selectionandqualification挑选和确认Contractagreementsonresponsibilitiesandtransactions职责和事务的合同协议EvaluatingresultsandauditingQualitySystem评估结果和质量系统审核1.17Personnel&Contractors人员&承包商SimonRusminMarch17and18,20061.17a QUICK SUMMARY快速总结 SOFTWARE软件软件&LIVEWARE 生生命件命件n Quality System(software)are rules to keep Process Variability low.质量系统（软件）是把过程变化保持到最低的准则质量系统（软件）是把过程变化保持到最低的准则n Personnel(liveware)is the operator of the Quality System.n人员（生命件）是质量系统的操作者人员（生命件）是质量系统的操作者n Rules must be good and correctly followed by people.准则必准则必须是有益的并且由人来正确执行须是有益的并且由人来正确执行SimonRusminMarch17and18,20061.18HardwarePyramid硬件金字塔SimonRusminMarch17and18,2006qSituation,Design,Construction位置，设计，建造Situatedatsuitablesurrounding,enclosedtopreventvermin放在合适的环境中，并且封起来以预防害虫等Designwithsufficientspacetopreventproductmix-up,cross-contamination,&contamination.要设计成足够的空间，以防止产品混淆，交叉污染和污染Dedicatedfacilityforpenicillin,hormones,cytotoxins对青霉素，激素，细胞毒素类要用专用设备qCEILINGsandWALLsdonotcontributedust,easytomaintainedandcleaned.FLOORsareresistanttouse,nodust/moisturecollection,drainsareeasilycleanedandsanitized.q天花板和墙壁不允许有灰尘，应容易维护和清洗，地板耐用，没有灰尘水堆积，排水装置应容易打扫和清洁qHVACprovidecleananddryairsuitableforoperationswithsufficientLIGHT.qHVAC利用充足的光，提供了适合操作的干净、干燥的空气qAREAsforrest/toilet,weighing,in-processstorageetc.休息厕所，称重，内控标准储藏等区域qSOP:“FacilityMaintenance&Repair设备维护和维修”(logbook日志).qVAL:IQ/OQ&Warehousequalification仓库确认(asequipment)1.19FACILITY设备SimonRusminMarch17and18,2006qUtilitiesaresuitableandwelldesignedandconstructed.Utilitiesconsistsof:公用设备都是相配的，而且设计和制造都很好，其包括下面的内容HVAC,Chiller冷却器,andElectricity电流Watersystems水系统(rawmaterials原料):City,Purified,WFICompressedAir压缩空气,Nitrogen氮Boilersandsteamgenerators(cleansteam)锅炉和蒸汽产生器（干净的蒸汽）qQA/QCunderstandtheprinciplesandoperationsqQA/QC理解法规和操作qSOP:“UtilitiesMaintenance公用设施维护&Repair维修”qPipinginManufacturingAreaprotectedandidentified(type&flowdirection).被保护和选定的生产区域内的管道系统（种类及流向）qMONITOR监测:Outputcontributingtoproductqualitymustbemonitored.和产品质量有关的输出必须被监测qVAL:IQ/OQ1.20UTILITIES公共事业设备SimonRusminMarch17and18,2006qEquipmentaretobedesignedandinstalledcorrectlytobesuitablefortheirpurposesandeaseofcleaning.q设备的设计和安装要适用于其使用，且容易清洗。qEquipmentaretobeidentifiedandtheidentitydisplayedwhennecessaryduringmanufacturing.q设备要被鉴定并且当生产中有必要时把特性显示出来qProduct-contact-surfacesarenottobereactive,adsorptive,oradditivetotheproducts.q产品的接触面对产品没有反应，吸附或附加作用。qSOP:“CleaningProceduresforXXX”qXXX清洁规程Cleaningtoolandequipment清洁工具和设备Cleaningagent清洗剂Documentation制成文件(logbook日志,label标签)qSOP:“MeasuringInstrumentCalibration测量仪器校准”qSOP:“EquipmentMaintenance&Repair设备维护和维修”qVAL:IQ/OQ,andElectronic-Controllervalidated有效的电子控制器.1.21EQUIPMENT设备SimonRusminMarch17and18,20061.21a QUICK SUMMARY快速总结 HARDWARE 硬件硬件n Processes CANNOT run without Hardware没有硬件工艺就无法运行没有硬件工艺就无法运行n Hardware deteriorates with time causing VARIABILITIESn To Clean,Maintain,Repair&Calibrate硬件随着时间会变坏，并硬件随着时间会变坏，并引起清洁，维护，维修及校准的变化引起清洁，维护，维修及校准的变化SimonRusminMarch17and18,2006qPurchasefromreliablevendorswithgoodQualitySystems(knownoriginalmanufacturer)anddefinedspecs.q供应商应可靠，且拥有良好的质量系统（已知的起始生产商）和确定的规格qAgreedonsupply,delivery,rejectreturns.q在供货，运货，拒收应意见一致qThreestoreareas:Receiving,Quarantine,Release,Reject(locked);Identifymaterialswithstickers(info).q三种储藏区域：接收，待验，放行，拒收（锁定）；使用标签进行材料鉴别qExaminepackage,invoiceandCoA;QCsamples&test(mustID-test),anddeterminestoreleaseorreject.q检查包装，货物和化验报告；QC样品&检验（必须是ID检验）及决定放行或拒收qRetainReference-SamplesforCriticalMaterialsq保持主要物料的相关样品qLabelsmustbekeptlocked.标签须被上锁保存qSOP:“IncomingMaterialsStorage来料储藏&Release放行”qVendorauditing,evaluation,andrating买主审核，评估及评价.qWATERisarawmaterialsformostproducts.水是大多数产品的原料1.22INCOMINGMATERIALS进厂物料Bad Materials make Bad Products坏原料制造出坏产品SimonRusminMarch17and18,2006qMANUFACTURINGMANUALcontains:生产手册包括q1.Purpose目的,2.Sitemap位置地图,3.Organization组织,Manufacturinglines生产线,4.MajorEquipmentlist主要设备清单,q5.SOPslistqSOPs清单qMANUFACTURINGconsistsofProductionofIntermediate&Bulk,and Packaging of Finishedproducts.q生产包括中间体及批量的生产和成品包装qPROCESSKNOWLEDGEtransferredfromDevelopmentisdesignedintoBatch Record=SOPofmaking&recordingproductsconsistentwithMarketing Authorization(NDAorANDA).q工艺知识被设计成批记录制造及记录与上市批准(NDAorANDA)一致的产品的SOPqMasterBatchRecordisapprovedandcontrolledbyQ-Unit,whoalsoreviewcompletedBatchRecord.qQ-Unit批准和控制主要的批记录，及审阅所有的批记录。qSOP:“BatchRecordIssuance,Use&Review批记录发布，使用及审阅”(QU).qVAL:ManufacturingProcessValidation生产工艺验证1.23MANUFACTURING生产SimonRusminMarch17and18,2006qWeighingofformulamaterialsareverifiable(electronicor2ndperson).原料的称重是可确认的（电子秤必须用外置二级标准砝码进行校正）qRecorddataattheendofeachprocessstepdirectlyontheBatchRecord,signanddateeachrecord.q在批记录上直接记录每一工序结束时的数据，标上标记和日期qRecordthestart-endtimeofTIME-DURATIONparametersorEND-POINTparameters.q记录持续参数或终点参数的起始结束时间qSignanddateanymechanicallygeneratedrecords.q给任何的机械生产记录标上标记及日期qStoreresults(intermediateorbulk)inassignedcontainerandlocation.在指定的容器和位置存储结果（中间体或批量）qReconcileresultsagainstinputmaterials.所得结果和所用材料相协调qRecordalldeviationsanddiscuss记录所有的偏差和讨论(withsupervisor/QU和管理人员).qClose-outBatchRecordandsubmittoQU.停止批记录并听从于QU.qDis-assembletheequipment.Cleantheequipmentandfacility.把设备拆卸，进行清洗1.24BULKPRODUCTION批量生产SimonRusminMarch17and18,2006qObtainandverifythecorrectpackagingmaterialsandlabels.获取及检验正确的包装材料和标签qVerifyline-clearance检验清除线(byQU由QU).qRecordstart-endtimeofafilling/packagingprocess.记录填充包装工艺的起始结束时间qConductin-processcontroltesting.Recordanyunusualline-stoppageanditsreasons.做内控标准试验，记录任何异样的线中断和其原因qStorethePackagedProductinthedesignatedplace;Reconciletheproductagainstthebulk.在指定位置储存包装好的产品；使得产品和批量相协调qReconcilelabelsandothercriticalpackagingmaterials.使得标签和其它主要包装材料相协调qRecorddeviationsinprocessingandreconciliation.记录工艺和协调中的偏差qClose-outBatchRecordandsubmittoQU.停止批记录并听从于QU.qDis-assembleequipment.Cleanequipmentandlines.把设备拆卸，进行清洗1.25FINISHEDPACKAGING最终包装SimonRusminMarch17and18,2006qCorrectlydesignandassignfacilityandworkflow.正确地设计、分配工具及工作流程qAssigndedicatedoperatorsforoneprocess.对于一个工艺指定操作者qTrainpersonnel(operators,mechanics,QCanalysts)onhazardsofcausingmix-up,cross-contamination,andcontamination;andonproperattire&behavior.对人员（机械操作人员，QC分析人员）在混淆，交叉污染和污染的危险性及合适的服装及行为方面进行培训qRestricttheentryofpersonsintotheproductionandpackagingareas.对于进入生产及包装区域的人员进行限制qMaintainedtheintegrityandcleanlinessofthefacilityandequipment.保证设施和设备的完整和清洁qMonitorfacilityandequipmentcleanlinessthroughauditingandmicrobialtesting.通过审核及微生物检验来监测设施和设备的清洁qImplement5S(sort,set-in-order,shine,standardize,sustain)workshoprules.使用车间规定（分门别类，归类，发亮，标准化，持续发展）1.26Preventmix-up&Contamination防止混淆及污染SimonRusminMarch17and18,2006qDEVIATIONSmaycausebulk,intermediate,andfinishedproductsnotmeetingspecifications,called“non-conformance”.q偏差可能引起批生产，中间体及成品不符合规格，叫做“不符合”qREWORKistreatingthenon-conformancewithanotherprocesstocorrect.REPROCESSINGisrepeatingtheprocesstocorrect.q重新加工是用另外的工艺来处理改正“不符合”，再加工是重复用同一种工艺改正qQUpre-approvesrework/reprocessingbasedagreedprotocol,andreviews&approves/rejectstheresults.Therework/reprocessingisdocumented.QU根据方案提前进行重新加工再加工批准及审阅&支持反对结果。重新加工再加工被写成文件qIfrework/reprocessingisveryoften,correctandvalidatethep