PDA-TR28 中英 無菌原料藥工藝模擬驗(yàn)證(2006年)

1、無菌原料藥（BPCs）的工藝模擬PDA第28份技術(shù)報告（2006年）Thisdocumentprovidesguidancerelativetothevalidationofasepticprocessingactivitiesassociatedwiththeproductionofsterilebulkpharmaceuticalchemicals.ItdrawsupontheconceptsandprinciplesdevelopedinPDAsandPhRMAspriorpublicationsonasepticprocessingtechnology(1,2,3).Thiseffor

2、texpandsuponthosedocumentstoprovideassistanceforindividualsandfirmsproducingsterilebulkpharmaceuticalchemicals.Ourgoalinthisrevisionwastoupdatethedocumenttoreflect6yearsofindustryexperiencewithit,aswellasanacknowledgementofacceptancecriterialimitationsthatwerepresentinthefirstedition(4).Wehavealsoen

3、deavoredtoaddresssomeoftheissuesraisedbyFDAintheirreviewoftheearlieredition.本文檔提供了無菌原料藥生產(chǎn)加工有關(guān)的驗(yàn)證指導(dǎo)。它借鑒了FDA和PhRMA以前出版的無菌加工技術(shù)(1,2,3)的概念和原則。這使得該文件可以為個人和企業(yè)的無菌原料藥生產(chǎn)提供幫助。我們在這次修訂的目的是更新文件,以歸納6年來的行業(yè)經(jīng)驗(yàn),以及驗(yàn)收標(biāo)準(zhǔn)的規(guī)定,這將在第1版(4)中稱述。我們還大量列舉一些美國FDA在其早期版本的回顧中提到的一些問題。Thepreparationofsterilematerialsinthequantityandscale

4、usedinthemanufactureofbulkpharmaceuticalchemicalsgenerallyrequiresequipmentandproceduresquitedifferentfromthoseusedinthemanufactureoffinishedpharmaceuticals.Theuniquenessoftheproductionmethodsforsterilebulksprecludesthedirectextrapolationoftheprocesssimulationapproachesemployedforasepticallyproduced

5、sterileformulations.原料藥生產(chǎn)中,無菌原料在數(shù)量和規(guī)模上的準(zhǔn)備,一般都需要相當(dāng)?shù)脑O(shè)備和過程,這與成品藥的制造有所不同。無菌原料生產(chǎn)方法的獨(dú)特,排除了用于無菌制劑的無菌生產(chǎn)上的工藝模擬直接推斷方法。Thistechnicalreportwasdisseminatedindraftforpublicreviewandcommentpriortopublication.Manyofthesubmittedcommentshavebeenincludedinthefinaldocument.Webelievethisapproachaccomplishedthewidestposs

6、iblereviewofthedocumentandensuresitssuitabilityasavaluableguidetoindustryintheareaofprocesssimulationtestingforsterilebulkpharmaceuticalchemicals.Thisdocumentshouldbeconsideredasaguide;itisnotintendedtoestablishanymandatoryorimpliedstandard.這份技術(shù)報告以草案形式提前發(fā)布供公眾審查和評論。大多數(shù)提交的意見將被列入最后版本中。我們相信,這種方法實(shí)現(xiàn)了對文件最廣

7、泛的審查,并確保作為一個針對無菌原料藥的工藝模擬試驗(yàn)領(lǐng)域的寶貴的指導(dǎo)性文件的合格性。這份文件應(yīng)被視為指南,而不是任何強(qiáng)制規(guī)定或標(biāo)準(zhǔn)。TableofConents目錄INTRODUCTION簡介Purpose目的SterileBulkPharmaceuticalChemicals.無菌原料藥Scope范圍SterileBPCProductionTechnology無菌BPC生產(chǎn)技術(shù)ClosedSystems封閉系統(tǒng)OpenSystems開放系統(tǒng)Considerations需考慮事項PROCESSSIMULATIONCONCEPTSANDPRINCIPLES工藝模擬的概念和原則NumberandF

8、requencyofTests測試的數(shù)量的頻率WorstCase最差條件3PROCESSSIMULATIONTESTMETHODS工藝模擬測試的方法TotalProcessSimulation總工藝模擬UnitOperation(s)Simulations單元操作模擬TESTMATERIALSUSEDINPROCESSSIMULATION過程模擬中用到的測試原料GrowthMediumSimulations生長介質(zhì)模擬PlaceboMaterialSimulation安慰劑原料模擬SimulationWithoutMaterial無原料模擬ProductionMaterialSimulatio

9、n生產(chǎn)原料模擬EVALUATIONOFSIMULATIONTESTMATERIALS模擬測試原料的評估EvaluationofEntireTestMaterial全體測試原料的評估EvaluationofTestMaterialSamples測試原料單體的評估DOCUMENTATION文件ENVIRONMENTALMONITORING環(huán)境監(jiān)測ELEMENTSOFPROCESSSIMULATIONTESTS工藝模擬測試的評估Interventions干擾DurationofSimulation時間模擬ProductionBatchSize/ProcessSimulationTestSize產(chǎn)品的

10、批產(chǎn)量/工藝模擬的批量IncubationConditions培養(yǎng)條件OperatingProcedures作業(yè)流程StaffingConsiderations人員的思考Campaigns活動EquipmentQualification設(shè)備限制INTERPRETATIONOFRESULTSANDACCEPTANCECRITERIA吉果的解釋和可接受水平Background背景ApproachesforAcceptanceCriteria可接受水平的判定方法Quantitative定量Qualitative品質(zhì)FAILUREINVESTIGATIONANDCORRECTIVEACTION失敗評估

11、和糾正措施PERIODICREASSESSMENT定期再評估APPENDIX1,SELECTIONANDSTERILIZATIONOFTESTMATERIALS附件1，測試原料的選擇和滅菌APPENDIX2,DEFINITIONS附件2，定義APPENDIX3,REFERENCES附件3，參考文獻(xiàn)INTRODUCTION簡介Purpose目的Thepreparationofsterilebulkpharmaceuticalchemicalsrequiresthecombinationofclassicalchemical/biologicalproductionmethodswiththewe

12、ll-definedconceptsforthepreparationofsterilematerials.Theintegrationofthesefieldsentailsprocessequipmentandoperatingprocedureswhichareoftensubstantiallydifferentfromordinarypracticeineitherdiscipline.Thisdocumentoutlinesprocesssimulationpracticesforsterilebulkpharmaceuticalchemicals(sterileBPCs),uti

13、lizingconceptsdrawnfrombothbulkpharmaceuticalchemicaloperationsandsterileproductmanufacturingandadaptedtofittheuniquenatureofthesematerials.Itpresentsoptionsfordeterminingtheadequacyofasepticoperationsperformedduringlargescalemanufacturingwhileallowingforrealisticacceptancecriteriaforsuchoperations.

14、無菌原料藥的制備需要典型的生化生產(chǎn)方法與無菌原料制備概念的明確理解相結(jié)合。這些領(lǐng)域的合并意味著工藝設(shè)備和作業(yè)流程實(shí)質(zhì)上往往與通常做法不同。本文件概述了無菌原料藥(無菌BPCs)的工藝模擬實(shí)踐，系統(tǒng)采用批量原料藥作業(yè)和無菌產(chǎn)品制造的概念來適應(yīng)這些材料的獨(dú)特性質(zhì)。報告在允許這些作業(yè)的實(shí)際驗(yàn)收標(biāo)準(zhǔn)的同時，陳述了在大規(guī)模生產(chǎn)中無菌作業(yè)的充分性的鑒定觀點(diǎn)。TheasepticproceduresutilizedintheproductionofsterileBPCscanbeevaluatedusingaprocesssimulationmethodology.However,incertaininst

15、ancestheuseofamicrobiologicalgrowthmediuminabulkmanufacturingplantcanposesignificantproblems.Itisoftennecessarytoconsiderothersimulationoptionswhichposelesspotentialrisktothemanufacturingarea.Itisusefultoutilizeanarrowerdefinitionofaprocesssimulationinthesecases.Thefollowingdefinitionsmakeacleardist

16、inctionbetweenpossiblemethods:無菌BPCS生產(chǎn)過程中使用的無菌流程可以用工藝模擬方法論來評估。然而，在某些情況下，在批量制造工廠中微生物培養(yǎng)基的使用可能造成重大問題。常常有必要考慮能減少對制造領(lǐng)域構(gòu)成潛在風(fēng)險的其他模擬方案。利用這些案件中工藝模擬的狹義定義是非常有意義的。下面的定義為各可行方法作出明確區(qū)分：ProcessSimulation(withoutmicrobiologicalgrowthmedia)工藝模擬(無微生物培養(yǎng)基)Methodofevaluatinganasepticprocessemployingmethodswhichcloselyappr

17、oximatethoseusedforsterilematerialsusinganappropriateplacebomaterial.與使用適當(dāng)安慰劑原料的無菌原料評估方法相類似的無菌工藝的評價方法，ProcessSimulation(withmicrobiologicalgrowthmedia)工藝模擬(有微生物培養(yǎng)基)Methodofevaluatinganasepticprocessusingamicrobialgrowthmediumemployingmethodswhichcloselyapproximatethoseusedforsterilematerials(5).與無菌原

18、料評估方法相類似的使用微生物的生長方法的無菌工藝評價方法。Theprocesssimulationtestalsoprovidesawaytoevaluatechangesmadetoanasepticprocessingoperationwhichmightaffectthesterilityofthefinalproduct.Itcanbeusefulinidentifyingpotentialweaknessesinanasepticprocessingoperationwhichmightcontributetothemicrobiologicalcontaminationofthep

19、roduct.這個過程模擬試驗(yàn)也提供了一種方法來評估可能影響最終產(chǎn)品失敗的無菌工藝的變化。它可以有助于鑒定在無菌工藝中的潛在弱點(diǎn)，這些弱點(diǎn)可能導(dǎo)致產(chǎn)品的微生物污染。SterileBulkPharmaceuticalChemicals無菌原料藥Forthepurposesofthisdocument,asterilebulkpharmaceuticalchemicalisdefinedasasterilematerialderivedfromchemical,fermentationorsemi-syntheticsourceswhichisfinalpackagedorstoredinbulk

20、form.Thebulkmaterialmaybeanactivepharmaceuticalingredient(API)oranexcipient.SterileBPCsaretypicallysolids,butmaybesolutionsorsuspensions.本文件的目的是定義無菌原料藥是由那些最后以批量的形式被包裝或存儲的化學(xué)藥品，發(fā)酵物或半派生的無菌材料而派生。其中大部分材料可能是一個活性成份(API)或賦形劑。無菌BPCs系統(tǒng)通常是固體，但也可能是溶液或懸浮物。Scope范圍Thisdocumentaddressesthevalidationofasepticprocess

21、ingduringsterilebulkmanufacturingactivities(referredtoasprimarymanufacturinginmanypartsoftheworld).Itdescribesmethodsandproceduresfortheconductofprocesssimulationtests,includingcrystallization,separation,purification,drying,milling,blendingandbulkpackagingofsterilebulkpharmaceuticalchemicalswhichare

22、asepticallyproduced.AsepticoperationsrequiredinthepreparationofsterileformulationsarenotapartofthisdocumentandhavebeenaddressedbyPDAelsewhere(4).這份文件涉及到無菌原料生產(chǎn)活動(在世界的許多地方也叫作二次生產(chǎn))的無菌工藝的驗(yàn)證。它描述了管理工藝模擬實(shí)驗(yàn)的方法和程序，包括結(jié)晶，分離，純化，干燥，加工，混合與無菌生產(chǎn)的無菌原料藥品的無菌包裝。有無菌操作要求的無菌原料和生物技術(shù)過程不包括在這份文件中，而在PDA(4)中被陳述。SterileBPCProduc

23、tionTechnology無菌BPC生產(chǎn)技術(shù)Thepreparationofsterilebulkmaterialsentailsthecompletionofaseriesofunitoperationsunderasepticconditions.TheequipmentutilizedfortheseasepticunitoperationsissterilizedusingavalidatedprocedurepriortotheintroductionofthesterileBPC.Dependingupontheprocess,theequipmentmaybeclassifie

24、daseitheraclosedoranopensystem(seebelow).Whileitisrecognizedthataclosedsystemisgenerallypreferred,thereareprocessandequipmentlimitationssuchthatopensystemsaretheonlymeansavailablefortheexecutionofcertainunitoperations.TheprocesstrainforasterileBPCmayincludebothopenandclosedportions.Thetestmethodsuse

25、dfortheprocesssimulationmustincludeallportionsofthesystemwhetheropenorclosedandtransitionsbetweenthem(seeSection3).大量無菌原料的制備需要在無菌條件完成一系列的單元作業(yè)。這些無菌單元操作所使用的設(shè)備預(yù)先采用無菌BPC技術(shù)進(jìn)行了滅菌。該設(shè)備可以分類為“封閉”或“開放”系統(tǒng)(見下文)。人們認(rèn)識到，雖然一個“封閉”系統(tǒng)被普遍采用，但由于工藝及設(shè)備的限制，“開放”系統(tǒng)對于某些單元操作來說是唯一可以利用的系統(tǒng)。無菌BPC的工藝培養(yǎng)可能既包括“開放”又包括“封閉”部分。在工藝模擬過程中使用的測

26、試方法必須包括系統(tǒng)的所有部分，不論是“開放”或“封閉”，或者是它們之間的過度系統(tǒng)的所有部分(見第3節(jié))。ClosedSystems封閉系統(tǒng)Aclosedsystemisonethatisdesignedtopreventtheingressofmicroorganismsbymeansofphysicalseparationfromthesurroundingenvironment.Aclosedsystem:“封閉”系統(tǒng)是旨在通過物理分離方法來防止周圍環(huán)境中的微生物的侵入?！胺忾]”系統(tǒng)：Isconstructed,installedandqualifiedinamannerwhichdemo

27、nstratesintegrityismaintainedthroughoutthefullrangeofoperatingconditions,andoveratimeperiodinclusiveofthelongestexpectedusage(i.e.,manufacturingcampaign).Thequalificationisdoneaccordingtoaformalprotocol,followinggenerallyacceptedengineeringprinciples,andisdocumented.建造，安裝的方式保持完整合格的整個運(yùn)作情況，并且在一段時間內(nèi)最長的

28、包容性的預(yù)期使用(即生產(chǎn)活動)。遵循普遍接受的工程原則、根據(jù)正式協(xié)議，條約被制定并記錄在案。Issterilized-in-placeorsterilizedwhileclosedpriortouseusingavalidatedprocedure就地消毒或在使用驗(yàn)證程序前封閉消毒Canbeutilizedforitsintendedpurposewithoutbreachtotheintegrityofthesystem可以利用其設(shè)計而不違反該系統(tǒng)的完整性Canbeadaptedforfluidtransfersinand/oroutwhilemaintainingasepsis保持無菌的狀

29、況下適應(yīng)液體的流進(jìn)和/或流出。Isconnectabletootherclosedsystemswhilemaintainingintegrityofallclosedsystems(e.g.,RapidTransferPort,steamedconnection,etc.)在保持所有封閉系統(tǒng)的完整性的同時可與其他封閉系統(tǒng)連接(例如，快速傳輸接口，蒸汽連接等)Issafeguardedfromanylossofintegritybyscheduledpreventivemaintenance.是否有防護(hù)措施以避免定期預(yù)防性維修產(chǎn)生的完整性損失。Utilizessterilizingfilter

30、sforsterilizationofprocessstreamswhichareintegritytestedandtraceabletoeachproductlot.利用除菌過濾器進(jìn)行工藝線的滅菌，過濾器進(jìn)行完整性測試并可追溯到每一個產(chǎn)品批次。Byvirtueoftheirdesign,closedsystemsprovideasubstantiallyincreasedmeasureofprotectiontothematerialsprocessedwithin.WhereasterileBPCcanbeprocessedinitsentiretywithinclosedsystems

31、,theriskofcontaminationisnegligible.由于他們的設(shè)計的優(yōu)越性，封閉系統(tǒng)提供了內(nèi)部材料加工保護(hù)措施。無菌BPC可以在整個封閉的系統(tǒng)內(nèi)處理，污染的危險是微不足道的。OpenSystems開放系統(tǒng)Anopensystemlacksoneormoreofthefeaturesofaclosedsystem.“開放”系統(tǒng)缺乏一個或多個“封閉”系統(tǒng)的功能。Considerations要考慮的事項Aholisticapproachmustbeusedtoadequatelyvalidateandcontrolasepticprocesses.Aprocesssimulati

32、ontestisonlyapoint-in-timerepresentationofthecapabilitiesofanasepticprocessingsystem,includingenvironment,equipment,proceduresandpersonnel.驗(yàn)證和控制無菌加工過程必須充分使用一個全面解決辦法。一個工藝模擬試驗(yàn)只是一個無菌處理系統(tǒng)能力的反映，包括環(huán)境，設(shè)備，程序和人員。Itdoesnotensurethatsterilebulkmaterialsproducedatothertimeswillhavethesamelevelofmicrobiologicalq

33、uality.它并不能保證在其他時間生產(chǎn)的無菌散裝物料將有相同的微生物質(zhì)量水平。However,throughcontrolandvalidationofrelatedprocesses,suchasenvironmentalmonitoring,qualificationofpersonnelandvalidationofcleaningandsterilizationcycles,itispossibletomaintainthelevelofasepsisdemonstratedduringtheprocesssimulationtest.但是，通過控制和相關(guān)的進(jìn)程的驗(yàn)證，如環(huán)境監(jiān)測，人

34、員評估和清洗驗(yàn)證以及消毒周期驗(yàn)證，它有可能在這個工藝模擬測試中保持無菌水平。Therefore,itisimportanttovalidatetherelatedsanitizationandsterilizationprocessesindependently,suchassterilization/depyrogenationoftheproduct,sterilizationoftheprocessequipmentincludingproductcontactsurfaces,sterilizationofcontainers(intermediateandfinalpackagedb

35、ulk),andsupportsystemssuchasair,water,ornitrogen(6,7,8).因此，重要的是要獨(dú)立驗(yàn)證相關(guān)的消毒和滅菌過程，例如滅菌/產(chǎn)品的除熱原，工藝設(shè)備的滅菌，包括產(chǎn)品接觸表面，容器的滅菌(中間產(chǎn)品和最終包裝)，支持系統(tǒng)，如空氣，水，或氮(6，7，8)。Confidenceinthesterilityofaspecificproductionlotisgatheredthroughanumberofprocesscontrolsandproceduresincluding:documentedandvalidatedsterilization/saniti

36、zationprocedures,in-processcontrolsregulatingtheproductionprocess,environmentalmonitoring,comprehensivebatchrecords,extensivequalificationofprocessequipment,andtrainingofoperatingpersonnel.對一個具體生產(chǎn)批次的無菌的確信是通過過程控制和程序的序列號來收集，包括：被記載和驗(yàn)證過的殺菌/消毒程序，對生產(chǎn)過程監(jiān)察的實(shí)時過程控制，環(huán)境監(jiān)測，全面記錄，工藝設(shè)備的全方位條件，和培訓(xùn)操作人員。PROCESSSIMULATI

37、ONCONCEPTSANDPRINCIPLES工藝模擬的概念和原理NumberandFrequencyofTests實(shí)驗(yàn)的次數(shù)和頻率Foranewfacilityorproductionprocess,processsimulationscanbeperformedaspartoftheoverallvalidation.Initialprocesssimulationtests,ifperformed,areconductedafterequipmentqualification,sterilizationprocessvalidation,andpersonneltraininghaveb

38、eenperformed,andenvironmentalmonitoringhasdemonstratedthatthenewfacilityisunderthedesiredstateofcontrol(9,10,11).Ifaprocesssimulationtestfailsintheabsenceofthissupportivework,identificationofapossiblerootcausewillusuallybemoredifficult.Threeconsecutivesuccessfulprocesssimulationtestsareperformedwhen

39、evaluatinganewfacilityorprocess.Priortoreleaseofthenewfacility,ornewprocessforproductionuse,acceptableresultsfromtheseprocesssimulationtestsshouldbeachievedtodemonstratethereproducibilityoftheprocess.對應(yīng)一個新的設(shè)施或生產(chǎn)工藝，工藝模擬應(yīng)該作為所有驗(yàn)證的一部分。最初的工藝驗(yàn)證應(yīng)該在設(shè)備確認(rèn)、滅菌工藝驗(yàn)證、人員培訓(xùn)已經(jīng)完成并且環(huán)境監(jiān)測證明新的設(shè)施已經(jīng)在預(yù)期的狀態(tài)中受控之后進(jìn)行(9,10,11)。如果

40、沒有作這些支持性的工作，工藝模擬實(shí)驗(yàn)失敗的話，將很難確定可能的原因。當(dāng)確認(rèn)一個新的設(shè)施或工藝時，驗(yàn)證一個工藝應(yīng)該進(jìn)行三次連續(xù)成功的模擬工藝實(shí)驗(yàn)。在為生產(chǎn)使用正式批準(zhǔn)一個新的設(shè)施、新的工藝之前，應(yīng)該完成這樣連續(xù)的可接受的結(jié)果，以證明工藝的可重復(fù)性。Inexistingfacilities,aprocesssimulationtestprogramshouldbeconsideredforeachasepticprocess.Additionalprocesssimulationtestsmaybeconsideredtoevaluatechangestoprocedures,practiceso

41、requipmentconfiguration(SeeSection11PeriodicReassessment).在現(xiàn)有設(shè)施，過程模擬測試程序應(yīng)被考慮到每個無菌過程。追加工藝模擬試驗(yàn)可被用來評估程序、實(shí)踐或設(shè)備配置的變更(見第11期再評估表)。Processsimulationsforclosedsystemscanbeperformedaftersterilizationtoconfirmtheacceptablesterilizationofthesystemsaswellastheappropriatenessoftheproceduresemployedwithin.Thedurat

42、ionofcampaignsforclosedsystemmaybeestablishedthroughphysicalmonitoringofsuchaspectsaspressuredifferentials,leakrates,filterintegritytests,etc.andisfurthersupportedbyapreventivemaintenanceprogram.Endofcampaignprocesssimulationsarethusnotrequiredfortheclosedportionsofaprocesssystem.Thedurationofcampai

43、gnsforopensystemsmaybeconfirmedthroughappropriateprocesssimulationsconductedattheendofarealorsimulatedcampaign.封閉系統(tǒng)的過程模擬可以在滅菌后實(shí)施，以確認(rèn)該系統(tǒng)的滅菌合格性以及內(nèi)部程序的適當(dāng)性。在封閉系統(tǒng)的工作持續(xù)時間可能將通過如壓力差，泄漏率，過濾器完整性測試等物理等方面的監(jiān)測來被確定，并進(jìn)一步被預(yù)防性維修計劃所支持。工作過程模擬的完成不需要一個工藝系統(tǒng)的封閉部分。開放系統(tǒng)的工作持續(xù)時間可能通過真實(shí)或模擬的工作結(jié)束時進(jìn)行的適當(dāng)?shù)墓に嚹M來被確認(rèn)。WorstCase最差條件Oneoft

44、hemoreprevalenttechniquesusedinthevalidationofpharmaceuticalprocessesistheemploymentofworstcasescenarios.在制藥工藝驗(yàn)證中最常采用的技術(shù)之一是采用“最差條件”Theuseofworstcasesituationsisintendedtoprovideagreaterchallengetotheprocess,systemorequipmentbeingvalidatedthanthatexperiencedunderroutineprocessingconditions.采用“最差條件”是有

45、意對工藝、系統(tǒng)、設(shè)備在更高的挑戰(zhàn)條件下進(jìn)行驗(yàn)證。If,underthecircumstancesoftheworstcasechallenge,acceptableresultsareachieved,thenthereisgreaterconfidenceinthereliabilityofthesystemundermorenormalsituations.如果在“最差條件”的挑戰(zhàn)下，仍能夠達(dá)到預(yù)期的可接受標(biāo)準(zhǔn)，那么在正常條件下，對系統(tǒng)的可靠性將有更高的信心。Processsimulationtestsreadilylendthemselvestoworstcasechallenges.S

46、omeofthetypesofchallengeswhichmaybeemployedwherepossibleare:工藝模擬實(shí)驗(yàn)很容易進(jìn)行“最差條件”的挑戰(zhàn)。下面提供了一些類型的挑戰(zhàn)：usingmaterials,equipment,utensilsandotheritemswhichhaveremainedintheasepticprocessingareaforextendedperiodsaftersterilization。使用的原料、設(shè)備、器具等在滅菌后于無菌工藝區(qū)保留時間超出期限。usingthemaximumnumberofpersonnelnecessarytoproces

47、sthebatch。使用人員數(shù)超過灌裝工藝所需。increasingthetimeperiodbetweenthecompletionofequipmentsterilizationandthestartoftheprocesssimulation。設(shè)備消毒的完成與開始模擬之間時間間隔過長usingagrowthpromotingmediumorplacebomaterialintheprocesssimulationtestratherthananinhibitorymaterial。在工藝模擬實(shí)驗(yàn)中使用促生長培養(yǎng)基或安慰劑，而不是使用有抑制性的處方。performingaprocesssi

48、mulationtestaftercompletionofthelastlotinaproductioncampaign。在最后的生產(chǎn)完成后進(jìn)行工藝模擬實(shí)驗(yàn)。Theconductofaprocesssimulationforasterilebulktypicallyincludesactivitiesandmanipulationsthatarespecificforitsexecution.對于無菌原料的工藝模擬的進(jìn)行通常包括大量特定的活動和操作。Theseaddedstepsintroduceahigherpotentialforcontaminationthanisinherentint

49、heroutineprocessandposeanincreasedriskforprocesssimulationfailure.相比固有的常規(guī)工藝，這些額外的步驟導(dǎo)致了更高的潛在污染，增加了過程模擬失敗的風(fēng)險。Inthedevelopmentofprotocolsorproceduresusedforthedefinitionofprocesssimulationtests,theuseofworstcasechallengessuchasthosedescribedaboveisanessentialelementofawell-foundedprogram.在建議用于定義工藝模擬試驗(yàn)的

50、方案或過程時，一個有良好根據(jù)的程序會使用上面提到的“最差條件”的挑戰(zhàn)oTheworstcasechallengesselectedmayvarybaseduponthespecifictypeofprocesssimulationutilized(seeSections3and4).對“最壞條件”的挑戰(zhàn)的選擇可能會根據(jù)運(yùn)用的工藝模擬的類型特點(diǎn)有所不同(見第3和4章)。Riskassessmentapproachessuchashazardanalysisandcriticalcontrolpoint(HACCP),failureeffectsmodeanalysis(FEMA)orfaultt

51、reeanalysis(FTA)maybeusedtodetermineappropriatechallenges.正式的風(fēng)險評估方法，例如HACCP、FEMA或FTA可以用于確定合適的挑戰(zhàn)。PROCESSSIMULATIONTESTMETHODS工藝模擬試驗(yàn)方法Theapplicationofthesegeneralprocedurestoanyspecificasepticproceduremayrequiremodificationofthemethodsdescribedherein.Theseadaptationsshouldbeaccomplishedinamannerwhichw

52、illnotimprovetheresultsofthesimulation,relativetoroutineoperations.這些一般程序在用于其他特定的無菌過程時可能需要對本文所訴的方法進(jìn)行修改。但修改需要注意不改變模擬結(jié)果以及相關(guān)慣例操作。Theconductofprocesssimulationtestsforsterilebulkpharmaceuticalsentailssimulationoftheprocessfromthepointofsterilizationthroughtothecompletionofbulkpackaging.Sterilebulkproces

53、sesgenerallyconsistofaseriesofunitoperationswhichintotalcomprisetheproductionprocesses.對無菌原料藥的工藝模擬試驗(yàn)，必須從滅菌開始到完全灌裝結(jié)束全過程的模擬。無菌原料工藝的總生產(chǎn)工藝一般由一系列的單元工藝構(gòu)成。Forthepurposesofprocesssimulationitmaybeappropriatetoconductevaluationsaroundeitherasingleoperationoragroupofoperations.Providedthatalloftheunitoperatio

54、nsutilizedintheproductionofasterileBPChavebeenevaluatedinanappropriatemanner,thesegmentedapproachtosimulationcanbeassuitableasacomprehensivetestinvolvingalloftheunitoperationsinasinglesimulation.基于工藝模擬的目的，圍繞一個操作或一組操作來進(jìn)行評估可能比較適當(dāng)。如果一個無菌BPC生產(chǎn)中所使用的所有操作單元都以適當(dāng)?shù)姆绞竭M(jìn)行評估，那么分段模擬方法作為一個全面的、在一次單獨(dú)模擬中涉所有操作單元的測試是非常合

55、適的。Thedecisionwhethertoperformtheprocesssimulationasasingleintegratedtestorintrialsbasedupononeormoreunitoperationsmustconsidertheprosandconsofeachapproach.Itshouldberecognizedthatthedecisiontoconductanoverallsimulationorstep-wisesimulationapproachisindependentoftheuseofmicrobiologicalgrowthmediaoro

56、thermaterialsinthesimulation.決定是否執(zhí)行作為一個單一的綜合過程模擬測試還是執(zhí)行一個或多個操作單元為基礎(chǔ)的過程模擬測試必須考慮每種方法的利弊。應(yīng)當(dāng)承認(rèn)，決定進(jìn)行整體模擬或分步模擬方法于對微生物生長介質(zhì)或其他材料在模擬中的使用是獨(dú)立的。TotalProcessSimulation總工藝模擬Inthistypeofsimulation,theentireasepticprocessisevaluatedinatrialwhichfollowstheprocessfromwherethematerialsarefirstmadesterile,throughsubdivi

57、sionintocontainersforshipment.在這種模擬方式中，整個無菌過程的評價是遵循從材料首次被無菌化到裝運(yùn)集裝箱的整個過程來評價的。Advantages優(yōu)勢Thesimulationmaybeabletofollowtheprocessmorecloselythanaseriesofsmallersimulations.相比一系列的小型模擬測試，該模擬測試更加貼近下列工藝。Requireslesstimetocompletethanaseriesofsmallersimulations.相比一系列的小型模擬測試，該模擬測試更加節(jié)省時間。Disadvantages缺點(diǎn)Ifco

58、ntaminationisdetectedtheidentificationandcorrectionofsourcesismoredifficultthaninaunitoperationsimulation.如果發(fā)現(xiàn)污染，污染源的識別和糾正比一系列單元操作模擬更加困難。Intheeventoffailure,theentiresimulationmustberepeatedaftercorrectivemeasureshavebeentaken.在發(fā)生故障時，整個模擬必須糾正后再次采取措施。Willgenerallyrequiretheuseofasingletestmaterial(ei

59、therliquidorsolid)throughouttheentiresimulationwhichmayintroducesignificantdifferencesinthesimulationandinhowcontaminationmightoccurwhencomparedtotheroutineproductionprocess.通常會要求在整個模擬測試中使用單個測試材料(或液體或固體)，和傳統(tǒng)的生產(chǎn)工藝相比，這有可能引起明顯的差異和污染。UnitOperation(s)Simulations單元操作模擬Inthisformofsimulation,aseriesofindiv

60、idualtrialsareconductedcoveringallofthestepsintheasepticprocess.Wherethesimulationisperformedinseveralsteps,theestablishmentofanacceptancecriterionmustaddressthecumulativecontributionfromeachoftheunitoperations.Thusthetotalnumbersoforganismsdetectedovertheentireprocessmustbeconsidered.在這個模擬的方式中，對個別進(jìn)