WHO961文件-附件6無菌藥品良好生產(chǎn)規(guī)范(中英文)要點(diǎn)

LIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD麗珠集團(tuán)福州福興醫(yī)藥?WorldHealthOrganizationWHOTechnicalReportSeries,No.961,2023WHO961，2023Annex6WHOgoodmanufacturingpracticesforsterilepharmaceuticalproducts6無菌藥品良好生產(chǎn)標(biāo)準(zhǔn)IntroductionFollowingimplementationoftheseWHOgoodmanufacturingpractices(GMP)guidelines(1)withinthecontextoftheWHOPrequali?cationofMedicinesProgramme,clarifying,editorialmodi?cationshavebeenproposed.Thesechangeswereadoptedformaintenancepurposes.InordertoeasereadingthefullguidelinehasbeenreproducedagainasanAnnextothecurrentreportoftheWHOExpertCommitteeonSpeci?cationsforPharmaceuticalPreparations.引言以下WHO藥品質(zhì)量治理標(biāo)準(zhǔn)〔GMP1〕指南在WHO已經(jīng)被提出。這些變更的應(yīng)用以維護(hù)的目的。為了便于閱讀，整篇指南已被重編制并作為WHO藥品標(biāo)準(zhǔn)專家委員會報告的一個附件。LIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD.ADD:JiangyinIndustrialZone,Fuqing,Fujian,350309,P.R.ChinaTEL:+86-591-85966928;+86-591-85966932;FAX:+86-591-85966925E-MAIL:xmdongwei@sina;fuxingra@sina;“mailto:regulation@fxpharm“regulation@fxpharmWEBSITE:“://fxpharm/“fxpharm1of47LIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD麗珠集團(tuán)福州福興醫(yī)藥WHOgoodmanufacturingpracticesforsterilepharmaceuticalproductsWHO無菌藥品良好生產(chǎn)標(biāo)準(zhǔn)\l“_TOC_250014“GENERALCONSIDERATIONS 3\l“_TOC_250013“總則 3\l“_TOC_250012“QUALITYCONTROL 3\l“_TOC_250011“質(zhì)量掌握 3SANITATION 5衛(wèi)生 5\l“_TOC_250010“MANUFACTUREOFSTERILEPREPARATIONS 6\l“_TOC_250009“無菌產(chǎn)品的生產(chǎn) 6STERILIZATION 245.滅菌 24\l“_TOC_250008“TERMINALSTERILIZATION 26\l“_TOC_250007“最終滅菌 26ASEPTICPROCESSINGANDSTERILIZATIONBY?LTRATION 32\l“_TOC_250006“無菌操作和過濾滅菌 32\l“_TOC_250005“ISOLATORTECHNOLOGY 35\l“_TOC_250004“隔離技術(shù) 35BLOW/?LL/SEALTECHNOLOGY 36\l“_TOC_250003“吹/灌/封技術(shù) 36\l“_TOC_250002“PERSONNEL 37\l“_TOC_250001“10. 人員 37PREMISES 4011.廠房 40\l“_TOC_250000“EQUIPMENT 44LIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD.ADD:JiangyinIndustrialZone,Fuqing,Fujian,350309,P.R.ChinaTEL:+86-591-85966928;+86591-85966932;FAX:+86-591-85966925E-MAIL:xmdongwei@sina;fuxingra@sina;“mailto:regulation@fxpharm“regulation@fxpharmWEBSITE:“://fxpharm/“fxpharm2of47LIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD麗珠集團(tuán)福州福興醫(yī)藥12. 設(shè)備 44FINISHINGOFSTERILEPRODUCTS 4513.無菌產(chǎn)品完成 45Generalconsiderations總則Theproductionofsterilepreparationsshouldbecarriedoutincleanareas,entrytowhichshouldbethroughairlocksforpersonneland/orforequipmentandmaterials.Cleanareasshouldbemaintainedtoanappropriatestandardofcleanlinessandsuppliedwithairthathaspassedthrough?ltersoftherequiredef?ciency.無菌產(chǎn)品的生產(chǎn)應(yīng)在干凈區(qū)進(jìn)展，人員和/或設(shè)備和物料進(jìn)入干凈區(qū)應(yīng)通過氣閘室進(jìn)入。干凈區(qū)應(yīng)保持適當(dāng)?shù)母蓛舳葮?biāo)準(zhǔn)并供給經(jīng)過有效的過濾的空氣。Thevariousoperationsofcomponentpreparation(suchasthoseinvolvingcontainersandclosures),productpreparation,?llingandsterilizationshouldbecarriedoutinseparateareaswithinthecleanarea.Theseareasareclassi?edintofourgrades(seesection4).組件的預(yù)備〔如相關(guān)的容器和密閉包裝，產(chǎn)品的制備、灌裝和滅菌操作應(yīng)在干凈區(qū)內(nèi)分區(qū)域進(jìn)展。這些干凈區(qū)分為四個等級〔4節(jié)。Manufacturingoperationsaredividedhereintotwocategories:—?rst,thosewheretheproductisterminallysterilized;and—second,thosewhichareconductedasepticallyatsomeorallstages.1.3生產(chǎn)操作在此可以劃分為兩類：—第一，僅在最終階段滅菌的產(chǎn)品；—其次，局部或全部工序承受無菌生產(chǎn)工藝的產(chǎn)品。Qualitycontrol質(zhì)量掌握Thesterilitytestappliedtothe?nishedproductshouldonlyberegardedasthelastinaseriesofLIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD.ADD:JiangyinIndustrialZone,Fuqing,Fujian,350309,P.R.ChinaTEL:+86-591-85966928;+86591-85966932;FAX:+86-591-85966925E-MAIL:xmdongwei@sina;fuxingra@sina;“mailto:regulation@fxpharm“regulation@fxpharmWEBSITE:“://fxpharm/“fxpharm3of47LIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD麗珠集團(tuán)福州福興醫(yī)藥controlmeasuresbywhichsterilityisassured.Thetestshouldbevalidatedfortheproduct(s)concerned.應(yīng)進(jìn)展驗(yàn)證。Samplestakenforsterilitytestingshouldberepresentativeofthewholeofthebatchbutshould,inparticular,includesamplestakenfrompartsofthebatchconsideredtobemostatriskofcontamination,forexample:forproductsthathavebeen?lledaseptically,samplesshould includecontainers?lledatthebeginningandendofthebatchandafteranysigni?cantinterruptionofwork;forproductsthathavebeenheatsterilizedintheir?nalcontainers,considerationshouldbegiventotakingsamplesfromthatpartoftheloadthatispotentiallythecoolest.品。無菌灌裝的產(chǎn)品，取樣應(yīng)包括灌裝前、灌裝后和有明顯中斷的時候。僅在在最終步驟進(jìn)展高溫滅菌的產(chǎn)品，應(yīng)考慮從最涼處取樣。Thesterilityofthe? nishedproduct isassuredbyvalidationofthesterilizationcycle insterilizedproducts,andby “mediasimulation”or “media? ll”runsforasepticallyprocessedproducts.Batch-processingrecordsand,inthecaseofasepticprocessing,environmentalqualityrecords,shouldbeexamined inconjunctionwiththeresultsofthesterilitytests.Thesterilitytestprocedureshouldbevalidatedforagivenproduct.Pharmacopoeialmethodsshouldbeusedforthevalidationandperformanceofthesterilitytest.Inthosecaseswhereparametricreleasehasbeenauthorizedinplaceofsterilitytestingspecialattentionshouldbepaidtothevalidationandthemonitoringoftheentiremanufacturingprocess.假設(shè)是無菌工藝生產(chǎn)的產(chǎn)品，應(yīng)確保進(jìn)展了“培育基模擬”和“培育基灌裝”。批生產(chǎn)記錄和環(huán)境質(zhì)量記錄〔無菌生產(chǎn)過程中的〕應(yīng)結(jié)合無菌度檢測結(jié)果進(jìn)展檢查。對給出的產(chǎn)品應(yīng)進(jìn)展無菌度檢測驗(yàn)證。驗(yàn)證和無菌度檢測應(yīng)使用藥典的方法。假設(shè)授權(quán)使用參數(shù)放行取代無菌度檢LIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD.ADD:JiangyinIndustrialZone,Fuqing,Fujian,350309,P.R.ChinaTEL:+86-591-85966928;+86-591-85966932;FAX:+86-591-85966925E-MAIL:xmdongwei@sina;fuxingra@sina;“mailto:regulation@fxpharm“regulation@fxpharmWEBSITE:“://fxpharm/“fxpharm4of47LIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD麗珠集團(tuán)福州福興醫(yī)藥測，應(yīng)留意特別關(guān)注驗(yàn)證和整個生產(chǎn)過程的監(jiān)測。Forinjectableproductsthewaterforinjectionandthe intermediate,ifappropriate,and?nishedproductsshouldbemonitoredforendotoxins,usinganestablishedpharmacopoeialmethodthathasbeenvalidatedforeachtypeofproduct.Forlarge-volumeinfusionsolutions,suchmonitoringofwaterorintermediatesshouldalwaysbedone,inadditiontoanytestsrequiredbyanapprovedmonographforthe?nishedproduct.Whenasamplefailsatest,thecauseofthefailureshouldbeinvestigatedandnecessary actionshouldbetaken.Alternativemethodsto thoseinthepharmacopoeiasmaybeusediftheyarevalidated,justi?edandauthorized.關(guān)于注射產(chǎn)品，對注射用水和中間體，假設(shè)適用，還有成品，應(yīng)承受已建立的經(jīng)過驗(yàn)證藥典方法進(jìn)展內(nèi)毒素監(jiān)測。對于大容量輸液劑，除了符合專論要求的成品檢測外，還應(yīng)對水合理并授權(quán)的方法取代藥典中的方法。Theuseofrapidmicrobiologicalmethodstoreplacethetraditionalmicrobiologicalmethods,andtoobtainearlierresultsonthemicrobiologicalqualityof,forexample,water,theenvironmentorbioburden,couldbeconsideredifappropriatelyvalidatedandifacomparativeassessmentoftheproposedrapidmethodisperformedagainstthepharmacopoeialmethod.2.5使用快速微生物學(xué)方法取代傳統(tǒng)的微生物學(xué)方法，假設(shè)微生物質(zhì)量牢靠，并可早點(diǎn)獲得并與藥典方法進(jìn)展比對評估。Sanitation3衛(wèi)生Thesanitationofcleanareas isparticularly important.Theyshouldbecleanedfrequentlyandthoroughlyinaccordancewithanapprovedwrittenprogramme.Wheredisinfectantsareused,morethanonetypeshouldbeemployed.Monitoringshouldberegularlyundertakentodetectcontaminationorthepresenceofanorganismagainstwhichthecleaningprocedureisineffective.Interactions between different cleaning materials should be validated. Appropriate validationshouldbecarriedouttoensuredisinfectantresidualscanbedetectedandareremovedbyLIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD.ADD:JiangyinIndustrialZone,Fuqing,Fujian,350309,P.R.ChinaTEL:+86-591-85966928;+86-591-85966932;FAX:+86-591-85966925E-MAIL:xmdongwei@sina;fuxingra@sina;“mailto:regulation@fxpharm“regulation@fxpharmWEBSITE:“://fxpharm/“fxpharm5of47LIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD麗珠集團(tuán)福州福興醫(yī)藥thecleaningprocess.應(yīng)不止一種。應(yīng)定期進(jìn)展監(jiān)測以檢測污染或清潔程序?qū)χ疅o效的生物體。應(yīng)確定不同清潔材料之間的相互作用。應(yīng)進(jìn)展適當(dāng)?shù)那鍧嶒?yàn)證，確保能檢測到清潔劑殘留并能通過清潔程序去除。Disinfectantsanddetergentsshouldbemonitoredformicrobialcontamination;dilutionsshouldbekeptinpreviouslycleanedcontainersandshouldonlybestoredforde?nedperiodsunlesssterilized.DisinfectantsanddetergentsusedinGradeAandBareasshouldbesterilebeforeuse.消毒劑和清潔劑應(yīng)進(jìn)展微生物污染監(jiān)測；稀釋劑應(yīng)保存在預(yù)先清潔的容器中并按規(guī)定的滅菌。Adisinfectantprogrammeshouldalsoincludeasporicidalagentsincemanycommondisinfectantsareineffectiveagainstspores.Theeffectivenessofcleaninganddisinfectantproceduresshouldbedemonstrated.消毒程序還應(yīng)包括殺孢子劑，由于通常的消毒劑對孢子是無效的。應(yīng)證明清潔和消毒程序是有效的。Fumigationofcleanareasmaybeusefulforreducingmicrobialcontaminationininaccessibleplaces.3.4干凈區(qū)熏蒸法對于削減死角的微生物污染有效。Manufactureofsterilepreparations無菌產(chǎn)品的生產(chǎn)Cleanareasforthemanufactureofsterileproductsareclassi?edaccordingtotherequiredcharacteristicsoftheenvironment.Eachcleanlinessintheoperationalstatetominimizetherisksofparticulateormicrobialcontaminationoftheproductormaterialsbeinghandled.manufacturingoperationrequiresanappropriatelevelofenvironmentalLIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD.ADD:JiangyinIndustrialZone,Fuqing,Fujian,350309,P.R.ChinaTEL:+86-591-85966928;+86-591-85966932;FAX:+86-591-85966925E-MAIL:xmdongwei@sina;fuxingra@sina;“mailto:regulation@fxpharm“regulation@fxpharmWEBSITE:“://fxpharm/“fxpharm6of47LIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD麗珠集團(tuán)福州福興醫(yī)藥干凈水平以削減產(chǎn)品或物料處理時微粒或微生物污染的風(fēng)險。Detailedinformationonmethodsfordeterminingthemicrobiologicalandparticulatecleanlinessofair,surfaces,etc.,isnotgivenintheseguidelines.ISO14644-1(2)shouldbeusedforclassi?cationofcleanlinessaccordingtoconcentrationofairborneparticles(determinationofnumberofsamplelocations,calculationofsamplesizeandevaluationofclassi?cationfromthedataobtained).Table1shouldalsobeusedtode?nethelevelstobeusedasthebasisformonitoringcleanareasforairborneparticles.本指南沒有給出空氣或外表等的微生物和微粒干凈度的具體檢測方法。依據(jù)空氣中懸浮粒子的濃度〔確定樣品監(jiān)測位置數(shù)目、計(jì)算取樣量和依據(jù)活的的數(shù)據(jù)進(jìn)展幾倍劃分評估ISO14644-〔2〕劃分干凈等級。表1〕Forthemanufactureofsterilepharmaceuticalpreparations,fourgradesofcleanareasaredistinguishedasfollows:GradeA:Thelocalzoneforhigh-riskoperations,e.g.?llingandmakingasepticconnections.unidirectionalair?owworkstation.Unidirectionalair?owsystemsshouldprovideahomogeneousairspeedof0.36–0.54m/s(guidancevalue)at ade?nedtestposition15–30cmbelowtheterminal ?lterorairdistributorsystem.Thevelocityatworkinglevel should not beless than 0.36 m/s. Theuniformityand effectivenessof theunidirectionalair?owshouldbedemonstratedbyundertakingair?owvisualizationtests.GradeB:Inasepticpreparationand?lling,thisisthebackgroundenvironmentfortheGradeAzone.GradesCandD:Cleanareasforcarryingoutlesscriticalstagesinthemanufactureofsterileproductsorcarryingoutactivitiesduringwhichtheproductisnotdirectlyexposed(i.e.asepticconnectionwithasepticconnectorsandoperationsinaclosedsystem).Aunidirectionalair?owandlowervelocitiesmaybeusedinclosedisolatorsandgloveboxes.對無菌產(chǎn)品的生產(chǎn)，干凈區(qū)可以分為以下四個等級：A級：高風(fēng)險操作的局部區(qū)域，如：灌裝和無菌操作連接。通常這些狀況是通過單向氣流工LIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD.ADD:JiangyinIndustrialZone,Fuqing,Fujian,350309,P.R.ChinaTEL:+86-591-85966928;+86-591-85966932;FAX:+86-591-85966925E-MAIL:xmdongwei@sina;fuxingra@sina;“mailto:regulation@fxpharm“regulation@fxpharmWEBSITE:“://fxpharm/“fxpharm7of47LIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD麗珠集團(tuán)福州福興醫(yī)藥作站實(shí)現(xiàn)的。單向氣流系統(tǒng)應(yīng)在規(guī)定的終端過濾器或空氣安排器系統(tǒng)下方15-30cm的位置供給指導(dǎo)值0.36m/s流的均一性和有效性應(yīng)在氣流可視化試驗(yàn)下證明。BA級區(qū)域的背景環(huán)境。CD級：較少的關(guān)鍵階段或生產(chǎn)中產(chǎn)品沒有直接暴露的生產(chǎn)活動〔如：無菌連接器的無菌連接和密閉系統(tǒng)的操作〕在此干凈區(qū)進(jìn)展。封閉的隔離器或手套箱可承受單向氣流和較低的速度。InordertoreachtheB,CandDairgradesthenumberofairchangesshouldbeappropriateforthesizeoftheroomandtheequipmentandpersonnelpresentinit.B、CD的空氣等級，換氣次數(shù)應(yīng)符合房間大小和里面的設(shè)備和人員要求。toaninstalled?lterleakagetestinaccordancewithISO14644-3(3)atarecommendedintervalofevery6months,butnotexceeding12months.Thepurposeofperformingregularleaktestsistoensurethe?ltermedia,?lterframeand?ltersealarefreefromleaks.TheaerosolselectedforHEPAleaktestingshouldnotsupportmicrobialgrowthandshouldbecomposedofasuf?cientnumberormassofparticles.HEPA?lterpatchingisallowedatthe?ltermanufacturerand insituoperationprovidedthatthepatchsizesandproceduresfollowtherecommendationsofISO1822-4(4).高效空氣過濾器〔HEPA〕應(yīng)依據(jù)ISO14644-3〔3〕進(jìn)展過濾器試漏檢測，建議間隔為6個月，但不超過12個月。進(jìn)展常規(guī)試漏試驗(yàn)是為了確保過濾介質(zhì)、濾框和過濾器密閉性無泄漏。用于試漏試驗(yàn)的氣溶膠應(yīng)不支持微生物的生長并應(yīng)由足夠數(shù)量的質(zhì)量微粒組成。HEPAISO1822-〔4。Cleanroomandclean-airdeviceclassication干凈室和空氣凈化設(shè)備分類LIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD.ADD:JiangyinIndustrialZone,Fuqing,Fujian,350309,P.R.ChinaTEL:+86-591-85966928;+86-591-85966932;FAX:+86-591-85966925E-MAIL:xmdongwei@sina;fuxingra@sina;“mailto:regulation@fxpharm“regulation@fxpharmWEBSITE:“://fxpharm/“fxpharm8of47LIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD麗珠集團(tuán)福州福興醫(yī)藥Cleanroomsandclean-airdevicesshouldbeclassi?edinaccorda ncewithISO14644(2–3,5–7).ISO14644〔2-3，5-7〕Classi?cation should be clearly differentiatedfrom operational process environmentalmonitoring.Themaximumpermittedairborneparticleconcentrationforeachgradeisgivenin1中給出了每個等級所允許的最大懸浮粒子濃度。Table1Maximumpermittedairborneparticleconcentrata.The“atrest”stateistheconditionwheretheinstallationiscompletewithequipmentinstalledandoperatinginamannerag uponbythecustomerandsupplier,butwithnopersonnelpresent.bThe“inoperation”stateistheconditionwheretheinstallationisfunctioninginthede?nedoperatingmodeandthespeci?ednumberofpersonnelispresent.Theareasandtheirassociatedenvironmentalcontrolsystemsshouldbedesignedtoachieveboththe“atrest”and“inoperation”states.1〕〕LIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD.ADD:JiangyinIndustrialZone,Fuqing,Fujian,350309,P.R.ChinaTEL:+86-591-85966928;+86-591-85966932;FAX:+86-591-85966925E-MAIL:xmdongwei@sina;fuxingra@sina;“mailto:regulation@fxpharm“regulation@fxpharmWEBSITE:“://fxpharm/“fxpharm9of47LIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD麗珠集團(tuán)福州福興醫(yī)藥等級0.5μm5.0μm0.5μm5.0μmA3,520203,52020B3,52029352,0002,900C352,0002,9003,520,00029,000abD3,520,000abD3,520,00029,000未規(guī)定未規(guī)定b“動態(tài)”是指按規(guī)定的操作模式安裝，有指定數(shù)量的人員在場的狀態(tài)。區(qū)域和相關(guān)關(guān)心環(huán)境掌握系統(tǒng)設(shè)計(jì)應(yīng)能滿足“靜態(tài)”和“動態(tài)”的需要。Forclassi? cationpurposesinGradeAzones,aminimumsamplevolumeof1m3shouldbetakenpersamplelocation.ReferringtoTable1,forGradeAtheairborneparticleclassi?cationisISO4.8dictatedbythelimitforparticles≥5.0μm.ForGradeB(atrest)theairborneparticleclassi?cationisISO5forbothparticlesizesconsidered.ForGradeC(atrestan dinoperation)theairborneparticleclassi?cationisISO7andISO8,respectively.ForGradeD(atrest)theairborneparticleclassi?cationisISO 8.Forclassi?cationpurposesISO14644-1(2)methodologyde?nesboththeminimumnumberofsamplelocationsandthesamplesizebasedontheclasslimitofthelargestparticlesizeconsideredandthemethodofevaluationofthedatacollected.ThesamplevolumeshouldbedeterminedaccordingtoISO14644-1(2)clauseB.4.2.However,forlowergrades(GradeCinoperationandGradeDatrest)thesamplevolumeperlocationshouldbeatleast2litresandthesampletimeperlocationshouldbenotlessthan1minute.以分類為目的，關(guān)于A級區(qū)域，每個取樣點(diǎn)應(yīng)取至少1m3的體積。參考表1，關(guān)于A級懸浮粒子級別是ISO4.8指定的≥5.0μm懸浮粒子限度。關(guān)于B級〔靜態(tài)〕懸浮粒子級別是ISO5中的兩種大小的微粒。關(guān)于C級〔靜態(tài)和動態(tài)〕懸浮粒子級別是ISO7ISO8。關(guān)于D〔2〕ISO14644-1〔2〕B.4.2。LIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD.ADD:JiangyinIndustrialZone,Fuqing,Fujian,350309,P.R.ChinaTEL:+86-591-85966928;+86-591-85966932;FAX:+86-591-85966925E-MAIL:xmdongwei@sina;fuxingra@sina;“mailto:regulation@fxpharm“regulation@fxpharmWEBSITE:“://fxpharm/“fxpharm10of47LIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD麗珠集團(tuán)福州福興醫(yī)藥然而，較低等級〔CD級干凈區(qū)的靜態(tài)〕每個取樣點(diǎn)的取樣體積應(yīng)至少為2L1分鐘。Portable particle counters with a short length of sample tubingshould be used classi?cationpurposestoavoidthelossofparticles≥5.0μm.Isokineticsampleheadsshouldbeusedinunidirectionalair?owsystems.應(yīng)當(dāng)使用采樣管較短的便攜式塵埃粒子計(jì)數(shù)器，以防止損失≥5.0μm的微粒。單向氣流系統(tǒng)中應(yīng)使用等動力學(xué)的取樣頭?！癐noperation”classi?cationmaybedemonstratedduringnormaloperations,simulatedoperationsorduringmedia?llsasworst-casesimulationisrequiredforthis.ISO14644-2(6)providesinformationontestingtodemonstratecontinuedcompliancewiththeassignedcleanlinessclassi?cation.4.6.4“動態(tài)”分級可以在正常操作，或最差狀況下的模擬操作或培育基灌裝條件下進(jìn)展。ISO14644-2〔6〕中給出了檢測信息，用以證明可以持續(xù)符合規(guī)定的干凈級別。Cleanroomandclean-airdevicemonitoring干凈室和空氣凈化設(shè)備的監(jiān)測Cleanroomsandclean-airdevicesshouldberoutinelymonitoredwhileinoperationandthemonitoringlocationsbasedonaformalriskanalysisstudyandtheresultsobtainedduringtheclassi? cationofroomsand/orclean-airdevices.動態(tài)時，干凈室和空氣凈化設(shè)備應(yīng)當(dāng)被日常監(jiān)測，檢測位置應(yīng)賜予風(fēng)險分析爭論和干凈室級別和/或空氣凈化設(shè)備的檢測結(jié)果。ForGradeAzones,particlemonitoringshouldbeundertakenforthefulldurationofcriticalprocessing,includingequipmentassembly,exceptwherejusti?edby contaminantsintheprocessthatwoulddamagetheparticlecounterorpresentahazard,forexample,liveorganismsandradiologicalhazards.Insuchcasesmonitoringduringroutineequipmentset-upoperationsshouldbeundertakenbeforeexposuretotherisk.Monitoringduringsimulatedoperationsshouldalsobeperformed.TheGradeAzoneshouldbemonitoredatafrequencyandsamplesizesuchthatallinterventions,transienteventsandanysystemdeteriorationwouldbecapturedandalarmstriggeredLIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD.ADD:JiangyinIndustrialZone,Fuqing,Fujian,350309,P.R.ChinaTEL:+86-591-85966928;+86-591-85966932;FAX:+86-591-85966925E-MAIL:xmdongwei@sina;fuxingra@sina;“mailto:regulation@fxpharm“regulation@fxpharmWEBSITE:“://fxpharm/“fxpharm11of47LIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD麗珠集團(tuán)福州福興醫(yī)藥ifalertlimitsareexceeded.Itisacceptedthatitmaynot alwaysbepossibleto demonstratelowlevelsof≥5.0μmparticlesatthepointof?llwhen?llingisinprogress,duetothegenerationofparticlesordropletsfromtheproductitself.關(guān)于A級區(qū)域，粒子監(jiān)測應(yīng)在整個關(guān)鍵工序的過程中進(jìn)展，包括設(shè)備的裝配，除非確定污染物有可能損壞微粒計(jì)數(shù)器或存在某種危害，如：活性生物和輻射危害。這種狀況下設(shè)備安裝操作應(yīng)在暴露在風(fēng)險前進(jìn)展監(jiān)測。模擬灌裝期間的監(jiān)測也應(yīng)當(dāng)做。A級干凈區(qū)監(jiān)測的頻率及取樣量，應(yīng)能準(zhǔn)時捕獲全部的干預(yù)、偶發(fā)大事及任何系統(tǒng)的損壞，并且當(dāng)戒備線超過時會觸發(fā)警報。在灌裝過程中，由于產(chǎn)品自身產(chǎn)生的微?；蛞旱?，允許灌裝位置消滅≥5.0μm的懸浮粒子不符合標(biāo)準(zhǔn)的狀況。ItisrecommendedthatasimilarsystembeusedforGradeBzones,althoughthesamplefrequencymaybedecreased.TheimportanceoftheparticlemonitoringsystemshouldbedeterminedbytheeffectivenessofthesegregationbetweentheadjacentGradeAandBzones.TheGradeBzoneshouldbemonitoredat afrequencyandwithasamplesizesuchthat changes levelsofcontaminationandanydeteriorationofthesystemwouldbecapturedandalarmstriggeredifalertlimitsareexceeded.建議在B級干凈區(qū)承受類似的系統(tǒng)，雖然可能會降低取樣頻率。粒子監(jiān)測系統(tǒng)的重點(diǎn)ABB級區(qū)域應(yīng)定期監(jiān)測并且取樣量能捕獲污染水平的變化和任何系統(tǒng)的惡化，假設(shè)超過戒備限會觸發(fā)警報。Airborneparticlemonitoringsystemsmayconsistofindependentparticlecounters;anetworkofsequentiallyaccessedsamplingpointsconnectedbymanifoldtoasingleparticlecounter;ormultiplesmallparticlecounterslocatednearmonitoringpointsandnetworkedtoadataacquisitionsystem.Combinationsofsystemscanalsobeused.Thesystemselectedshouldbeappropriatefortheparticlesizeconsidered.Whereremotesamplingsystemsareused,thelengthoftubingandtheradiiofanybendsinthetubingshouldbeconsideredinthecontextofparticlelossesinthetubing.Theselectionofthemonitoringsystemshouldtakeaccountofanyriskpresentedbythematerialsusedinthemanufacturingoperation,forexample,thoseinvolvingliveorganismsorradiopharmaceuticals.LIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD.ADD:JiangyinIndustrialZone,Fuqing,Fujian,350309,P.R.ChinaTEL:+86-591-85966928;+86-591-85966932;FAX:+86-591-85966925E-MAIL:xmdongwei@sina;fuxingra@sina;“mailto:regulation@fxpharm“regulation@fxpharmWEBSITE:“://fxpharm/“fxpharm12of47LIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD麗珠集團(tuán)福州福興醫(yī)藥計(jì)數(shù)器，或在監(jiān)測點(diǎn)四周有多個小型微粒計(jì)數(shù)器并通過網(wǎng)絡(luò)獵取數(shù)據(jù)。也可使用組合系統(tǒng)。所選擇的系統(tǒng)應(yīng)適用于相關(guān)的粒徑。物料。Thesizesofsamplestakenformonitoringpurposesusingautomatedsystemswillusuallybeafunctionofthesamplingrateofthesystemused.Itisnotnecessaryforthesamplevolumetobethesameasthatusedforformalclassi?cationofcleanroomsandclean-airdevices.干凈室分類和空氣凈化設(shè)備一樣。TheairborneparticleconditionsgiveninTable1forthe“atrest”stateshouldbeachievedinshort“clean-up”or“recovery”periodofabout15–20minutes(guidancevalue),aftercompletionoftheoperations.TheparticulateconditionsgiveninTable1forGradeA“inoperation”shouldbemaintainedin thezoneimmediatelysurroundingtheproductwhenevertheproductoropencontainerisexposedtotheenvironment.The“clean -up”or“recovery”testshoulddemonstrateachangeinparticleconcentrationbyafactorof100withintheprescribedtime(ISO14644-3clauseB.12)(3).1中給出的“靜態(tài)”15-20分鐘〔指導(dǎo)值〕的“清潔”或“自凈”后實(shí)現(xiàn)的。只要產(chǎn)品或開放容器暴露在環(huán)境中應(yīng)馬上維持產(chǎn)品四周的環(huán)境為表1中A級“動態(tài)”“清潔”或“自凈”〔ISO14644-3B.1〔3〕100倍。Inordertodemonstratecontrolofthecleanlinessofthevariouscleanareasduringoperation,theyshouldbemonitoredforairborneparticlesandmicrobialcontamination.Inadditionto“atrest”and“inoperation”classi?cation,airborneparticlesshouldbemonitoredperiodically“inLIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD.ADD:JiangyinIndustrialZone,Fuqing,Fujian,350309,P.R.ChinaTEL:+86-591-85966928;+86-591-85966932;FAX:+86-591-85966925E-MAIL:xmdongwei@sina;fuxingra@sina;“mailto:regulation@fxpharm“regulation@fxpharmWEBSITE:“://fxpharm/“fxpharm13of47LIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD麗珠集團(tuán)福州福興醫(yī)藥operation”atcriticallocations.Thesamplingplanneednotbethesameasthatusedforclassi?cation.Locationsandsamplesizesshouldbedeterminedbasedonanassessmentoftheprocessandcontaminationrisk.為了證明不同干凈區(qū)操作過程中的干凈度得到掌握，應(yīng)當(dāng)監(jiān)測懸浮粒子和微生物污染。除了在“靜態(tài)”和“動態(tài)”分類時，還應(yīng)在動態(tài)時定期監(jiān)測關(guān)鍵位置的懸浮粒子。取樣打算不必干凈區(qū)分級時一樣。取樣位置和取樣量應(yīng)依據(jù)工藝評估和污染風(fēng)險確定。ThemonitoringofGradeCandDareasinoperationshouldbeperformedinaccordancewiththeprinciplesofqualityriskmanagement.Therequirementsandalert/actionlimitswilldependonthenatureoftheoperationscarriedout,buttherecommended“clean-upperiod”shouldbeattained.應(yīng)當(dāng)依據(jù)質(zhì)量風(fēng)險治理的原則對C級干凈區(qū)和D級干凈區(qū)進(jìn)展動態(tài)監(jiān)測。監(jiān)測要求以及戒備/行動限可依據(jù)操作的性質(zhì)確定，但自凈時間應(yīng)當(dāng)?shù)竭_(dá)規(guī)定要求。Othercharacteristicssuchastemperatureandrelativehumiditydependontheproductandnatureoftheoperationscarriedout.Theseparametersshouldnotinterferewiththede?nedcleanlinessstandard.準(zhǔn)沖突。ExamplesofoperationstobecarriedoutinthevariousgradesaregiveninTable2(seealsosections4.12–4.20).4.7.92中給出了不同級別中的操作例子(4.12-4.20局部〕LIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD.ADD:JiangyinIndustrialZone,Fuqing,Fujian,350309,P.R.ChinaTEL:+86-591-85966928;+86-591-85966932;FAX:+86-591-85966925E-MAIL:xmdongwei@sina;fuxingra@sina;“mailto:regulation@fxpharm“regulation@fxpharmWEBSITE:“://fxpharm/“fxpharm14of47LIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD麗珠集團(tuán)福州福興醫(yī)藥2等級A最終滅菌產(chǎn)品操作舉例等級A最終滅菌產(chǎn)品操作舉例(4.12-4.15)產(chǎn)品灌裝時的特別風(fēng)險C溶液配制時的特別風(fēng)險。產(chǎn)品灌裝D溶液配制和隨后成份的灌裝等級A無菌工藝操作舉例(4.16-4.20)無菌配制和灌裝C待過濾溶液配置D洗滌后組分的處理Tocontrolthemicrobiologicalcleanlinessof GradesAD inoperationthecleanareasshouldbemonitored.Whereasepticoperationsareperformed,monitoringshouldbefrequentusingLIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD.ADD:JiangyinIndustrialZone,Fuqing,Fujian,350309,P.R.ChinaTEL:+86-591-85966928;+86-591-85966932;FAX:+86-591-85966925E-MAIL:xmdongwei@sina;fuxingra@sina;“mailto:regulation@fxpharm“regulation@fxpharmWEBSITE:“://fxpharm/“fxpharm15of47LIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD麗珠集團(tuán)福州福興醫(yī)藥methodssuchassettleplates,volumetricairandsurfacesampling(e.g.swabsandcontactplates).Samplingmethodsusedinoperationshouldnotinterferewithzoneprotection.Resultsfrommonitoringshouldbeconsideredwhenreviewingbatchdocumentationfor?nishedproductrelease.Surfacesandpersonnelshouldbemonitoredaftercriticaloperations.Additionalmicrobiologicalmonitoringisalsorequiredoutsideproductionoperations,e.g.aftervalidationofsystems,cleaningandsanitization.A-D〔例如：擦拭或接觸皿〕等方法進(jìn)展監(jiān)測。動態(tài)時，使用的取樣方法應(yīng)不會對保護(hù)區(qū)造成干擾。當(dāng)最終產(chǎn)品放行審核批記錄時應(yīng)考慮監(jiān)測結(jié)果。關(guān)鍵操作完畢后需要對外表和人員進(jìn)展檢測。非生產(chǎn)操作還需要額外進(jìn)展微生物檢測，如：系統(tǒng)驗(yàn)證、清潔和消毒后。Levelsofdetectionofmicrobialcontaminationshouldbeestablishedforthepurposeofsettingalertandactionlimitsandformonitoringthetrends inenvironmentalcleanliness inthefacility.Limitsexpressedincolony-formingunits(CFU)forthemicrobiologicalmonitoringofcleanareasinoperationaregiveninTable3.Thesamplingmethodsandnumericalvaluesincludedinthetablearenotintendedtorepresentspeci?cations,butareforinformationonly.應(yīng)當(dāng)建立微生物污染的檢測水平，以便建立戒備和行動限以及監(jiān)測廠房環(huán)境干凈度的趨3中，干凈區(qū)動態(tài)微生物監(jiān)測的限度單位為菌落形成單位CF法和數(shù)值，僅供參考，不代表標(biāo)準(zhǔn)。LIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD.ADD:JiangyinIndustrialZone,Fuqing,Fujian,350309,P.R.ChinaTEL:+86-591-85966928;+86-591-85966932;FAX:+86-591-85966925E-MAIL:xmdongwei@sina;fuxingra@sina;“mailto:regulation@fxpharm“regulation@fxpharmWEBSITE:“://fxpharm/“fxpharm16of47LIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD麗珠集團(tuán)福州福興醫(yī)藥CFU,colony-formingunits.Theseareaveragevalues.Individualsettleplatesmaybeexposedforlessthan4hours.3等級浮游菌等級浮游菌(CFU/m3)沉降菌接觸皿手套印(直徑90mm)(55mm)(五指)(CFU/4h)b(CFU/皿)(CFU/手套〕A<1<1<1<1B10555C1005025—D20010050—CFU,菌落形成單位這些為平均值個別沉降皿暴露時間可能少于4小時。Appropriate alert and action limits should be set for the results of particulate microbiologicalmonitoring.Iftheactionlimitsareexceededoratrendisidenti?edinthealertlimits,investigationshouldbeinitiatedandtheappropriatecorrectiveactionsshouldbetaken,asprescribedintheoperatingprocedures.對粒子和微生物檢測結(jié)果應(yīng)當(dāng)設(shè)置適宜的戒備限和行動限。假設(shè)超出行動限或確定趨勢處于戒備限，應(yīng)依據(jù)操作規(guī)程，進(jìn)展調(diào)查并實(shí)行適當(dāng)訂正措施。Theareagradesasspeci?edinsections4.12to4.20shouldbeselectedbythemanufactureronthebasisofthenatureoftheprocessoperationsbeingperformedandvalidationruns(e.g.asepticmedia?llsorotherstypesofprocesssimulations)areusedtoestablishprocessingholdtimesandamaximum?llduration.ThedeterminationofanappropriateprocessareaenvironmentandatimeLIVZONGROUPFUZHOUFUXINGPHARMACEUTICALCO.,LTD.ADD:JiangyinIndustrialZone,Fuqing,Fujian,350309,P.R.ChinaTEL:+86-591-85966928;+86-591-85966932;FAX:+86-591-85966925E-MAIL:xmdongwei@sina;fuxingra@sina;“mailto:regulation@fxpharm“regulation@fxpharmWEBSI