cGMP培训讲解学习

SIXSYSTEMAPPROACH

TOGMPINMANUFACTURING

OFSOLIDDOSAGEFORM

固体制剂的六大体系Presentedby

sFDA&AlliancePharm

on

浙江省药监局&美国洲际药业17,18March2006

Hangzhou,ChinaSpeaker

SimonRusmin,Ph.D.SimonRusminMarch17and18,2006

SEMINARCONTENTS

研讨会内容

QualitySystemApproachtoGMP

Microbesinnon-sterilemanufacturing

ValidationPrinciplesandPractices

Preparingforregulatoryinspection

SimonRusminMarch17and18,2006QUALITYSYSTEM

APPROACHTOGMP

GMP的质量系统

SimonRusminMarch17and18,2006TheFDAexpertsstudiedall

qualitysystemsincluding

thoseofnon-pharmaceutical.FDA认证专家研究了所有的包括非制药的质量系统InAugust2002theUSA-FDAinitiated

science-based&risk-basequalitysystem

approachtoCGMP.2002年八月，美国FDA成立了以科学和风险为基础的CGMP质量系统TobeincompliancewithUSACGMP&EUGMP,weneedtounderstandtheapproaches&toknowhowtoimplementthem.为了达到美国CGMP&欧盟GMP要求，我们需要知道方法及如何执行。FirstweneedtounderstandtheconceptandscienceofQUALITYandthepresentdayQUALITYSYSTEMS.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?SimonRusminMarch17and18,2006Unlikeadultwildanimals,humanbeingsneedproducts(goodsandservices)providedbyothers.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）

QUALITYisthecharacteristics

ofGoodsandServicesthat

theusersLIKE.质量是使用者对物品和服务喜欢的特征Inthescienceofmanufacturing

Qualityisdocumentedas

measurableSPEFICIATIONS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–1850sBeforetheINDUSTRIALREVOLUTION在工业革命以前ProductisUNIQUE

(oneofakind).产品是唯一的（一种一个）Personalskills&pride

makeQUALITY人类的技能和自尊心造就了质量Highvariability.

可变化性高After工业革命后……ProductisUNIFORM产品是统一的Scientificcontrols

makeQUALITY科学控制造就了质量Lowvariability

可变化性低SimonRusminMarch17and18,20061.4StatisticalQualityControl

统计质量控制–1920sNatureisinherentlynon-UNIFORM.ItsvariabilityisofNormallyDistribution.本质上不再统一，其可变性有了正态分布In1920sSchewartpioneeredthescienceofstatisticalqualitycontrols:在二十年代，休哈特倡导了统计质量控制StatisticalSampling统计抽样StatisticalProcesscontrol统计工艺控制ProcessCapability加工能力DesignofExperiment实验设计

WorldWarII二次世界大战(1945)-thePEAKofIndustrialRevolution,andthesubsequentfloodofconsumergoodsafterward.工业革命的鼎盛时期，出现了后来的生活消费品潮SimonRusminMarch17and18,20061.5TheRaceofQuality质量的赛跑–1970sAfterWWII,Demingtaught

Japaneseindustrymethods

andtechniquesofquality

management&improvement.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及改进方法JapanperfectedqualityintoTotalQualityManagement日本把质量完善为总的质量管理:Topmanagementcommitstoquality主管管理质量Everyoneparticipateinquality人人参与质量Processesarecontinuouslyimproved工艺不断改进In1976theUSA-FDAissuedGoodManufacturingPractices.1976年美国FDA发布了质量生产规范GMPSimonRusminMarch17and18,2006Inthe1980stheUSAindustrylearnedtheJapanesewaysofmanufacturingandcaughtupinquality.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Motorola&GeneralElectricinitiated

theSix-SigmaManufacturing

qualitysystem,followed

byLean-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

Sixsigma六西格码=defectof~3/106

3/106的缺陷Lean精益

=highestvalueatlowestcost

以最小的成本得到最大的价值Currentqualitysystemconceptsarethebase

ofFDA’sQualitySystemApproachtoCGMP.当前的质量系统理念是FDA的CGMP质量系统的基础1.6Qualityinthe21thCentury

21世纪的质量SimonRusminMarch17and18,2006

QUALITYIS质量是………

WhattheCustomers

Like

．．．消费者喜欢什么measuredbySpecifications根据规格进行测量gotbyReducingVariabilityof

manufacturing通过减少生产可变性得到1.6aQUICKSUMMARY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ProcessKnowledgeisthepower

tocontroltheprocess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Businessisachangeofprocesses–theoutputof

oneprocessistheinputofthenextprocess商业是过程的变更－一个过程的输出是下一个过程的输入SimonRusminMarch17and18,2006ProductDevelopmentleadstoManufacturingAuthorization(NDA,ANDA,DMF–process/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Establishmaintenance/calibration.建立维护/校准Process-mapping,Risk-analysis(FMEA,HACCP),&establishProcess-controls.工艺描述，风险分析(FMEA,HACCP),&建立工艺控制EstablishMaterial-testingandProcess-monitoring,In-process,intermediate,andfinishedproducttesting.Set-upTesting-laboratories.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DocumentationandKnowledge-transfertooperators&managersthroughcontinuoustraining.不断的对操作者&管理者进行文件建立及知识培训Change-control&Problem-solving(Deviation,OOS,&conformance),andestablishCAPA.变更控制&问题解决（偏差，超标&一致性），建立CAPAAudit(self-inspection)&AnnualQualityReview(health-check).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SimonRusminMarch17and18,20061.12

FDASixQualitySystemsApproach

FDA的六个质量系统方法SimonRusminMarch17and18,2006

QUALITYSYSTEM质量系统是………

istheMEANStocontrolprocessvariability,byMapping&AnalyzingtheProcess,andEstablishingSixControlPoints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1.12aQUICKSUMMARY快速总结SimonRusminMarch17and18,20061.13DocumentPyramid文件金字塔SimonRusminMarch17and18,2006AsaSHOWCASEtointroducethequalityoperationsofthecompany.把企业的质量操作当作一种优势介绍TheQUALITYPOLICYstatementisthecommitmentofthehighestmanagementtoQUALITY质量方针陈述是质量的最高管理承诺Displaysthesitesofmanufacturingandtheproductsmanufacturedinthesites.把生产的位置和所在位置生产的产品显示出来Definetheorganizationandpersonnelinvolvedinquality,andeachfunctionresponsibilities(QualityUnit(QualifiedPersonofEU)isindependentofManufacturing.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）AppendedwithListofothermanuals(Manufacturing/AnalyticalLabs),SOPs,andotherdocumentsasaGATEWAYtoviewthecompletequalitysystems.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SimonRusminMarch17and18,2006TheveryfirstSOPdescribinghowtowrite

anSOPandmanageGMPdocuments.第一份SOP描述的是如何编写SOP和管理GMP文件FORMAT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.CONTENTS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PROCESS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.CONTROL控制TheDocumentControllerfunctionsinSOPs&Records.SOPs&记录中的文件管理者作用

1.15QualitySystemDocumentation质量系统文件SimonRusminMarch17and18,2006MajorSYSTEMSOPscreatedbyQUinclude：QU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CreationofINSTRUCTIONSOPsarebytheusersofeachorganizationalfunctions(beginwithflowcharting).

指令ＳＯＰＳ是由行为组织者创造的（从流程图开始）HandlingofRECORDSisdescribedingrand-fatherSOP.有关记录的处理在起始ＳＯＰ中有描述1.16SOPsandRecords

SOPs和记录SimonRusminMarch17and18,2006SOP:“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SOP:“WorkplaceAttire工作场所服装&OperatingRules操作规则”

(safeguardsofproductqualityandpersonalsafety产品质量和人员安全保障)SOP:“TrainingProgram培训计划&documentation文件”SOP:“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SimonRusminMarch17and18,20061.17aQUICKSUMMARY快速总结

SOFTWARE软件&LIVEWARE生命件…

QualitySystem(software)arerulestokeepProcessVariabilitylow.质量系统（软件）是把过程变化保持到最低的准则Personnel(liveware)istheoperatoroftheQualitySystem.人员（生命件）是质量系统的操作者Rulesmustbegoodandcorrectlyfollowedbypeople.准则必须是有益的并且由人来正确执行SimonRusminMarch17and18,20061.18HardwarePyramid硬件金字塔SimonRusminMarch17and18,2006Situation,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CEILINGsandWALLsdonotcontributedust,easytomaintainedandcleaned.FLOORsareresistanttouse,nodust/moisturecollection,drainsareeasilycleanedandsanitized.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HVACprovidecleananddryairsuitableforoperationswithsufficientLIGHT.

HVAC利用充足的光，提供了适合操作的干净、干燥的空气AREAsforrest/toilet,weighing,in-processstorageetc.休息／厕所，称重，内控标准储藏等区域SOP:“FacilityMaintenance&Repair设备维护和维修”(logbook日志).VAL:IQ/OQ&Warehousequalification仓库确认(asequipment)1.19FACILITY设备SimonRusminMarch17and18,2006Utilitiesaresuitableandwelldesignedandconstructed.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）QA/QCunderstandtheprinciplesandoperationsQA/QC理解法规和操作SOP:“UtilitiesMaintenance公用设施维护&Repair维修”PipinginManufacturingAreaprotectedandidentified(type&flowdirection).被保护和选定的生产区域内的管道系统（种类及流向）MONITOR监测:Outputcontributingtoproductqualitymustbemonitored.和产品质量有关的输出必须被监测VAL:IQ/OQ1.20UTILITIES公共事业设备SimonRusminMarch17and18,2006Equipmentaretobedesignedandinstalledcorrectlytobesuitablefortheirpurposesandeaseofcleaning.设备的设计和安装要适用于其使用，且容易清洗。Equipmentaretobeidentifiedandtheidentitydisplayedwhennecessaryduringmanufacturing.设备要被鉴定并且当生产中有必要时把特性显示出来Product-contact-surfacesarenottobereactive,adsorptive,oradditivetotheproducts.产品的接触面对产品没有反应，吸附或附加作用。SOP:“CleaningProceduresforXXX”

XXX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)SOP:“MeasuringInstrumentCalibration测量仪器校准”SOP:“EquipmentMaintenance&Repair设备维护和维修”VAL:IQ/OQ,andElectronic-Controllervalidated有效的电子控制器.1.21EQUIPMENT设备SimonRusminMarch17and18,2006

1.21aQUICKSUMMARY

快速总结

HARDWARE硬件…

ProcessesCANNOTrunwithoutHardware没有硬件工艺就无法运行HardwaredeteriorateswithtimecausingVARIABILITIESToClean,Maintain,Repair

&Calibrate硬件随着时间会变坏，并引起清洁，维护，维修及校准的变化SimonRusminMarch17and18,2006PurchasefromreliablevendorswithgoodQualitySystems(knownoriginalmanufacturer)anddefinedspecs.

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Agreedonsupply,delivery,rejectreturns.在供货，运货，拒收应意见一致Threestoreareas:Receiving,Quarantine,Release,Reject(locked);Identifymaterialswithstickers(info).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Examinepackage,invoiceandCoA;QCsamples&test(mustID-test),anddeterminestoreleaseorreject.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RetainReference-SamplesforCriticalMaterials保持主要物料的相关样品Labelsmustbekeptlocked.标签须被上锁保存SOP:“IncomingMaterialsStorage来料储藏&Release放行”Vendorauditing,evaluation,andrating买主审核，评估及评价.WATERisarawmaterialsformostproducts.水是大多数产品的原料1.22INCOMINGMATERIALS进厂物料BadMaterialsmakeBadProducts坏原料制造出坏产品SimonRusminMarch17and18,2006MANUFACTURINGMANUALcontains:

生产手册包括1.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,5.SOPslist

SOPs清单MANUFACTURINGconsistsofProductionofIntermediate&Bulk,andPackagingofFinishedproducts.生产包括中间体及批量的生产和成品包装PROCESSKNOWLEDGEtransferredfromDevelopmentisdesignedintoBatchRecord=SOPofmaking&recordingproducts

consistentwithMarketingAuthorization(NDAorANDA).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SOPMasterBatchRecordisapprovedandcontrolledbyQ-Unit,whoalsoreviewcompletedBatchRecord.Q-Unit批准和控制主要的批记录，及审阅所有的批记录。SOP:“BatchRecordIssuance,Use&Review批记录发布，使用及审阅”(QU).VAL:ManufacturingProcessValidation生产工艺验证1.23MANUFACTURING生产SimonRusminMarch17and18,2006Weighingofformulamaterialsareverifiable(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）RecorddataattheendofeachprocessstepdirectlyontheBatchRecord,signanddateeachrecord.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Recordthestart-endtimeofTIME-DURATIONparametersorEND-POINTparameters.记录持续参数或终点参数的起始－结束时间Signanddateanymechanicallygeneratedrecords.给任何的机械生产记录标上标记及日期Storeresults(intermediateorbulk)inassignedcontainerandlocation.在指定的容器和位置存储结果（中间体或批量）Reconcileresultsagainstinputmaterials.所得结果和所用材料相协调Recordalldeviationsanddiscuss记录所有的偏差和讨论(withsupervisor/QU和管理人员／ＱＵ).Close-outBatchRecordandsubmittoQU.停止批记录并听从于QU.Dis-assembletheequipment.Cleantheequipmentandfacility.把设备拆卸，进行清洗1.24BULKPRODUCTION批量生产SimonRusminMarch17and18,2006Obtainandverifythecorrectpackagingmaterialsandlabels.获取及检验正确的包装材料和标签Verifyline-clearance检验清除线(byQU由QU).Recordstart-endtimeofafilling/packagingprocess.记录填充／包装工艺的起始－结束时间Conductin-processcontroltesting.Recordanyunusualline-stoppageanditsreasons.做内控标准试验，记录任何异样的线中断和其原因StorethePackagedProductinthedesignatedplace;Reconciletheproductagainstthebulk.在指定位置储存包装好的产品；使得产品和批量相协调Reconcilelabelsandothercriticalpackagingmaterials.使得标签和其它主要包装材料相协调Recorddeviationsinprocessingandreconciliation.记录工艺和协调中的偏差Close-outBatchRecordandsubmittoQU.停止批记录并听从于QU.Dis-assembleequipment.Cleanequipmentandlines.把设备拆卸，进行清洗

1.25FINISHEDPACKAGING

最终包装SimonRusminMarch17and18,2006Correctlydesignandassignfacilityandworkflow.正确地设计、分配工具及工作流程Assigndedicatedoperatorsforoneprocess.对于一个工艺指定操作者Trainpersonnel(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Restricttheentryofpersonsintotheproductionandpackagingareas.对于进入生产及包装区域的人员进行限制Maintainedtheintegrityandcleanlinessofthefacilityandequipment.保证设施和设备的完整和清洁Monitorfacilityandequipmentcleanlinessthroughauditingandmicrobialtesting.通过审核及微生物检验来监测设施和设备的清洁Implement5S(sort,set-in-order,shine,standardize,sustain)workshoprules.使用５Ｓ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SimonRusminMarch17and18,2006DEVIATIONSmaycausebulk,intermediate,andfinishedproductsnotmeetingspecifications,called“non-conformance”.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”REWORKistreatingthenon-conformancewithanotherprocesstocorrect.REPROCESSINGisrepeatingtheprocesstocorrect.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QUpre-approvesrework/reprocessingbasedagreedprotocol,andreviews&approves/rejectstheresults.The

rework/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Ifrework/reprocessingisveryoften,correctandvalidatetheprocess.如果重新加工／再加工很频繁，对工艺进行改正和验证SOP:“ReworkandReprocessing重新加工和再加工”

1.27Rework&Reprocessing

重新加工及再加工SimonRusminMarch17and18,2006DISTRIBUTIONisdonebyMarketing/Salesdepartments.分发由市场／销售部来做Thedistributionofproductsperlotnumbersmustbetraceableforthepurposeofrecallingtheproducts.为了方便召回产品，每批量的产品分发都必须有可追溯性。RECALLiscausedbydefectiveproductsdiscoveredafterrelease.Isvoluntaryoraregulatoryaction.Voluntaryrecallmustbereported.召回是由放行后出现的有缺陷产品引起的，是自发的或常规的行为，自发的召回必须作报告FDA’sTypeI,II,IIIrecalls(frommosttoleastserious).FDA召回种类I,II,III（从最严重的到最不严重的）

SOP:“ProductRecallandReporting产品召回和报告”.RETURNisbringingproductbacktotheplantbecausetheproductsareunsoldordamaged.退货是因为产品没有卖出去或被损坏而把产品退回到工厂Returnsaredocumentedandstoredseparately,andmustbeinspected/testedbeforere-releasebyQU.退货产品必须分开备案和储存，在重新放行前必须由QU进行检查／检验SOP:“ProductReturnandRe-releasing产品退货和再放行”

1.28Distribution,Return,Recall

分发，退货，召回SimonRusminMarch17and18,2006QC“SEE”ifthematerials(INPUT)and

theproducts(OUTPUT)meetSpecifications.QC来检查原料（输入）和产品（输出）是否符合规格

1.29QualityControlTasks

质量控制任务SimonRusminMarch17and18,2006QCLABMANUALbeprepared,containing:1.Purpose,2.Sitemap,3.Organization,3.SampleFlows,4.MajorTestInstrument,5.ListofSOPsQC实验室手册包括：１．目的，２．位置图，３．组织，４．样品流程，５．SOPs清单Hassufficientqualifiedequipment/instrumentandqualifiedanalyststorunthelabs.要有足够的合格设备／工具和合格的分析人员来运作实验室ThereisaCalibrationProgramformeasuringinstruments对于测量工具有一个校准程序ThereareSpecificationSheetsforMaterials,In-process,intermediates,Bulk,andFinishedproducts.对于材料，内控，中间体，批量和成品有规格表SamplesarecollectedaccordingtoSamplingPlantoberepresentativeofitemstested(ANSI/ASQCZ1.4-1993).根据检测项目的有代表性的取样计划取样（ANSI/ASQCZ1.4-1993).SOP:“SampleCollection,Testing,andResultsReporting样品收集，检验及结果报告”.

1.30QCLaboratories-1

QC实验室－１SimonRusminMarch17and18,2006ReservedsamplesaretakenofBulkandFinishedforprobleminvestigationandStabilityStudies.用于问题和稳定性研究的保留样品来自于批量和成品SOP:“ProductLongTermStabilityProgram产品长期稳定性计划”Microbiologylaboratoryneedsabiologisttorun微生物实验室需要有一位生物学家.HazardousWasteDisposaliscontrolled.对危险废品处理进行控制VAL:IQ/OQofLabFacility,Utilities,Equipment/Instrument,实验室设施的IQ/OQ，公用设施，设备／仪器VAL:Qualificationofcompendiaanalyticalmethods;Validationofproductspecificanalyticalmethods.分析方法概略的确认；产品细节分析方法的验证ReferencetoGoodLaboratoryPractices根据实验室操作规范:US-FDA21CFRPart50,&EUDirective87/18/EEC

1.31QCLaboratories-2

QC实验室SimonRusminMarch17and18,2006

QCIS…

ＱＣ是．．．

TheEARSand

EYESofMANUFACTURING.．．．生产的耳朵和眼睛QC’sDATAmustbeAccurateandTimely.QC的数据必须是准确及时的1.31aQUICKSUMMARY

快速总结SimonRusminMarch17and18,2006

1.32Maintain&ImproveSystems

维护和改进系统

SimonRusminMarch17and18,2006VALIDATION-anewprocessmustbeconfirmedthatitworksasdesigned(seePart3ofSeminar)验证－必须保证新的工艺按照所设计的进行（见研讨会Part3）CHANGECONTROL–anychangestoaprocesshavetobeevaluatedandapprovedbytheQUbeforeimplementation.Changesinclude:inputmaterials,theprocedures,thefacilityandequipment,thetestingandmonitoring.变更控制－在使用前，工艺的任何变化都必须经过QU评估和批准。变更包括：所用材料，规程，设备和设施，检验和监测SOP:“ManufacturingChangesEvaluationandApproval生产变更的评估和批准”(QU批准approvals).CAPA–Investigationofdeviationsandnon-conformance,resultinginCorrectiveActionsandPreventativeActions.偏差和不符合研究，形成了矫正和预防措施OOS–InvestigationofdoubtfulanalyticaltestresultstodeterminecausesofOut-of-Specificationseitherfromthetestoperationorasaproductfailure.试验操作或产品过失中的超标是对需测定的有疑问的试验结果进行研究的原因

1.33Maintain&Improve-1

维护和改进系统SimonRusminMarch17and18,2006MONITORING监测–Continuousoratfixedfrequencymeasurementoffactorsthatmayeffectproductquality(cleanlinessofareas,manufacturingmachines,inputwaterquality)连续的或因素在固定频率的测量可能影响产品质量（区域清洁，生产机器，所用水质量）TRENDING趋向–Resultsofmonitoringisnotreleasecriteria.Resultsaredisplayedtoobservetrends.监测的结果不是放行标准，而是为了观察趋向NON-CONFORMANCE–aresituationsoractionsnotinaccordancetoGMPelementsorrequirements.不符合－是指位置或措施和GMP要素或要求不一致AUDIT–PeriodicexaminationofQualitySystemimplementation,resultingincorrectionsofnon-conformance(inspectionofself,supplier/contractor)–SOP.审核－执行质量系统的定期检查，对不符合（自我检查，及供应商／承包商检查）的纠正－SOPCOMPLAINTfromcustomersareinvestigatedandcorrected.–SOP.顾客的投诉被调查并改正–SOP.ANNUALREVIEW年度审阅–PeriodicreviewofthewholemanufacturingoperationsrelatedtoQuality.有关质量的总体生产操作的定期审阅

1.34Maintain&Improve-2

维护及改进SimonRusminMarch17and18,2006ANNUALREVIEWtoinclude年度审阅包括:CHANGEStoqualityorganization&personnel;facility,utilities,equipment;materials;processes;testingandmonitoring;newproductintroduction质量机构及人员的变更，设施，公用设施，设备，原料，工艺，检验和监测，新产品介绍Summaryofmaterial&productreleased/rejectedandtrends;rework/reprocessing/returns/recall;monitoringtrends;investigationofdeviations/non-conformance/OOS,customercomplaints/otherqualityproblems/regulatorinspections.有关原料及产品发放／拒收和趋向；重新加工／再加工／退货／召回；监测趋向；偏差／不符合／超标的调查研究，顾客投诉／其它质量问题／校准仪的检查总结SummaryofStabilityStudies稳定性研究的总结.COMPANYTOTALQUALITYHEALTHEXAMINATION公司总的质量健康检查CONTINUOUSIMPROVEMENT不断提高–UsingknowledgefromAnnualReviewtoplanandexecuteimprovementprojects.利用从年度审阅中获得的知识做计划，并改进项目。1.35Maintain&Improve-3

维护及改进SimonRusminMarch17and18,2006MICROBESINNON-STERILEMANUFACTURING

非无菌生产中的微生物SimonRusminMarch17and18,20062.1MicrobesinManufacturingAreas

生产区域中的微生物Therearetwogroupsofmicro-organismscommonlyfoundinpharmaceuticalplant:在制药工厂里常见的有两组微生物TheBACTERIA&theFUNGI:细菌和真菌SimonRusminMarch17and18,20062.2Fungus,Bacteria,Virus真菌，细菌，病毒Microscopiclook显微镜观察:SimonRusminMarch17and18,20062.3Prokaryotes&Eukaryotes

原核生物和真核细胞Anorganismmusthavetwocapabilitiestostayaliveandpropagate:一个生物体必须有生存和繁殖的能力a)METABOLSIM新陈代谢作用–changinginorganicH2OandCO2intoorganicsbyplant,andeatingotherorganicstobecomeitsownbyotherorganisms;andb)GENETICS–DNAmoleculesthatrecordthecharacteristicoftheorganismthatcanbereproducedtomakemoreofitself.a)新陈代谢作用–通过种植把无机的水和二氧化碳转化成有机物，通过食用别的有机物，在其它生物作用下变成无机物，b)遗传–可以表现生物特性的DNA能够进行自我繁殖TheDNAandmetabolicmachineryarepackagedintoaCELL.DNA和新陈代谢器官在同一个细胞里TheCellofabacteriaissimplewheretheDNAislooselystoredinsidethecell–calledProkaryote.ThecelloffungushasanucleuswheretheDNAistightlypacked–calledEukaryote.DNA松散存储在简单细胞里面的细菌，称作原核生物，菌类的DNA紧密排列在有细胞核的细胞里面，称作真核细胞VirusisapieceofDNApackagedintoaboxofprotein,thereforeitcannotmetabolize.Itfindsotherorganismstomakemoreofitself.病毒具有蛋白质外壳的基因组

，它利用其它生物来满足自身需求SimonRusminMarch17and18,20062.4HowaVirusPropagate

病毒如何繁殖SimonRusminMarch17and18,20062.5RolesofMicrobesinNature

微生物在自然中的角色Bacteriacanbefoundinmoreplacesthanotherorganismsonearth.Fungusisthemaincomponentofsoil.Microbesrecycletheorganicsofdeadplantsandanimals.相对于其它生物来说，细菌可以在地球上的更多地方被发现，菌类是土壤的主要成分，生物可以对死亡的动植物进行分解SimonRusminMarch17and18,20062.6TheFiveKingdomsonEarth

地球上的五大区域SimonRusminMarch17and18,20062.7EvolutionofLifeonEarth

地球上的生物演变SimonRusminMarch17and18,20062.8HumanareMicrobeCarrier

人类是微生物的载体SimonRusminMarch17and18,20062.9HumanShedMicrobes

人类传播微生物SimonRusminMarch17and18,20062.10MicrobePrevention

微生物预防MICROBESneedwatertoliveandcannotbeintoohighortoolowtemperature.Microbesarealsosusceptibletomanychemicals.微生物的生存需要水，它们不能在高温或低温中存活，而且对很多化学品也很敏感MICROBESthriveindirtoforganicsubstancesandarecarriedbydustintheair.微生物在有机泥土中存活旺盛，并且通过空气进行传播HUMANarethemaincarrierofmicrobesinthemanufacturingplantaftertheplacesaremadeclean.在干净的厂区，人类是微生物的主要载体Withtheaboveprinciples,preventingmicrobesintheplantareasisby根据上面几点，厂区里微生物的预防可通过以下方面:KeepingtheWorkplaceDRYandCLEAN保持车间干燥、洁净TRAINtheoperatorsinpersonalcleanliness,wearproperclothingandhairprotection,andhandlingproductswithglovedhandsandcorrecttechniques.操作人员要注意个人清洁，穿着得体，头发不能外露，处理产品时要戴手套，并使用正确的技术SimonRusminMarch17and18,20062.11MicrobePreventioninProducts

产品中的微生物预防

Thetechnologiestopreventmicrobesfromgrowinginproductsare预防产品中的微生物生长技术有:PRESERVATION预防–Tokeepfoodsanddrugsfromallowingmicrobesgrowingon/init,bydrying,refrigerating,freezing,addinghighsalt/sugar/acid,oraddingpreservativechemicals为了预防食品和药品的表面或里面没有微生物生长，采取干燥，冷却，冷冻，添加高盐/糖/酸或防腐剂等措施SANITATION卫生–Toreducethenumberofbacterialbycleaningandkillingusingchemicals(sanitants),andleavingthearea/equipmentDRYandPROTECTEDfromdustandhumantouching.通过清洁，使用化学品杀菌，保持生产区域/设备干燥而且没有灰尘及人员接触的方式来减少细菌的数量DISINFECTION消毒–Toreduceharmfulmicrobesbyusingchemicalkillingmicrobes,butnotharminghumanbodypartsorequipment.通过使用化学杀菌剂来减少有害的微生物，但是不能危害到人或设备SimonRusminMarch17and18,20062.12CompleteElimination

完全消灭Eliminatingmicrobesfromproduct,objects,orspaceiscalledSTERILIZTION.Methodsare:把产品，物体或空间中的微生物消灭掉被称为灭菌，方法有：STEAMSTERILIZTION蒸汽灭菌法–steamathighpressure,e.g.Autoclave.高压蒸汽，举例说：高压锅DRYHEATSTERILATION干热灭菌法–airathightemperature,e.g.Oven.高温气体，举例说，烤箱GASSTERILIZATION气体灭菌法–gaswithkillingpower,e.g.ETO(ethyleneoxide)andhydrogenperoxidegases.有杀伤力的气体，举例说ETO（环氧乙烷

）和过氧化氢气体IRRADIATONSTERILIZATION放射灭菌法–highpowerelectro-magneticwaves,e.g.gammarays.高杀伤力的电磁波，如伽马射线FILTRATIONSTERILIZATION过滤灭菌法–excludebutnotkillthemicrobes;0.22micrometerporesizefilters.去除但不杀死微生物，0.22微米孔径过滤器SimonRusminMarch17and18,2006VALIDATIONPRINCIPLES&PRACTICES

验证法则和规范SimonRusminMarch17and18,20063.1WhatisValidation

什么是验证SimonRusminMarch17and18,2006