工艺验证方案模板电子教案.doc

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1、Good is good, but better carries it.精益求精，善益求善。工艺验证方案模板-ProcessValidation(PV)ProtocolXXXXXX工艺验证方案Writtenby起草人Writtendate起草日期年月日Reviewedby审核人Revieweddate审核日期年月日Approvedby批准人Approveddate批准日期年月日Writtendepartment起草部门Effectivedate生效日期年月日Issuedby:颁发部门：Copynumber:拷贝号：Changerecord:Revisionnumber变更记载：Dateofap

2、provalEffectivedate修订号批准日期生效日期Changereasonandgoal:变更原因及目的：Distributiondepartment:分发部门:所长办公室人力资源部后勤保卫部物资供应部工程服务部生产管理部质量保证部销售部仓储部疫苗一室疫苗二室疫苗三室疫苗五室疫苗六室生化制品室细胞因子室血清制品室实验动物室分包装室培养基室Verificationdepartment(department):验证科室（部门）：Verifycompletiondate:验证完成日期：Validity:有效期：Index目录1.Purpose目的52.Scope范围53.Responsib

3、ility职责53.1AAAresponsibilitiesAAA的职责53.2XXXresponsibilitiesXXX的职责64.RegulationandGuidance法规和指南85.Abbreviations缩略语96.ProtocolDescription方案说明117.ProductAndProcessDescription产品和工艺描述147.1Productspecification147.2DrugapprovalNo.147.3StandardFollowed:147.4RawMaterialsandAdjuvants原辅料情况147.5Processdescripti

4、on:167.6ProcessRecipe工艺处方：217.7ListofProductionPlants生产车间一览267.8ListofProductionEquipment生产设备一览297.9ProcessFlowDiagram工艺流程图337.10CPPIdentificationCPP确认347.11ValidationPlan验证计划498.Validationprerequisite验证先决条件518.1PersonalIdentification人员确认518.2ProcessDocumentationVerification生产文件确认518.3TrainingVerifi

5、cation培训确认528.4SystemandEquipmentInstrumentsCalibrationVerification系统和设备仪表校验确认528.5SystemandEquipmentInstrumentsCalibrationVerification生产相关验证状态确认538.6TestInstrumentsCalibrationVerification测试仪器和仪表校验确认538.7TestingMethodValidationVerification检验方法验证的确认548.8RawMaterialandExcipientVerification原辅料确认549.Sam

6、plingPlanandEvaluationCriteria取样计划及评估标准5610.SampleCodingMethod样品编码原则7011.ProcessValidationTestExecution工艺验证执行7211.1LiquidPreparation液体配制7211.2CellResurrectionandPassage细胞复苏及传代7411.3Harvestliquidtest收获液检测8111.4ClarificationFiltrationEfficacyTest澄清过滤效果检测8311.5UFConcentration1EfficacyTest超滤浓缩1效果检测8311.

7、6Ammoniumsulfateprecipitationefficacytest硫酸铵沉淀效果检测8511.7Potassiumbromideextractionefficacytest溴化钾提取效果检测8611.8Firstdensitygradientcentrifugationefficacytest一次密度梯度离心效果检测8711.9Seconddensitygradientcentrifugationefficacytest二次密度梯度离心效果检测8811.10UFConcentration2EfficacyTest超滤浓缩2效果检测8911.11Chromatographypur

8、ificationproducttest层析纯化产物检测9012.BulkDetermination原液检验9213.ProcessValidationSummarization工艺验证总结9314.PVReport工艺验证报告9414.1ProcessValidationReport工艺验证报告9414.2ProcessValidationAnalysisandEvaluation工艺验证分析与评价9415.RequirementsonExecutionRecords执行记录要求9516.DeviationHandling偏差处理9517.ChangeHandling变更处理9518.Tes

9、tForm测试表96表格1缩略语9表格2原辅料质量标准表11表格3物料消耗表121表格4物料消耗表221表格5所用液体配料表22表格6生产车间一览表26表格7主要生产设备一览表29表格8工艺风险分析表33表格9工艺时间表49表格10取样计划表56表格11样品编码原则70表格12配液取样检测信息表72表格13复苏和传代取样表74表格14复苏和传代样品编码80表格15收获液标准82表格16澄清过滤标准83表格17超滤浓缩1标准84表格18硫酸铵沉淀标准85表格19溴化钾提取标准86表格20一次密度梯度离心标准87表格21二次密度梯度离心标准88表格22超滤浓缩2标准89表格23纯化产物标准90表格

10、24原液标准921. 表格25测试表列表96Purpose目的Thispurposeofthisprocessvalidationistoprovidedocumentedevidencetoshowthatthecombinationofthepersonnel,materials,equipment,methods,environmentalconditionsandtheotherrelatedutilitiesXXXCo.,LTD(XXX)canensuretheconsistentproductionofproductsconformingtotheenterpriseinterna

11、lstandardsandthenationalstandards,andtheprocessesarereliableandconformingtotheGMPrequirements.Theprocessvalidationandthetestresultsaretobedocumentedbasedonthisvalidationprotocol.本工艺验证用于提供文件化的证据，证明XXX疫苗一室生产XXX原液的人员、材料、设备、方法、环境条件以及其它有关公用设施的组合可以始终如一的生产出符合企业内控标准及国家法定标准的产品，工艺稳定可靠，符合GMP要求，工艺验证的过程和检查的结果将按照

12、该验证方案进行记录。2. Scope范围ThisprotocolisapplicabletotheprocessvalidationofXXXproducedbytheequipmentlocatedXXX.本方案适用于XXX原液生产的工艺验证。由于工作细胞库制备的过程并非常规生产过程，因此，不在本次验证中进行考察。ThelabelingandpackagingprocessesarenotwithinthescopeofthisdocumentsincetheseprocesseshavebeenvalidatedperPQprotocol(labeling)andPQprotocol(pa

13、ckaging),andtheseprocesseshaveminimalimpactonfinishedproductquality.贴标签和包装也不在此文件范围内，因为这些工艺已经按照PQ方案（贴标签）和PQ方案(包装)验证过，并且这些工艺对产品质量极少有影响。3. Responsibility职责3.1 AAAresponsibilitiesAAA的职责 CompileProtocol方案的编写 GuideProtocolexecution,datacollection/Providetestdataforreviewuponrequestbycustomer指导方案的实施，数据的收集/

14、在客户要求时提供测试数据供其审核 FinalreportReview/Analyzeandcompiledataintothesummaryreport最终报告的审核/对数据进行分析并将其编辑入总结报告之中3.2 XXXresponsibilitiesXXX的职责n Productiondepartment生产部 Reviewandapproveprotocol审核并批准验证方案 Assurealltheequipmentusedforvalidationcanbemaintainedtimely保证验证用所有设备均能按SOP进行及时的维护和保养 Assurealltherawmaterial

15、susedforvalidationcanbesuppliedtimelyandcomplywithdomesticqualitycriteriaofenterprise保证验证用原辅包装材料能按时到货，并符合企业内控标准n Researchanddevelopmentdepartment研发部 Provideproductregistrationcriteriaandreviewwhetherrecipeandprocessstepdescribedintheprotocoliscomplyingwithregisteredcriteria提供产品的注册工艺，审核方案中生产处方、工艺与注册资

16、料的一致性 Reviewandmakeassurancethecomplianceofrawmaterialsupplierwithregisteredsupplier审核原辅料供应商和注册资料的一致性 Reviewrelevantqualitycriteriaincludingrawmaterial,intermediaandfinishedproduct审核原辅料标准、中控质量标准和成品的质量标准n VaccineonePlant疫苗一室 Coordinationandimplementationofthisvalidationprotocol协调、实施本验证方案 Trainingofpe

17、rsonnelbasedonthisvalidationprotocol按验证方案对有关人员进行培训 Collection,sortingandreviewingofvalidationdataanddraftingofvalidationreports(includingthedeviationreport,ifthereareanydeviations)收集、整理和审核验证数据，起草验证报告（如方案执行有偏差，要完成偏差报告）。n Utilitysupportdepartment工程服务部 Assistanceinimplementationofthisvalidationprotocol

18、协助本验证方案的实施 Calibrationofinstrumentsrelatedtothisvalidationprotocolandprovidingrelevantcalibrationcertificatesandqualitycertificates负责校验和本验证方案有关的仪器、仪表，出具校验报告并贴合格证 Assurenormaloperationoftheutilitysystem保证公用系统的正常运行 FinalreportReview最终报告的审核n Qualitycontrolofqualitydepartment质量部质量控制 Determinationoftestm

19、ethodsusedinthisvalidationprotocol负责确定本验证方案的检验方法 ValidationofthenecessarytestmethodsforXXXXXinvolvedinthisvalidationprotocol负责本验证方案涉及的重组乙型肝炎疫苗（CHO细胞）原液生产的必要的检验方法的验证 ThequalityinspectionsonXXXXXTabletinvolvedinthisvalidationprotocol,andpresentingfullitemcertificatesofanalysisandqualityinspectionrepor

20、tsandrecords负责本验证方案涉及的重组乙型肝炎疫苗（CHO细胞）原液生产的质量检验，并出具全项检验报告，提供质量检验报告书及检验记录 Providingtechnicalsupportsandguidancefortestsateachoftheprocesssteps负责各工序检验的技术支持和指导 Coordinatingtheplantintheimplementationofthisvalidationprotocol协同车间实施本验证方案 FinalreportReview最终报告的审核n Qualityassuranceofqualitydepartment质量部质量保证

21、Supervisionofvalidationprocess,reviewandapprovalofthisprotocol,andensuringtheimplementationfollowingthisprotocol负责验证过程监督，方案的审核与批准，确保按批准的方案执行 Samplingateachprocessstepsduringtheprocessvalidation负责工艺验证中各工序的取样 Coordinationamongdifferentdepartmentsinvolvedinthevalidationactivities负责验证涉及到的各部门之间的协调 Provid

22、ingequipmentvalidationreportsrelatedtothisvalidationprotocol负责提供和本验证方案有关的设备验证报告 Identification,auditandassessmentofsuppliers供应商的确认、审计及评价 Assessmentandhandlingofchangesanddeviationsoccurduringthisprocessvalidation负责对工艺验证实施过程中出现的变更和偏差的评价和处理 FinalreportReview最终报告的审核4. RegulationandGuidance法规和指南 EudraLe

23、xVolume4EUGuidelinestoGoodManufacturingPracticeMedicinalProductsforHumanandVeterinaryUse,November,2008EudraLex第四卷欧盟药品生产质量管理规范指南医药产品人用及兽用，2008年11月 FinalVersionofAnnex15totheEUGuidetoGoodManufacturingPractice:QualificationandValidation,September2001EudraLex第四卷药品生产质量管理规范，附录15验证与确认，2001年9月 EMEA-Noteforg

24、uidanceonprocessvalidation,September2001欧洲药品管理局工艺验证指南，2001年9月 EMEA-AnnexIItonoteforguidanceonprocessvalidation,January2005欧洲药品管理局附录II工艺验证指南 FDA21CodeofFederalRegulations,Part211,currentGoodManufacturingPracticeforFinishedPharmaceuticals,April2011FDA联邦法典第21篇第211部分，现行药物制剂生产质量管理规范，2011年4月 FDAProcessVal

25、idation:GeneralPrinciplesandPractices,January2011FDA工艺验证：一般原则和实践，2011年01月 SFDAGoodManufacturingPractice(2010Revision),March,2011SFDA药品生产质量管理规范（2010年修订），2011年03月 PICPIC/SPharmaceuticalInspectionConvention,PharmaceuticalInspectionCo-operationScheme,“RecommendationsonValidationMasterPlan,Installationan

26、dOperationalQualification,Non-sterileProcessValidation,CleaningValidation”,July2004PIC/S药品监管公约，药品监管合作计划，“有关验证主计划、安装和运行确认、非无菌工艺验证、清洁验证的建议”，2004年7月 AWHOGuidetogoodmanufacturingpractice(GMP)requirements,Part2Validation,1997WHO关于GMP要求的指南，第二部分：验证，1997年 ChinesePharmacopoeia(CP)2010Edition中国药典（CP）2010年版 Pr

27、ocessValidationofProteinManufacturing(TechnicalReportNo.42SupplementVol.59,No.S-4September/October20052005byPDA)蛋白生产的工艺验证（技术报告42，PDA，2005年版）5. Abbreviations缩略语Theabbreviationswhichwillbeusedinthisprotocolarelistedinthefollowingform.在下面的表格中规定了本方案中使用的缩略语。表格Error! No sequence specified.缩略语Abbreviations

28、缩略语Definition定义APIActivePharmaceuticalIngredient(or“DrugSubstance”)原料药（或药品物质）CPPCriticalProcessParameter关键工艺参数CQACriticalQualityattribute关键质量属性CVCleaningValidation清洗验证IQInstallationQualification安装确认MFVMediaFillValidation培养基模拟灌装试验N/ANotapplicable不适用OQOperationQualification运行确认PLCProgrammableLogicCont

29、roller可编程逻辑控制器PQPerformanceQualification性能确认PVProcessValidation工艺验证PWPurifiedWater纯化水QAQualityAssurance质量保证RARiskAssessment风险分析SOPStandardOperationProcedure标准操作程序URSUserRequirementSpecification用户使用要求VMPValidationMasterPlan验证主计划WFIWaterforInjection注射用水6. ProtocolDescription方案说明n Usingthisdefinedproce

30、ssvalidationshallbeperformedfortheresultsoftheProcessRiskAssessment.本方案实施的工艺验证，是基于工艺风险评估结果的。n UsingthisdefinedprocessvalidationshallbeperformedforthreeconsecutivesuccessfulrunsbasedonGMPrequirementstodemonstratetheprocesscontrolreliabilityandtherepeatability.鉴于XXX的生产已经有近20年历史，本次验证仅是对生产地址发生变更后且主要设备未发

31、生变化的再验证，考虑到本产品生产周期长（总生产周期为158天）的原因，本方案实施的工艺验证将生产1批成功的产品以证明其可靠性。n Thedeterminationoftheintermediateandfinalproductwillimplemententerpriseinternalstandardbutreleasefinishedproductshouldbeinaccordancewithcriteriaoftheitem“XXX”inChinesePharmacopoeia2010Edition.n 半成品、成品按企业内控标准检验，成品发放按中国药典2010版三部“XXX”标准执行

32、Rawmaterialinternalstandard原辅料内控标准：表格Error! No sequence specified.原辅料质量标准表QualityStandardDoc.质量控制标准文件Doc.Number文件编号SodiumChloride(BP)QualitySpecification氯化钠（药用级）检验质量标准SodiumDihydrogenPhosphate(BP)QualitySpecification磷酸二氢钠（药用级）检验质量标准CrystalAluminumChlorideARQualitySpecification结晶氯化铝AR检验质量标准Glucose(BP

33、)QualitySpecification葡萄糖（药用级）检验质量标准GlutamineQualitySpecification谷氨酰胺质量标准PotassiumBromideQualitySpecification溴化钾质量标准DisodiumEdetateQualitySpecification乙二胺四乙酸二钠质量标准SodiumHydroxide(BP)QualitySpecification氢氧化钠（药用级）质量标准DisodiumHydrogenPhosphate(BP)QualitySpecification磷酸氢二钠(药用级)质量标准Merthiolate(BP)QualityS

34、pecification硫柳汞（药用）质量标准HydrochloricAcid(BP)QualitySpecification盐酸（药用级）检验质量标准Proline(BP)QualitySpecification脯氨酸（药用）质量标准SodiumBicarbonate(BP)QualitySpecification碳酸氢钠（药用级）检验质量标准DMEMQualitySpecificationDMEM质量标准FormaldehydeSolution(BP)QualitySpecification甲醛溶液(药用)质量标准AmmoniumSulfateARQualitySpecification硫

35、酸铵AR质量标准Glycine(BP)QualitySpecification甘氨酸（药用）质量标准Trypsin(BP)QualitySpecification胰蛋白酶(药用)质量标准NewBornBovineSerumQualitySpecification新生牛血清质量标准Methotrexate氨甲喋呤DimethylSulphoxide二甲基亚砜Semi-productofXXXstandard,includetheHarvestliquid,thePurificationliquidandtheBulk.XXX中间品质量标准，包括细胞收获液、纯化产物、原液（文件号：XXX）Fina

36、lproductofXXXstandardXXX成品质量标准：（文件号：XXX）n Thevalidationprocedures,itemsandcontentsaredividedbasedonthesystemprocesssteps.Theprocesssteps,validationitems,samplingmethods,testingmethodsandacceptancecriteriaaredescribedforeachoftheprocesssteps.验证的程序、项目和内容中以系统工序为单位，对各工序中的所涉及的工艺步骤、验证项目、取样方法、检验方法和接受标准进行了规

37、定和描述。n TheprocessrecipeofBulkofXXX(RegistrationbatchNo.:for20g:GUOYAOZHUNZIXXX,andfor10gGUOYAOZHUNZIXXX)isbrieflydescribedinthisprotocol.Thecontentsoftherecipearedescribedandtheprocessflowdiagramislisted.Theprocessprocedureisconformedtotheregistrationstandard.本方案对XXX原液的工艺处方（注册批号：20g：国药准字XXX、10g：国药准字

38、XXX）进行了简介，对处方内容进行描述，并且列出直观化的工艺流程图。工艺规程与注册标准一致。n Thisprotocolisusedtospecifythepurposeandthescopeofthisvalidationandtheresponsibilitiesofeachofthedepartmentsduringtheimplementationofthisvalidationprotocol.本方案旨在指明验证的目的、范围，并规定了该验证方案在实施过程中的各部门的职责。n Summarizeandevaluatetheentireprocessvalidationbasedonth

39、evalidationofeachoftheprocessstepsandrecordtheevaluationresultstothereport.在各工序验证的基础上，对整个工艺验证进行了总结评价，评价结果记录到验证报告中。7. ProductAndProcessDescription产品和工艺描述7.1 Productspecification(1)Ampoule,onehumandoseof1.0ml,containing10gofHBsAg(1)安瓿瓶，每1次人用剂量为1.0ml，含HBsAg10g；(2)Ampoule,onehumandoseof1.0ml,containing2

40、0gofHBsAg(2)安瓿瓶，每1次人用剂量为1.0ml，含HBsAg20g；(3)Vial,onehumandoseof1.0ml,containing20gofHBsAg(3)西林瓶，每1次人用剂量为1.0ml，含HBsAg20g；(4)Vial,onehumandoseof0.5ml,containing10gofHBsAg(4)西林瓶，每1次人用剂量为0.5ml，含HBsAg10g。7.2 DrugapprovalNo.20g：GUOYAOZHUNZIS1096004720g：国药准字S1096004710g：GUOYAOZHUNZIS109600807.3 10g：国药准字S109

41、60080StandardFollowed:ChinesePharmacopoeia2010Edition执行标准：中国药典2010版7.4 RawMaterialsandAdjuvants原辅料情况TableError! No sequence specified.RawMaterialsandAdjuvants表格Error! No sequence specified.原辅料信息表NameSpecificationsManufacturerPackagingSpecificationsSodiumChlorideBPTianjinHaiguangPharmaceuticalIndustr

42、ialCo.,Ltd.1000g/bagDisodiumhydrogenphosphateBPHunanJiudianPharmaceuticalCo.,Ltd.0.5kg/bottleCrystalAluminumChlorideAPBeijingYiliFineChemicalCo.,Ltd.500g/bottleGlucoseAPBaitaikeBioltechnologyCo.,Ltd.(filling)500g/bottleGlutamineuspGradeinvitrogencorporation(Gibco)1kg/drumPotassiumBromideAPBeijingYil

43、iFineChemicalCo.,Ltd.500g/bottleDisodiumEdetateAPSinopharmChemicalReagentCo.,Ltd250g/bottleSodiumHydroxideAPBeijingChemicalFactory500g/bottleMono-waterdisodiumhydrogenphosphateBPHunanJiudianPharmaceuticalCo.,Ltd.0.5kg/bottleMerthiolateBP(USP/BP/EP)GIHON1kg/drumHydrochloricacidAPBeijingChemicalFactor

44、y2500ml/bottleProline-ShanghaiXieheAminoAcidCo.,Ltd.500g/bagSodiumbicarbonateAPBeijingChemicalFactory500g/bottleDMEM-Gibco6687g/drumFormaldehydeAPSinopharmChemicalReagentCo.,Ltd500ml/bottleAmmoniumsulfateAPBeijingYiliFineChemicalCo.,Ltd.25kg/drumGlycineAPSinopharmChemicalReagentCo.,Ltd100g/bottlePan

45、creatin-BD500g/bottleGibco100g/bottleMethotrexate99.0%sigma-aldrich（fluka-analytical）100mg/tubeDimethylSulphoxide-SERVAElectrophoresisGmbH1L/bottleNewbornbovineserumTopgradeWuhanSanliBiotechnologyCo.,Ltd.1000ml/bottle-InnerMongoliaJinyuankangBiotechnologyCo.,Ltd.500ml/bottle原辅料名称规格生产厂家包装规格氯化钠药用级天津海光药业有限公司1000g/袋磷酸氢二钠药用级湖南九典制药有限公司0.5kg/瓶结晶氯化铝分析纯北京益利精细化学品有限公司500g/瓶葡萄糖分析纯宝泰克生物科技公司（分装）500g/瓶谷氨酰胺uspGradeinvitrogencorporation（Gibco）1kg/桶溴化钾分析纯北京益利精细化学品有限公司500g/瓶乙二胺四乙酸二钠分析纯国药集团化学试剂有限公司250g/瓶氢氧化钠分析纯北京化工厂500g/瓶一水磷酸二氢钠药用级湖南