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利、特權、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，現場檢查最難的，也是出現問題最多的領域就是無菌原料藥的制造。在過去幾年中，有數批來自不同制造商的無菌原料藥出現了微生物污染。一個制造商在6個月中有100批產品有污染。另一個在相同的時間內出現了25批污染。其它一些供應商由于缺少無菌保證而召回了產品。雖然大宗原料藥的現場檢查指南在對無菌原料藥的檢查上提供了一些指導，但它未能提供所需要的

6、詳細指導。I.INTRODUCTION簡介Inthemanufactureofthesterilebulkpowdersitisimptanttorecognizethatthereisnofurtherprocessingofthefinishedsterilebulkpowdertoremovecontaminantsimpuritiessuchasparticulatesendotoxinsdegradants.在大宗無菌粉的制造

7、中，認識到下面一點很重要，即最終無菌粉生產出來之后，再也沒有別的程序來去除微粒、內毒素和降解物。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，應向檢查官提供拒絕使用的批（不合格批）及拒絕的各thenonsteriletothesterilesubstanceistoreduceendotoxinsbyonelogthendatashouldsupptthisstep.從內毒素角度來看該轉換的驗證(有菌到無菌)，重點應放在實驗室或定點規(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毒素含量，只需監(jiān)控批

12、生產過程。如任何驗證過程一樣，每一步的目的和有效性均需證實。例如，如果一個記錄顯示有菌到無菌的轉換（結晶）減少了內毒素，那么，該數據應支持該步驟。Sinceendotoxinsmaynotbeunifmlydistributeditisalsoimptanttomonitthebioburdenofthenonsterilesubstance(s)beingsterilized.Fexamplegramnegativecontamina

13、tsinanonsterilebulkdrugsubstancepritosterilizationareofconcernparticularlyifthesterilization(filtration)crystallizationstepsdonotreducetheendotoxinstoacceptablelevels.Therefemicrobiologicalaswellasendotoxindataonthecriti

14、calcomponentsoperationalstepsshouldbereviewed.由于內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荷也很重要。例如，有菌原料藥中的某些污染在滅菌前會很嚴重，特別是如果滅菌和結晶過程不能減少內毒素含量。因此，應當審閱關鍵設備部分和操作環(huán)節(jié)的微生物和內毒素數據。III.FACILITY設施Facilitydesignftheasepticprocessingofsterilebulk

15、drugsubstancesshouldhavethesamedesignfeaturesasanSVPasepticprocessingfacility.Thesewouldincludetemperaturehuitypressurecontrol.Becausesterilebulkasepticfacilitiesareusuallylargerproblemswithpressuredifferentialssanitizat

16、ionhavebeenencountered.Fexampleamanufacturerwasfoundtohavethegowningareaundergreaterpressurethantheadjacentasepticareas.Theneedtoremovesolventvapsmayalsoimpactonareapressurization.無菌原料藥的無菌加工設備的設計應與SVP無菌設備具有相同的設計特征。這包括溫度、

17、濕度和壓力控制。由于無菌設備通常更大，壓力不均和清潔問題常常遇到。例如，在現場檢查中發(fā)現，一個制造商在更衣區(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鍵設備，如木剎車和叉車，應當標記。詢問大量無菌

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

20、Inquireabouttheuseofasbestosfilters.cGMP條例禁止在溶液的最終過濾時使用石棉過濾器。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