fda無菌原料藥檢查指南-中英文版

1、GUIDETOINSPECTIONSOFSTERILEDRUGSUBSTANCEMANUFACTURERSFDA無菌原料藥檢查指南Note:ThisdocumentisreferencematerialfinvestigatsotherFDApersonnel.ThedocumentdoesnotbindFDAdoesnoconferanyrightsprivilegesbenefitsimmunitiesfonanyperson(s)

2、.注：本文件是FDA現(xiàn)場檢查官和其他FDA人員的參考資料。本文件并不束縛FDA，也不賦予任何人任何權(quán)利、特權(quán)、好處以便獲得赦免。Oneofthemedifficultprocessestoinspectonewhichhaspresentedconsiderableproblemsovertheyearsisthatofthemanufactureofsterilebulkdrugsubstances.Withinthepastseve

3、ralyearstherehavebeenanumberofbatchesofsterilebulkdrugsubstancesfromdifferentmanufacturerswhichexhibitedmicrobiologicalcontamination.Onemanufacturerhadapproximately100batchescontaminatedina6monthtimeperiod.Anotherhadappr

4、oximately25batchescontaminatedinasimilarperiod.Othermanufacturershavehadrecallsduetothelackofassuranceofsterility.AlthoughtheInspectionGuidefBulkDrugSubstancesprovidessomedirectionftheinspectionofthesterilebulkdrugsubsta

5、nceitdoesnotprovidethedetaileddirectionneeded.在過去多年中，現(xiàn)場檢查最難的，也是出現(xiàn)問題最多的領(lǐng)域就是無菌原料藥的制造。在過去幾年中，有數(shù)批來自不同制造商的無菌原料藥出現(xiàn)了微生物污染。一個(gè)制造商在6個(gè)月中有100批產(chǎn)品有污染。另一個(gè)在相同的時(shí)間內(nèi)出現(xiàn)了25批污染。其它一些供應(yīng)商由于缺少無菌保證而召回了產(chǎn)品。雖然大宗原料藥的現(xiàn)場檢查指南在對無菌原料藥的檢查上提供了一些指導(dǎo)，但它未能提供所需要的

6、詳細(xì)指導(dǎo)。I.INTRODUCTION簡介Inthemanufactureofthesterilebulkpowdersitisimptanttorecognizethatthereisnofurtherprocessingofthefinishedsterilebulkpowdertoremovecontaminantsimpuritiessuchasparticulatesendotoxinsdegradants.在大宗無菌粉的制造

7、中，認(rèn)識(shí)到下面一點(diǎn)很重要，即最終無菌粉生產(chǎn)出來之后，再也沒有別的程序來去除微粒、內(nèi)毒素和降解物。Aswithotherinspectionsanyrejectedbatchesalongwiththevariousreasonsfrejectionshouldbeidentifiedearlyintheinspectiontoprovidedirectionftheinvestigat.Fexamplelistsofbatchesrej

8、ectedretestedoveraperiodoftimeshouldbeobtainedfromthemanufacturertoprovidedirectionfcoveragetobegiventospecificprocessessystems.Becausesomeoftheactualsterilebulkoperationsmaynotbeseenbecauseofthecomplexityoftheprocessiti

9、sparticularlyimptanttoreviewreptssummariessuchasvalidationstudiesrejectlistsEnvironmentalMonitingSummaryReptsQAInvestigationLogsetc.ThesesystemsothersarediscussedintheBasicInspectionGuide.Thisisparticularlyimptantfthefei

10、gnsterilebulkdrugsubstancemanufacturerwheretimeislimited.Inthepreparationfasterilebulkdrugsubstanceinspectionaflowtwiththemajprocessingstepsshouldbeobtained.Generallythemanufactureofasterilebulksubstanceusuallyincludesth

11、efollowingsteps:與其它檢查一樣，在檢查的早期，應(yīng)向檢查官提供拒絕使用的批（不合格批）及拒絕的各thenonsteriletothesterilesubstanceistoreduceendotoxinsbyonelogthendatashouldsupptthisstep.從內(nèi)毒素角度來看該轉(zhuǎn)換的驗(yàn)證(有菌到無菌)，重點(diǎn)應(yīng)放在實(shí)驗(yàn)室或定點(diǎn)規(guī)模的研究來確定該步驟的有效性。一旦確定該工藝可以帶來可接受的內(nèi)毒素含量，只需監(jiān)控批

12、生產(chǎn)過程。如任何驗(yàn)證過程一樣，每一步的目的和有效性均需證實(shí)。例如，如果一個(gè)記錄顯示有菌到無菌的轉(zhuǎn)換（結(jié)晶）減少了內(nèi)毒素，那么，該數(shù)據(jù)應(yīng)支持該步驟。Sinceendotoxinsmaynotbeunifmlydistributeditisalsoimptanttomonitthebioburdenofthenonsterilesubstance(s)beingsterilized.Fexamplegramnegativecontamina

13、tsinanonsterilebulkdrugsubstancepritosterilizationareofconcernparticularlyifthesterilization(filtration)crystallizationstepsdonotreducetheendotoxinstoacceptablelevels.Therefemicrobiologicalaswellasendotoxindataonthecriti

14、calcomponentsoperationalstepsshouldbereviewed.由于內(nèi)毒素可能不是均勻分布，因此，監(jiān)控滅菌中的有菌原料藥的生物負(fù)荷也很重要。例如，有菌原料藥中的某些污染在滅菌前會(huì)很嚴(yán)重，特別是如果滅菌和結(jié)晶過程不能減少內(nèi)毒素含量。因此，應(yīng)當(dāng)審閱關(guān)鍵設(shè)備部分和操作環(huán)節(jié)的微生物和內(nèi)毒素?cái)?shù)據(jù)。III.FACILITY設(shè)施Facilitydesignftheasepticprocessingofsterilebulk

15、drugsubstancesshouldhavethesamedesignfeaturesasanSVPasepticprocessingfacility.Thesewouldincludetemperaturehuitypressurecontrol.Becausesterilebulkasepticfacilitiesareusuallylargerproblemswithpressuredifferentialssanitizat

16、ionhavebeenencountered.Fexampleamanufacturerwasfoundtohavethegowningareaundergreaterpressurethantheadjacentasepticareas.Theneedtoremovesolventvapsmayalsoimpactonareapressurization.無菌原料藥的無菌加工設(shè)備的設(shè)計(jì)應(yīng)與SVP無菌設(shè)備具有相同的設(shè)計(jì)特征。這包括溫度、

17、濕度和壓力控制。由于無菌設(shè)備通常更大，壓力不均和清潔問題常常遇到。例如，在現(xiàn)場檢查中發(fā)現(xiàn)，一個(gè)制造商在更衣區(qū)域的壓力比臨近的加工區(qū)域的壓力更大。過濾和結(jié)晶過程使用的壓縮空氣也可能影響著潔凈區(qū)域的壓力。Unnecessaryequipmentequipmentthatcannotbeadequatelysanitizedsuchaswoodenskidsfklifttrucksshouldbeidentified.Inquireabout

18、themovementoflargequantitiesofsteriledrugsubstancethelocationofpassthroughareasbetweenthesterilecenonsterileareas.Observetheseareasreviewenvironmentalmonitingresultssanitizationprocedures.不能充分清洗的非關(guān)鍵設(shè)備，如木剎車和叉車，應(yīng)當(dāng)標(biāo)記。詢問大量無菌

19、原料藥的流動(dòng)和在有菌和無菌區(qū)域的穿行。觀察這些區(qū)域，審閱環(huán)境監(jiān)控結(jié)果和清洗程序。TheCGMPRegulationsprohibittheuseofasbestosfiltersinthefinalfiltrationofsolutions.Atpresentitwouldbedifficultfamanufacturertojustifytheuseofasbestosfiltersffiltrationofairsolutions.

20、Inquireabouttheuseofasbestosfilters.cGMP條例禁止在溶液的最終過濾時(shí)使用石棉過濾器。目前，制造商很難找出使用石棉過濾器來過濾空氣或溶液的理由，向FDA詢問使用石棉過濾器的問題已無必要。Facilitiesusedfthegeadditionofnonsterilecomponentssuchasthenonsteriledrugsubstanceshouldbesimilartothoseusedf

21、thecompoundingofparenteralsolutionspritosterilization.Theconcernissolubleextraneouscontaminantsincludingendotoxinsthatmaybecarriedthroughtheprocess.Observethisareareviewtheenvironmentalcontrolsspecificationstodetermineth