驗(yàn)證主計劃(VMP)浙江華海藥業(yè)

,.,.驗(yàn)證總打算ValidationMasterPlan文件編號ProtocolNumber VMP-001編寫日期PreparationDate 2023.07編寫部門PreparationDepartment質(zhì)量治理部保管部門StorageDepartment 質(zhì)量治理部LTD

浙江華海藥業(yè)股份ZHEJIANGHUAHAIPHARMACEUTICALCO.,文件批準(zhǔn)DocumentApproval下面簽字者已閱讀了該文件并同意該文件中描述的設(shè)施設(shè)備驗(yàn)證總打算。此外，簽字人還認(rèn)cGMPTheundersignedhavereadandagreewiththeFacilityValidationMasterPlanasoutlinedinthisdocument.Furthermore,theundersignedagreethattheproceduresoutlinedinthisplanprovidesufficientevidenceofHUAHAIPHARMA’sdedicationtovalidationandcurrentGoodManufacturingPracticeswithrespecttothefacilitydescribedbythisplan.部門質(zhì)量治理部Q.A.Dept.質(zhì)量治理部Q.A.Dept.QCDept.制劑設(shè)備部Dept.ProductionDept.EHSDept.工程負(fù)責(zé)人ProjectLeader

姓名及職務(wù)NameTitle

簽名與日期Date

職能Role批準(zhǔn)ApprovalcGMPCompliancewithcGMP起草文件FinisheddocumentReview正確性和完整性Correctness&Completeness審核ReviewCorrectness&CompletenessReview正確性和完整性Correctness&Completeness審核ReviewCorrectness&Completeness審核ReviewCorrectness&CompletenessCorrectness&Completeness,.,.Contents一.前言Preface 4\l“_TOC_250013“二.目的Purpose 5\l“_TOC_250012“三.定義Definition 7\l“_TOC_250011“四.范圍Scope 17\l“_TOC_250010“五.驗(yàn)證理念ValidationPhilosophy 21\l“_TOC_250009“六.組織與職責(zé)OrganizationandResponsibilities 24\l“_TOC_250008“七.支持程序SupportProcedure 26\l“_TOC_250007“八.工藝驗(yàn)證ProcessValidation 30\l“_TOC_250006“九.返工ReworkProcedure 33\l“_TOC_250005“十.包裝驗(yàn)證PackagingValidation 33\l“_TOC_250004“十一.清潔驗(yàn)證CleaningValidation 36\l“_TOC_250003“十二.分析方法驗(yàn)證TestMethodValidation 38\l“_TOC_250002“十三.設(shè)備驗(yàn)證EquipmentQualification 40\l“_TOC_250001“十四.公用系統(tǒng)Utilities 45十七.驗(yàn)證文件要求Documentation 51\l“_TOC_250000“十八.變更記載及緣由RevisionHistory 53Preface1989120231.1萬平方米，建筑2.2萬平方米。口服固體制劑車間〔包括片劑和硬膠囊劑〕位于制劑大樓內(nèi)。車間3500202310萬級凈化標(biāo)準(zhǔn)設(shè)計建筑；倉35003000平方米。固體制劑車間年設(shè)計1025個產(chǎn)品〔7個包裝規(guī)格，見附件一〕。ZhejiangHuahaiPharmaceuticalCo.,Ltd.,establishedinJanuary1989,isdevotedtothedevelopment,production,distributionandrelativeservices,ofAPIandPreparation.Thepreparationbuildingareais11,000m2,floorspaceis22,000m2andareawasbuiltin2023.Theoralsolidfinisheddosageformworkshop(includingtabletsandhardcapsules)islocatedinthebuilding.Thefloorspaceoftheworkshopis3,500m2,cleanroomareais2,000m2,anditwasdesignedandconstructedaccordingtoclass100,000.Theareaofthewarehouseis3,500m2whilethefloorspaceforutilityroomandauxiliaryroomis3,000m2.Theannuallycapacityis:1billiontablets,andcapsules200million.Theworkshopswhichhousetheimportedproductionlines,nowproduce5productsincludingParoxetineHydrochloride,IrbesartanTabletsandNevirapineTabletsusedforanti-AIDS(7packingspecifications,seeappendix1).cGMPcGMP要求，確保產(chǎn)品質(zhì)量。Thecompanyhasestablished:aqualityassurancesystem.ThefacilityandequipmentsweredesignedandconstructedaccordingtocGMPs.Thecontrolofmaterial,productionandsalesalsocomplywiththecGMPs,aswellasthecompany’sownproductqualityassurancepolicies.Mainsectioninplant：生產(chǎn)區(qū)、生產(chǎn)關(guān)心區(qū)、倉儲區(qū)及廠前區(qū)〔見華海藥業(yè)廠區(qū)平面布置總圖〕。Manufacturingsectionsupportmanufacturingareawarehouseandsquareinfrontofplant〔seeHuahaiPharmaceuticalGeneralLayout〕.該文件至少每年復(fù)審一次，驗(yàn)證狀態(tài)及驗(yàn)證時間表〔附錄四〕，每年更一次。Thisdocumentwillbereviewedannually.Validationandqualificationstatusandtimeschedulesarelocatedinappendix4.二Purpose浙江華海藥業(yè)。至此簡稱華海藥業(yè)，從事于研發(fā)、制造及分銷藥物制劑。華海FDA，中國藥監(jiān)部門及其它國際組織的質(zhì)量標(biāo)準(zhǔn)。華海堅信對高質(zhì)量的承諾是其到達(dá)其次步目標(biāo)，成為世界級制藥公司并為全球各地供給安全、有效的藥物產(chǎn)品的根底。為實(shí)現(xiàn)其目標(biāo)，華海需要先進(jìn)的FDA床及正常消費(fèi)的華海藥品的生產(chǎn)。ZhejiangHuahaiPharmaceuticalCo.,Ltd.HeretoforeHUAHAIPHARMA,isdedicatedtothedevelopment,manufactureanddistributionofpharmaceuticals.HUAHAIPHARMA’sprimarygoalistodevelopandmanufactureitsproductsaccordingtostandardsthatmeetorexceedthequalitystandardsrequiredbytheUnitedStatesFoodandDrugAdministration(FDA),Chinesegovernmentalagenciesandotherinternationalauthorities.HUAHAIPHARMAbelievesthatitscommitmenttohighqualityisfundamentaltoachievingitssecondarygoalofbecomingaworld-classpharmaceuticalcompanyprovidingsafeandefficaciousnewpharmaceuticalproductstotheglobalcommunity.Tomeetitsgoals,HUAHAIrequiresastate-of-the-artpharmaceuticalmanufacturingfacility.Thefacility,locatedatLizhuangXunqiaozheng,insouthofLinhaicitywillbeanFDAcompliantfacilitymanufacturingHUAHAIPHARMA’sproductsforclinicalandconsumeruse.VMPVMP施，目的是給出額外的可信度：它們是與其生產(chǎn)目的想適應(yīng)且按預(yù)期標(biāo)準(zhǔn)運(yùn)行。此外，VMPcGMPVMPThisValidationMasterPlan,heretoforeVMP.TheVMPpertainstoalldirectandindirectimpactresources/processesinthefacilityandisintendedtogiveanadditionallevelofassurancethattheyaresuitableforuseandwillperformasintended.Furthermore,theVMPdescribesthecommitmentbyHuahaitoperformvalidationofthenecessaryfacilities,equipmentandprocessesinaccordancewithcurrentGoodManufacturingPractice(cGMP)requirements,andapplicablegovernmentalorinternationalstandards,inordertomeetitsgoals.TheVMPisspecificallyintendedtoprovidethefollowing:-使華海藥業(yè)確定與設(shè)施、公用系統(tǒng)及產(chǎn)品相關(guān)的法規(guī)要求-EnableHUAHAIPHARMAtoidentifytheregulatoryrequirementsassociatedwiththefacility,specificutilitiesandequipment,andmanufacturedproduct.-描述并確定華海藥業(yè)的驗(yàn)證及再驗(yàn)證方法-DescribeanddefineHUAHAIPHARMA’sapproachtovalidationandrevalidation.DefinitionAcceptanceCriteria–Thepredeterminedresultofaspecifiedtest.應(yīng)當(dāng)是在批準(zhǔn)在實(shí)施之前。ChangeControl–Processbywhichproposedchangestoaqualifiedsystemareassessedbeforeimplementationtodetermineimpactonthesystem.Proposedchangesshouldbeapprovedpriortoimplementation.試運(yùn)轉(zhuǎn)-一個有了充分的打算,形成文件,并且處理工程學(xué)方法對起動和轉(zhuǎn)交設(shè)施,系統(tǒng),和設(shè)備給最終用戶一個牢靠的結(jié)果和符合預(yù)定設(shè)計要求和業(yè)主期望的功能環(huán)境。Commissioning– Awellplanned,documented,andmanagedengineeringapproachtothestart-upandturnoveroffacilities,systems,andequipmenttotheEnd-Userthatresultsinasafeandfunctionalenvironmentthatmeetsestablisheddesignrequirementsandstakeholderexpectations.CommissioningPlan– Aplanwhichdefinesthefacilities,systemsandequipmentthatwillbecommissionedbasedontheagreedtosystemboundaries.ConcurrentValidation– Validationconductedduringthemanufactureofinitialbatchesofproductfordistribution.2/3GMP筑圖要始終保存。ConstructionDrawings– 2d/3ddrawingsofallsystems,schedules,details,dimensions,notes,references,etc.Thesedrawingsareoften‘red-lined’duringconstructionandupdatedatprojectcompletion.Constructiondrawingsarekeptuptodateformaintenance,safetyandorGMPreasons.的質(zhì)量有直接的影響。CriticalComponent– Acomponentwithinasystemwheretheoperation,contact,data,control,alarmorfailuremayhaveadirectimpactonthequalityoftheproduct.DesignforImpact– Describesthepracticeofmakingconsciousdesigndecisionswithrespecttotheimpactofthesysteminoperationatthebeginningofdesigndevelopment.物、安裝和測試同時產(chǎn)生。DetailedDesign–Designstagewhenthedocumentsrequiredforconstructionbiddingandcontracting,aswellassystemandequipmentpurchase,fabrication,installationandtestingareproduced.工程治理質(zhì)量標(biāo)準(zhǔn)和附加標(biāo)準(zhǔn),都屬于確認(rèn)和驗(yàn)證標(biāo)準(zhǔn)必需依存現(xiàn)行藥品質(zhì)量治理標(biāo)準(zhǔn)。DirectImpactSystem–Asystemthatisexpectedtohaveadirectimpactonproductquality.ThesesystemsaredesignedandoftencommissionedinlinewithGoodEngineeringPracticeandinaddition,aresubjecttoqualificationorvalidationpracticesnecessaryforcGMPcompliance./或者動態(tài)測試支持設(shè)備確認(rèn)或系統(tǒng)的運(yùn)行的和供給商供給的文件證明。FactoryAcceptanceTests(FATs)– Inspectionandstaticand/ordynamictestingofsystemsormajorsystemcomponentstosupportthequalificationofequipmentorsystemsconductedanddocumentedatthesuppliersite.工程質(zhì)量治理標(biāo)準(zhǔn)(GEP)–工程建設(shè)方法和標(biāo)準(zhǔn)它被應(yīng)用在整個工程生命周期過程中以交付適當(dāng)?shù)牡捅惧X的解決方案。GoodEngineeringPractice(GEP)– Establishedengineeringmethodsandstandardsthatareappliedthroughouttheprojectlifecycletodeliverappropriate,cost-effectivesolutions.歷史文件–一個時間點(diǎn)文檔的再現(xiàn)或者是文件的快照。HistoricalDocuments–Documentsrepresentingapoint-in-time,orsnapshot.影響轉(zhuǎn)變變化–給一個系統(tǒng)一個變化，要求重評估確定這個系統(tǒng)的類型是否發(fā)生轉(zhuǎn)變。ImpactAlteringChange– Achangethatismadetoasystemthatrequiresareassessmentbeperformedtodetermineifthesystemtypehaschanged.影響評估-評估一個系統(tǒng)的運(yùn)行,掌握,報警和故障條件對一個產(chǎn)品質(zhì)量的影響的過程。ImpactAssessment– Theprocessofevaluatingtheimpactoftheoperating,controlling,alarmingandfailureconditionsofasystemonthequalityofaproduct.響系統(tǒng)。IndirectImpactSystem– Asystemthatisnotexpectedtohaveadirectimpactonproductquality,buttypicallywillsupportadirectimpactsystem.料以及任何相關(guān)的法律或同這些領(lǐng)域相關(guān)的校準(zhǔn)要求相符合。Inspection– Theprocessbywhichtheconstructionandinstallationisverifiedasinaccordancewiththedetaileddesign,specifiedconstructionstandardsandmaterialsandanyrelevantlegalorregulatorydemandsrelatingtothesesareas.安裝確認(rèn)(IQ)– 證明可能影響產(chǎn)品質(zhì)量的全部設(shè)備或系統(tǒng)的方面,可以供給的標(biāo)準(zhǔn)和安裝,遵守說明書和正確地安裝了談到全部必需的公用設(shè)施和空間。InstallationQualification(IQ)– Thedocumentedverificationthatallaspectsofequipmentorsystems,thatcanaffectproductquality,adheretoapprovedspecificationsandinstalledcorrectlywithrespecttoallrequiredutilitiesandspacerecommendations./或確認(rèn)期間伴隨著設(shè)備系統(tǒng)或工程要求被修改或被更。LivingDocument– Documentsmaintainedthroughoutthecommissioningand/orqualificationperiodasequipment/systemsorprojectrequirementsaremodifiedorupdated.沒有影響系統(tǒng)–一個系統(tǒng),它對產(chǎn)品質(zhì)量不會有任何直接的和間接的影響。NoImpactSystem– Asystemthatwillnothaveanyimpact,eitherdirectlyorindirectly,onproductquality.量將有一個間接的或直接的影響。Non-CriticalComponent– Acomponentwithinasystemwheretheoperation,contact,datacontrol,alarmorfailurewillhaveanindirectornoimpactonthequalityofaproduct.運(yùn)行限度-保證和產(chǎn)品的安全需要符合的微小值并且/或者最大值。OperatingLimits– Theminimumand/ormaximumvaluesthatwillensurethatproductandsafetyrequirementsaremet.運(yùn)行確認(rèn)(OQ)– 夠影響產(chǎn)品質(zhì)量的全部設(shè)備或系統(tǒng)的有證明文件的驗(yàn)證，在整個過程中按意圖運(yùn)行全部的預(yù)期范圍或者生產(chǎn)指定參數(shù)〔凹凸極限值〕。OperationalQualification(OQ)– Thedocumentedverificationthatallaspectsofequipmentorsystems,thatcanaffectproductquality,operateasintendedthroughoutallanticipatedrangesorwith-inmanufacturerspecifiedparameters(highandlowlimits).性能確認(rèn)(PQ)運(yùn)行條件下，按意圖完成和預(yù)先確定可承受的標(biāo)準(zhǔn)全都。PerformanceQualification(PQ)– Thedocumentedverificationthatallaspectsofequipmentorsystems,thatcanaffectproductquality,performasintendedandmeetpredeterminedacceptancecriteriaundernormal(specific)operatingconditions.作用的系統(tǒng)產(chǎn)量和交付的必需職責(zé)或生產(chǎn)量全都，證明系統(tǒng)的相互依靠的作用是和指定的全都，并且適宜。PerformanceTesting– Theprocessbywhichtheperformanceofinterdependentsystemsisdemonstratedaswithintherequiredtolerance,theoutputofinterdependentsystemsisdemonstratedasdeliveringtherequireddutyorcapacity,theinterdependentfunctionsofsystemsaredemonstratedtobeasspecifiedandappropriate.管道和儀表流程圖(P&IDs)P&IDs備配置、過程參量、儀表,和建筑材料。PipingandInstrumentationDiagrams(P&IDs)– P&IDsdepictdesigninformationforutilitysystemsandprocessequipment,includingprocessflow,equipmentconfiguration,processparameters,instrumentation,andmaterialsofconstructionforutilitysystemsandprocessequipment.預(yù)先確定的標(biāo)準(zhǔn)和質(zhì)量特征全都的產(chǎn)品。ProcessValidation– Establishingdocumentedevidence,whichprovidesahighdegreeofassurancethataspecificprocesswillconsistentlyproduceaproductmeetingitspre-determinedspecificationandqualityattributes.確認(rèn)也進(jìn)展在一個產(chǎn)品的銷售或者在一個可能影響到產(chǎn)品特性的生產(chǎn)過程修改下的產(chǎn)品生產(chǎn)前過程確認(rèn)。Prospectivevalidation-Validationconductedonequipment/instrumentsandancillarysystemspriortotheiruseinacGMPcapacity.Prospectivevalidationalsoreferstoprocessvalidationconductedpriortothedistributionofanewproduct,orproductmadeunderarevisedmanufacturingprocess,wheretherevisionsmayaffecttheproduct”scharacteristics.果確保一個系統(tǒng)安裝、運(yùn)行和性能與預(yù)確認(rèn)標(biāo)準(zhǔn)全都?！怖惭b確認(rèn)、運(yùn)行確認(rèn)、性能確認(rèn)方案〕。QualificationProtocol– Adetaileddocumentthatdescribesthesystemunderconsideration,thetestingplans,theacceptancecriteriaandtestresultsthatensurethatasystemisinstalled,operatesandperformsinaccordancewithpredeterminedspecification(i.e.IQ,OQandPQprotocols).驗(yàn)證總結(jié)報告–總結(jié)一個驗(yàn)證方案實(shí)行結(jié)果的報告。QualificationSummaryReport– Reportsummarizingtheresultsofanexecutedqualificationprotocol.質(zhì)量保證–一個團(tuán)隊或者團(tuán)隊的行為對確保設(shè)備/系統(tǒng)和藥品生產(chǎn)質(zhì)量治理標(biāo)準(zhǔn)要求全都負(fù)責(zé)。QualityAssurance(QA)– Theactivityoforgroupresponsibleforensuringthatequipment/systemsmeetGMPrequirements.質(zhì)量掌握–一個團(tuán)隊或者一個團(tuán)隊的作用對相關(guān)同等者的行為負(fù)責(zé)，和分析測試打算和執(zhí)行相關(guān)聯(lián)。QualityControl(QC)– Processoforgroupresponsibleforcoordinatingtheactivitiesassociatedwithanalyticaltestplanningandexecution.回憶性驗(yàn)證–對已經(jīng)使用了現(xiàn)行的藥品質(zhì)量治理標(biāo)準(zhǔn)生產(chǎn)后的設(shè)備/儀器和關(guān)心系統(tǒng)進(jìn)展驗(yàn)證?；貞浶则?yàn)證也指對一個已經(jīng)在銷售的產(chǎn)品的根底上積聚的產(chǎn)品進(jìn)展加工驗(yàn)證測試和掌握數(shù)據(jù)。Retrospectivevalidation–Validationconductedonequipment/instrumentsandancillarysystemsalreadyusedinacGMPcapacity.Retrospectivevalidationalsoreferstoprocessvalidationconductedforaproductalreadyindistributionbaseduponaccumulatedproduction,testingandcontroldata.間/運(yùn)行根底上的評估使用重復(fù)性驗(yàn)證。Revalidation– Validationofapreviouslyvalidatedsystemthathasbeenchangedormodified.Revalidationcanbeperformedasaresultofasystemchange,oratime/performancebasedassessment.現(xiàn)場驗(yàn)收測試– 檢查或者系統(tǒng)動態(tài)測試或者主要系統(tǒng)的組成局部驗(yàn)證---建立有文件證明的證據(jù)對設(shè)備/儀器和關(guān)心系統(tǒng)將依據(jù)規(guī)定或要求、標(biāo)準(zhǔn)始終如一的運(yùn)行供給一個高度的保證。SiteAcceptanceTesting(SAT)– Inspectionand/ordynamictestingofthesystemsormajorsystemcomponentsValidation-Establishingdocumentedevidencethatprovidesahighdegreeofassurancethatequipment/instrumentsandancillarysystemswillconsistentlyperformaccordingtostated,orrequired,specifications.技術(shù)說明– 清楚明確的定義要求、代號和標(biāo)準(zhǔn)的文件，在構(gòu)筑物和建筑物建設(shè)、測試要求、承受標(biāo)準(zhǔn)和相關(guān)可交付的時候遵守。Specifications– Documentationwhichclearlyandexplicitlydefinesthesystemrequirements,codesandstandardstobefollowedduringfabricationandconstruction,testrequirements,acceptancecriteriaandtheassociateddeliverables.標(biāo)準(zhǔn)操作規(guī)程–確保活動每次以執(zhí)行同樣方式的書面和被批準(zhǔn)的規(guī)程。StandardOperatingProcedure(SOP)– Writtenandapprovedprocedurestoensurethatactivitiesareperformedthesamewayeachtime.硬件、計算機(jī)軟件,等...)System– Anorganizationofengineeringcomponents,whichhaveadefinedoperationalfunction(i.e.piping,instrumentation,equipment,facilities,computerhardware,computersoftware,etc…).系統(tǒng)界限-極限被畫在系統(tǒng)四周規(guī)律上定義什么是包括在系統(tǒng)之內(nèi)什么不包括在系統(tǒng)。SystemBoundary– Alimitdrawnaroundasystemtologicallydefinewhatisandwhatisnotincludedinthesystem.SystemDescription– Generaldescriptionofasystemdescribingitscomponents,functionalcapabilities,criticalfunctionsandsystemboundaries.驗(yàn)證總打算(VMP)-建立一個傘形驗(yàn)證打算為一個完整全部工程的一個高級別文件。ValidationMasterPlan(VMP)– Ahighleveldocumentthatestablishesanumbrellavalidationplanforanentireproject./參數(shù)和驗(yàn)收標(biāo)準(zhǔn)。參見確認(rèn)方案。Validationprotocol-Awrittenplanstatinghowthevalidationwillbeconducted.Thisincludestestprocedures/parametersandacceptancecriteria.SeealsoQualificationProtocol.供給商/承包商審計-供給商的交付一個合格產(chǎn)品/效勞的力量的評估。Vendor/ContractorAudit– Anevaluationofthesupplier’sabilitytodeliveraqualityproduct/service.最差狀態(tài)-一種狀況包含的上部和更低的操作或處理極限和狀況,包括那些在標(biāo)準(zhǔn)操作程致操作或過程故障。Worstcase-Asetofconditionsencompassingupperandloweroperatingorprocessinglimitsandcircumstances,includingthosewithinstandardoperatingprocedures,whichposethegreatestchanceofoperationorprocessfailurewhencomparedtoidealconditions.Suchconditionsdonotnecessarilyinduceoperationorprocessfailure.ScopecGMP要的活動。將包括，但不僅限于，華海藥業(yè)的制劑樓及相關(guān)試驗(yàn)室的設(shè)施〔構(gòu)造、空間及公用系統(tǒng)〕、工藝公用系統(tǒng)、生產(chǎn)設(shè)備、檢測儀器、校驗(yàn)程序及檢測設(shè)備、預(yù)修理原則及相應(yīng)的計算機(jī)掌握系統(tǒng)。Thisprotocolwillapplyto,andguide,requisiteactivitiesrelatingtothevalidationofallnecessaryfacilities,equipmentandprocessesthataresubjecttocGMP’sanddefinedasdirectorindirectimpactresources.Thiswillinclude,butisnotlimitedto,facilities(structures,spacesandutilities),processutilities,manufacturingandfinishingequipment,analyticalinstrumentation,calibrationproceduresandtestequipment,preventativemaintenancepolicyandthespecificcomputerrelatedsystemsof:HUAHAIPHARAM’sFinishedDosageformBuildingandassociatedlaboratories.其范圍包括以下系統(tǒng)的驗(yàn)證：Thescopeofthisdocumentistocovervalidation/qualificationactivitiesforthefollowingsystems:Premiseandfacilities主廠房布局見“制劑廠房平面布置圖”。MainPharmaceuticalBuildingLayoutsee“Facilitylayout”.人流及物流見“制劑廠房平面布置圖”。PeopleFlowandMaterialFlowsee“Facilitylayout”.-公用系統(tǒng)，包括工藝用水系統(tǒng)、空調(diào)系統(tǒng)、壓縮空氣系統(tǒng)；included.燈、安排管道及各用點(diǎn)組成。PurifiedWaterSystemiscomprisedof:rawwatertank,sand-filter,carbonfilter,finefilter,firsthighpressurepump,firstRO,middletank,secondhighpressurepump,secondRO,purifiedwatertank,PWdistributionpump,UV,distributionpipeandusepoints.及掌握工作區(qū)的塵埃、水汽、廢氣及氣味；并處理循環(huán)風(fēng)及外排風(fēng)。HVACiscomprisedof:supplyandexhaustfan,heatingandcoolingcoils,filters,humidifyingunit,ductwork,instrumentsandcontrolsystems.Theseareusedtosupplycleanairandmonitortoworkingarea.Captureandcontrolanydusts,vapors,gasesorfumesgenerated,aswellastreatmentofre-circulatedand/orexhaustair.生產(chǎn)區(qū)干凈級別圖見“制劑廠房平面布置圖”。WorkingAreaCleanClasssee“facilitylayout”.空氣流向圖見“HVACAirFlowsee“HVACDiagram”.壓縮空氣系統(tǒng)，主要由無油空氣壓縮機(jī)、儲罐、過濾器、空氣枯燥器、管道及掌握系統(tǒng)等組成,以便以正確的壓力產(chǎn)生和輸送壓縮空氣到使用點(diǎn)。穎空氣、安排系統(tǒng)都對輸往用點(diǎn)的空氣質(zhì)量有重要影響。Compressedairsystemiscomprisedof:theoil-freecompressor,tank,filters,air-dyer,pipe-workandcontrolsusedtogenerateanddeliverthematthecorrect pressure to the points of use. The fresh air supplied to compressorsandthedistributionsystem,allhaveanimportantbearingonthequalityofcompressedairdeliveredtotheenduser.制造與包裝；ProcessingandPackaging生產(chǎn)工藝流程示意圖見附錄三.Processflowchartseeappendix3.分析方法驗(yàn)證；AnalyticalMethodValidation清潔驗(yàn)證；CleaningValidationEquipmentQualification；〔包括移動及固定設(shè)備〕、測量設(shè)備及試驗(yàn)室設(shè)備。Includespecificproductionandancillaryequipment(includethemovableandun-movable),measuringequipment/instrument,andlaboratoryequipment.FacilityOverview:cGMP1.12.23500方米〔102023〕，35003500TheHUAHAIPHARMApreparationworkshopisusedforthedevelopmentandmanufactureofdosageformpharmaceuticals.TheworkshopwasdesignedandconstructedaccordingtothecGMPrequirements.Theareaofbuildingis11,000m2;thefloorspaceis22,000m2.Whichthenisdividedintothefollowing:theoralsolidpreparationworkshopfloorspaceis3,500m2(class100,000cleanroomis2,000m2),thewarehouseis3,500m2,andtheutilityandancillaryroomis3,500m2.2QC，3ThesecondfloorhousestheQClaboratories.Officesandthetrainingroomarelocatedonthethirdfloor.GMPGMPTheworkshopisbrokendownintoGMPandNonGMPzones.GMP106TheGMPareareferstothewarehouseandproductionsections.Thewarehouseisusedformaterialandpackingmaterialstorage.Theproductionarea,whichusedforthepreparation,andpackagingofthedrugsisclass100,000.Theenvironmentcontrolsinplacearedesignedtoinsurethequalityoftheproducts.Themicrobiologylabislocatedintheexecutiveofficebuilding.GMPGMP區(qū)域的驗(yàn)證測試活動。Thenon-GMPregionreferstothereceptionarea,office,loading,dining,andbathrooms.TherearenoGMPrequirementsfortheseareas.However,theyshouldbemaintainedtocreateacomfortableworkingcondition.ThereisnovalidationandtestingactivityforthisregionintheVMP.TheGroundFloorLayout制劑大樓二層平面圖TheSecondFloorLayoutTheThirdFloorLayoutRooftopLayoutAreaClassificationsLayout人流/物流/Personnel/Material/WasteFlowseeaboveLayoutValidationPhilosophy依據(jù)華海藥業(yè)的質(zhì)量政策，全部供給市場產(chǎn)品的生產(chǎn)過程〔生產(chǎn)，包裝，清潔，測試，〕均應(yīng)是已驗(yàn)證的，以確保其牢靠性及重現(xiàn)性，并符合中國和美國現(xiàn)行的藥品生產(chǎn)的法規(guī)要求。AccordingtothequalitypolicyofHUAHAIPHARMAthatallproductsmarketedmustbevalidated(productionprocess,packaging,cleaningandanalysismethod,storageanddistribution,etc.)toensurethattheprocessisreproducibleandreliableandismanufacturedinaccordancewithP.R.ChinaandUSFDARegulations.生產(chǎn)工藝，清潔程序，計算機(jī)掌握系統(tǒng)及分析測試方法，對產(chǎn)品質(zhì)量、安全、純度、效/物料掌握/產(chǎn)品分析的分析方法需閱歷證，與上述有關(guān)的設(shè)備、儀器、設(shè)施與公用系統(tǒng)需經(jīng)確認(rèn)。Manufacturingprocesses,cleaningprocedures,computerizedcontrolsystems,andanalyticaltestingmethods,usedinmanufacturing,materialmanagementandcontrolofdrugproductsthathaveanimpactontheproductquality,safety,purityorefficacymustbevalidated.Equipment,instrumentation,facilitiesandutilitiesusedinconjunctionwiththeabovemustbequalified.完善的組織實(shí)施的驗(yàn)證可供給以下好處：Aproperlymanagedandexecutedvalidationprogramprovidesthefollowingadvantages:確保生產(chǎn)工藝的牢靠性及重現(xiàn)性。Reliableandreproducibilityprocess.降低檢查、測試、返工、鋪張及投訴Reducesinspectiontestingreworkscrapandproductcomplaints.便利質(zhì)量治理及質(zhì)量掌握Easymanagementandcontrolofquality.增加對工藝過程的生疏程度Betterunderstandingoftheprocesses.對工藝過程的潛在危急更加了解Highlightspotentialweaknessesinprocesses有利于消滅問題后行動打算的提出Allowscorrectiveactionstobetakenwhendeemedappropriate.削減修理費(fèi)用及停工時間Reducesmaintenancecostsandequipmentdowntime.一個驗(yàn)證了的過程／方法長期來看是經(jīng)濟(jì)的Aproven(validated)process/methodwillsaveTIMEandMoneyinthelongrun.提高合格產(chǎn)品的批次Increasethenumberofproductionlots,whichmeetspecifications.QA、QC、生產(chǎn)、物流、設(shè)備部等，均應(yīng)參預(yù)其中以實(shí)現(xiàn)各部門的職能。Amultidisciplineteamisrequiredforplanningandexecutionofvalidationstudies.Experts/specialistfromrelativedepartments,QA,QC,Production,Logistic,EM,shallbeincludedtoexecuteindividualdepartmentfunction.QA果與方案中的可承受標(biāo)準(zhǔn)相比較，并寫出書面報告。Eachvalidationactivitymustbeconductedasperapprovedprotocol.Oncethevalidationprotocolhasbeenexecuted,resultswillbecomparedagainstthepre-determinedspecifications/acceptancecriteriaoutlinedintheprotocolandaformalreportwillbeissued.每一個驗(yàn)證都應(yīng)當(dāng)有偏差報告Deviationswillbereportedforeachvalidation.假設(shè)驗(yàn)證中消滅偏差并不意味著驗(yàn)證失敗。驗(yàn)證團(tuán)隊在再分析的根底上給出結(jié)論。Ifthereisdeviation,itdoesnotmeanthevalidationhasfailed.Aconclusionwillbebasedontheassessmentmadebyvalidationteam.全部用于驗(yàn)證數(shù)據(jù)測量的儀器均應(yīng)校驗(yàn)。測試方法均應(yīng)是已驗(yàn)證的。Allequipment/instrumentsusedinavalidationstudytocollect/measureresultsoroutcomewillbecalibrated.Allanalyticalmethodsusedtoanalyzesamplesofavalidationstudywillbevalidated.性、有效性、純度及藥效的影響。Allequipmentwillbeadequatelycleanedandsanitizedsoastominimizeanycontaminationfromchemicaland/ormicrobialcontaminants,whichmayhaveimpactonsafety,identity,strength,andpurityofthedrugproducts.OrganizationandResponsibilities各部門的親熱合作才能有效實(shí)施。Avalidationstudyisacross-functionproject,whichrequiresaclosejointeffortofallrelativedepartments.質(zhì)量治理部經(jīng)理協(xié)調(diào)其他部門：QADepartmentmanagerworkstogetherwithotherdepartmentstoestablish:-制定華海藥業(yè)驗(yàn)證方針政策ValidationpoliciesofHUAHAIPHARMA.-制定驗(yàn)證總打算ValidationMasterPlan-負(fù)責(zé)起草各類驗(yàn)證治理程序Responsibleforestablishingsystemmanagementproceduresonvalidationandqualification-年度驗(yàn)證培訓(xùn)打算的編制并參與驗(yàn)證培訓(xùn)工作Annualtrainingplanandexecutingtheplan-起草或指導(dǎo)起草，審核驗(yàn)證方案及報告Draftorguideprotocolcreating,reviewandapproveprotocol/reports-參與及指導(dǎo)驗(yàn)證的實(shí)施、結(jié)果評價Participateorguidevalidationexecution,andresultevaluation-解決驗(yàn)證工作中存在的問題〔如偏差處理，時間沖突，資金，人手等〕Problemshandling(deviationhandlingtimeconflictionbudgetHRetc.)AnnualassessmentonvalidationtosupportVMPrevision.EngineeringDepartment-計量人員負(fù)責(zé)對所用儀表、計量器具進(jìn)展校驗(yàn)，并有校驗(yàn)合格證。Theengineeringpersonnelareresponsibletoverifyallthemeasuringinstruments,andthemeasuringinstrumentshavetheverificationcertificates.告。Theengineeringpersonnelareresponsiblefortheinstallation,thedebuggingandtheconfirmationworkforvarioussystemsandtheequipment,andprovidevarioussystemsandtheequipmentconfirmationreport.Laboratory-QCTheQCmanagerisresponsiblewiththedraftofthevalidationprotocolandtheactivityrelatedtoqualitycontrolintheimplementationprocess-QCThequalitycontrolpersonnelareresponsiblefortheexaminationarrangementandreexaminesofallthesamplesProductionDepartment的驗(yàn)證，確保全部的驗(yàn)證結(jié)果都有記錄并供給正確的報告。Productiondepartmentmanagerisresponsibleforthetrainingofworkshoppersonnel.Themanagerwillarrange,accordingtotherequestofthevalidationmasterplantocarryouttheconfirmationoftheprocesscraftandtheequipment.ThemanagerinsurealltheconfirmationresultshavebeenrecordedandwillgeneratethefinalreportSupportProcedure種：Validationexecutionandvalidatedstatusmaintainingrelyonsomesupportprocedures.Theseproceduresare：PreventiveMaintenanceProcedure檢驗(yàn)以及更換局部接近時效的零部件。預(yù)防修理程序適用于全部的生產(chǎn)設(shè)備及公用設(shè)施。Preventivemaintenanceisdifferentfrommachinetrouble-shooting/repairing.Itspurposeistokeepthemachineinnormaloperatingconditionconsistently.Conductmaintenancebeforemachineproblemsoccurs,suchas,cleaning,adjustment,lubricating,andreplacingwornmachineparts.Allproductionrelatedmachinesshouldbecoveredbythepreventivemaintenanceprocedures.維護(hù)打算。Projectleadermustinformmaintenanceunitformally,andPMplanshallbeestablishedbymaintenanceunitaccordingtothevendor’stechnicaldocuments.SOPN－013。TheprocedureofmanagementofPMforequipmentwillbeperformedasperSOPN－013.CalibrationManagementProcedure計量治理程序用于保證公司內(nèi)用于生產(chǎn)過程掌握、產(chǎn)品質(zhì)量檢驗(yàn)以及公用設(shè)施監(jiān)測計量用的全部測量設(shè)備在使用中工作狀態(tài)完好牢靠，所供給的測試數(shù)據(jù)準(zhǔn)確無誤。CalibrationManagementProcedureguaranteethatallinstrumentsforproductionprocesscontroltest/analysisutilitiesinspectionarereliableandinoperatingconditionThedataoutputiscorrectandaccurate.〔A〕、重要測量設(shè)備〔B〕、一般測量設(shè)備〔C〕。Thereare3categoriesforallinstruments:criticalinstruments〔A〕,importantinstruments〔B〕,non-criticalinstruments〔C〕應(yīng)有測量標(biāo)準(zhǔn)Theremustbemeasuringstandards要組成局部。Theremustbeaninstrumentlist,andallinstrumentsmustbecontrolled.Calibrationisakeycomponentofvalidation.SOPD-051。TheinstrumentcalibrationwillbeperformedasperSOPD-051.StandardOperatingProcedure持的前提條件。設(shè)備功能一旦發(fā)生變化，以上程序應(yīng)進(jìn)展相應(yīng)修訂并實(shí)施必要的再驗(yàn)證。ThereareSOPs,suchasequipmentoperationSOP,equipmentcleaningSOPandprocess/systemcontrolSOP,etc.TheestablishmentandimplementationofSOPcorrectlyisthefoundationofsystem/equipmentsmoothlyrunningandensurethequalityofproducts.Itisalsotomaintainthevalidatedstatusofsystem/equipment.Iftherearechangestothesystem/equipment,theSOPmustbechanged,aligned,andrevalidation/re-qualificationshallbeexecutedifnecessary.TrainingProcedure質(zhì)量的前提。每進(jìn)展一次培訓(xùn)，應(yīng)作好培訓(xùn)記錄，并應(yīng)對培訓(xùn)的效果進(jìn)展確認(rèn)。培訓(xùn)記錄應(yīng)進(jìn)展存檔，妥當(dāng)保存。Trainingisessentialforalloperationsrelatedwithproductmanufacturing(production,analysis,equipmentmaintenance/repairing,Validation)toinsurethequalityofthematerialproducedAlltrainingshallberecordedassessedandfiled.SOPK-002。ThemanagementoftrainingwillbeperformedasperSOPK-002.Non-conformancehandling偏差處理程序措施，評估該偏差對驗(yàn)證目標(biāo)的影響。Ineachvalidationprotocol,non-conformance/deviationhandlingrequirementshallbedescribed.Forallnon-conformance/deviationconductinvestigations,seektherootcauseandperformcorrectionactions.Evaluationtheaffectonthevalidationforalldeviation/non-conformanceoccursduringvalidation.SOPG-051。Themanagementofnon-conformancefromvalidationwillreferenceSOPG-051.ControlofChangeQAQA的，它可能直接或間接地影響到產(chǎn)品質(zhì)量。任何變更實(shí)施前，均應(yīng)對變更結(jié)果進(jìn)展評的變更。HUAHAIPHARMACOCproceduremustbefollowedwhenmakingchangesonvalidated/qualifiedsystem,process,equipment,andtestmethod,specification.NochangesareacceptablewithoutQAapproval.Changeswithoutevaluation/QAapprovalisadirectorindirectrisktoproductquality.BasedonCOCassessment,sometimes,revalidation/re-qualificationwillbenecessarytokeepthevalidated/qualifiedstatus.AlltheCOCformmustbefiledappropriately.Anannualassessmentwillbeperformedtofindanychangesthatmayhavebeenmadewithoutthepropercontrol.SOPG-036。ThemanagementofCOCwillbeperformedasperSOPG-036.ProcessValidation工藝驗(yàn)證分類為：Processvalidationswillbecategorizedas:ProspectiveValidation工藝預(yù)驗(yàn)證。Validationconductedpriortothedistributionofproduct.Allnewcommercialproductsandsignificantchangestoproductsandprocesseswherethechangesmayaffecttheproduct’sattributesmustbeprospectivelyvalidated.史數(shù)據(jù)(如，生產(chǎn)，測試及掌握數(shù)據(jù))回憶。Establishingdocumentedevidencethataprocesscurrentlyinusedoeswhatitpurportstodoandinsomecasescanbeusedforaretrospectivevalidation.Thismaybebasedonreviewandanalysisofhistoricinformation(duction,testingandcontroldata).ConcurrentValidation的工藝過程滿足產(chǎn)品生產(chǎn)對該工藝過程的要求。Establishingdocumentedevidencethataprocessdoeswhatitpurportstodobasedonproduction,testing,controlandotherdata/informationaccumulatedduringtheimplementationoftheprocess.QAThebatchesfromtheconcurrentvalidationprogramcanbeusedforsaleorsupply.Itisimportantinthesecasesthatthedeci