PDA-TR-80《制药实验室数据完整性管理体系》(中英文对照版).docx

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1、PDATR80制药实验室数据完整性管理体系(中英文对照版)5.0DataIntegrityinthePharmaceuticalMicrobiologyLaboratory5.0微生物实验室的数据完整性5.1GeneralConsiderationsandRisks一般原则及风险Theapproachesusedtoinvestigatetheoccurrenceofsuspecteddataintegrityissuesthathrecentlyourredinapharmaceuticalmicrobiologylaboratorycanbechallengingand,insomecas

2、es,maybeverydifferentthanthoseusedtoevaluatesimilaroccurrencesinananalyticalchemistrylaboratory,Manymicrobiologicalmethodsareperformedmanually;subsequently,therecordedresultsareoftenbasedonthevisualobsen/ationsbyanindividualscientistperformingthetests.制药企业微生物实验室对可疑数据完整性问题的调查方法，越来越成为个挑战，并且在一些情况下，与同样发

3、生可疑数据的化学分析实验室的调查方法完全不同。很多微生物测试方法都是手动操作，以及所有的测试结果都由微生物测试人员人工检查并记录。Listedbelowareafewexamplesofregulatoryobservations,WarningLetters,orotherinstitutionalaccountsthatnotedataintegrityproblemsassociatedwithmicrobiologicallaboratoryrecords.Theseareonlyexamplesandarenotintendedtobeanall-inclusivelistofcon

4、cerns:以下是一些官方检查项，警告信，或其他官方检查关于微生物实验室记录数据完整性问题的情况列举，这些仅是举例并不完全代表所有与微生物实验室数据完整性相关的问题：Companyfailedtorecordandreportreliableandaccuratedatafortheenvironmentalmonitoring(EM)results;forexample,contaminationinGradeAroomswererecordedandreportedashavingnoviablemicroorganismspresentwhen,infact,microbialconta

5、minationwaspresent.Specifically,thesettleagarplatesusedintheseareaswerefelselyreportedashavingnocoloniespresentbutwerefoundtocontain16colony-formingunits(CFU),morethancouldbereasonablyoverlooked.公司未记录和报告真实准确的环境监测结果数据：例如，A级区实际存在微生物污染但实际记录和报告为零。特别是A级区沉降菌报告为1无菌落生长”，但实际上发现沉降菌结果为16cfu,可能会有更多类似的情况被掩盖。Comp

6、anyfailedtoimplementanadequatequalityassurancesystemasevidencedby:productsterilitytestfailuresthatoccurredandwerenotreported,investigated,ordocumented;fivebatchesofviralharveststhatwererejectedduetocontamination,yetnoreportswereinitiated；andacompanypracticethatproductsterilitytestfailre(s)wereinvest

7、igatedonlyifmorethanonetestjarperbatchofthefirstorsecondharvestsfailedforsterility.公司质量保证体系未有效执行，具体表现为：产品无菌测试失败未报告，调查或记录：5批次产品由于病毒污染而被拒绝放行，但没有任何调查报告被发起，以及某些公司仅在第二次无菌失败或同一批次超过瓶出现无菌样品失败的情况下，才会发起无菌调查Companyusedacontractlaboratorytoperformmicrobiologicaltesting;however,thecompanyauditchecklistusedtoeval

8、uatethesuitabilityofthislaboratorywascompletedbythecontractlaboratory,notthecompany,withnofollow-upverification.公司存在委托实验室进行微生物检测的情况，然而，对委托实验室符合性审计的主体是由该委托实验室进行而非公司，且并未进行任何确认。Privatetestinglaboratoryclaimedtohaveconductedmicrobiologicaltesting,yetitdidnothavethelaboratoryequipment(i.e.,incubators)and

9、/ormedianecessarytoperformtheanalysis.公司声称内部进行微生物实验测试，但实验室并没有实验相关的设备(如培养箱)和/或测试所必须使用的培养基。Companyusedanunofficia,notebooktorecordmicrobialcontaminationintheplantswatersystem;however,therewasnoofficialinvestigationordocumentationregardingthewatersystemcontaminationwithaknownpathogen(Pseudomonasaerugin

10、osa).Comment:Thistypeofobservationrelatestoboththemicrobiologylaboratoryandoperatorsbehaviors.Periodically,deceptiveindividualswillusethesametechniquetomislead,misrepresent,and/orobscureemergingmicrobialproblemsinmanufacturingequipmentthatcanimpactproductquality.公司使用“非正式”的记录本以记录工厂内水系统的微生物污染情况：然而，当发现

11、水系统中存在已知控制菌(铜绿假单胞菌)污染时，公司并未针对此污染情况发起任何正式的调查或记录。CompanyrecordedresultsthatthegrowthpromotiontestonthemediausedforsimulationstudiessupportedgrowthmeetingthestandardsetbyUSPChapterSterilityTestswhen,infact,themicroorganismsdidnotgrow(30).Inanothercase,filamentousfungiwereseengrowinginallfivespikedmedia

12、tubes,indicatingcontamination,yetlaboratoryrecordsclaimedthatallfivedistinctspeciesofmicroorganismswereactuallygrowingpertheUSPstandard.公司记录用于培养基模拟灌装的培养基促生长测试结果符合USP无菌检测章节的标准菌种生长要求，然而事实上，XX(30)微生物并未生长。另一个情形中检查人员发现，真菌菌丝在5管液体培养基试管中生长，显示了污染，但实验室记录却显示按照USP标准5管试验管中显示各测试菌种生长良好。Again,whilethislistisnotexha

13、ustive,itdoespresentactualinspectionobservationsmadebyseveralregulatoryauditorsduringtheirdocumentationofdataintegrityanomaliesinpharmaceuticalmicrobiologylaboratories.虽然以上显示的清单并不详尽，但却来源于多次官方审计检查中微生物实验室存在的缺陷检查记录清单。5.1.1 InterviewingAnalysts问询分析人员Onecriticalelementinconductinganauditfordataintegrityp

14、roblemsinamicrobiologicallaboratoryisinterviewingtheindividualswhoperformtheQA/QCtests,inparticular,thelaboratoryanalystsortechnicians.WhenreviewinganalyticalresultsrecondedonworksheetsordataprintoutsfromtheLIMS1forexample,itisextremelydifficulttodetectdatathatshouldhavebeenrecordedbutwasnot.Muchofw

15、hatanalystslearncomesfromon-the-jobtraining,yetunofficialdialoguewithcowokersorsupervisorsisrarelycapturedordocumented.Forinstance,whenasenioranalystinstructsajunioranalystonhowtohandletheappearanceofunwantedmicroorganismsfoundgrowingonanalyticalpetriplates(suchaswritethenumericalcountofthesuspected

16、coloniesonthelidofthepetridishbutdontrecorditontheofficialworksheetuntilthesupervisorhasachancetoreviewit)，thisunofficia,practicewillnotbefoundinthecompany,sstandardoperatingprocedures(SOPs).Anauditorcanbestassessthepotentialforinappropriatepractices,first,byverifyingtheacceptancecriteriadescribedin

17、SOPsand,then,byinquiringoftheanalystsortechniciansiftheyhavebeeninstructedtoadjustormodifydataordivertfromthelaboratorySOPsinanyform.Withoutconductingsuchfoce-to-faceinterviews,thiskindofmicrobiologicaldatamanipulationwouldbeextremelydifficulttodetect.对微生物实验室数据完整性问题的审计一项重要的基本要素是问询执行微生物测试的QA/QC人员，特别是

18、实验室的分析师和技术人员。当审核记录于工作表或从LlMS系统中打印的分析结果时，很难发现本应被记录而未被记录的数据。大部分分析人员的知识来源于在岗培训，因此同事间的或与主管间的非正式谈话就很难被捕捉或记录。例如，当一个高级技术员指导新员工进行培养皿微生物计数，当发现培养皿上不好的(或非预期生长的)微生物时(例如，在主管审核结果之前将计数结果写在培养皿上而不是记录表格中)，这种“非正式的操作就不会出现在公司SoP描述中。审核员可以评估潜在不当做法的最佳方式是，确认SoP中描述的验收标准，然后，通过询问分析员或技术人员，去分析他们是否被指示调整或修改数据或以任何形式从实验室SoP转移。如果不进行这

19、种面对面的面谈，这种微生物数据操纵将极其难以察觉。如果没有面对面的这种沟通，这种类型的微生物实验室数据操作将很难被发现。5.1.2 On-siteLaboratoryandSamplingReview公司内实验室和取样环节审核Thereareseveralproceduralstepswhenhandling,shipping*andstoringmicrobiologicalsamplesthatcandramaticallyandnegativelyimpactfinalanalyticalresults.Specificexamplesofmanagingsamplesthatcandi

20、minishrecoveryofmicrobiologicalorendotoxinresultsand,thus,shouldbeavoidedthroughproceduresandadequateemployeetraining,arelistedbelow:文件中有很多关于微生物样品取样，运输，储存的步骤会对最终微生物测试结果存在显著的、不良的影响。为避免影响微生物及内毒素测试结果应当包括完善的管理文件和足够的人员培训，例子包括：Collectingin-processproductorwatersamplesinaninappropriatecontainerthatmaybind(

21、orremove)abacterialendotoxinfromthesamplemaylaterreducethetruelevelofbacterialendotoxinswithinthattestportion.使用不合适的容器取中间产品样品或水的样品可能会弱化(或去除)样品中的细菌内毒素水平，随后可能减少被测试样品中真正的内毒素水平。 Theexcessiveuseofdisinfectantstospraythesamplingport(s)priortotakingthesamplemayresultinthedisinfectantdrippingintothesamplebo

22、ttleandreducingtheactualbioburdenoftheproductsample.Samplingfromthesampleportsshouldcloselysimulatethecommonpracticesperformedduringroutineproductionoperations.取样前对取样口使用消毒剂过度喷洒可能导致消毒剂滴落在取样瓶中导致降低所取样品中真正的微生物负载水平。从取样口取样应当正常模拟日常生产时使用该取样点的情况。 Whenusingin-linesamplecollectionmanifoldsforcollectingintermed

23、iate-stageproductmanufacturing,themanifoldneedstocooldownafterheatsterilizationsoitdoesnotkillthemicrobescollectedforlaboratorytesting.采用在线样品收集管道抽取中间体产品时，收集管道在加热灭菌后需要冷却，以免杀死供实验室检测用样品中收集到的微生物。 ProductsamplecollectionbagsshouldnotbehelddirectlyunderaUVlightwithinastoragecabinet.ExposuretoUVlightwillki

24、llthemicrobespresentbeforethesamplecollectionbagsaredeliveredtothelaboratoryfortesting.取样瓶不应该直接放在有UV紫外灯的传递窗中。样品瓶传递至实验室之前暴露在UV紫外灯下将杀灭取样器中的微生物 Microbiologicalsamplebagsshouldnotbestoredinafreezerorextremelycoldrefrigerator,whichmayinjureorstressindigenousmicrobes.Microbialsamplesshouldbeplacedwithinac

25、ontrolledenvironmenttoprecludeanyharmfulordeleteriousimpactonthesamples;then,analysesshouldcommenceassoonasreasonablypossible.微生物取样瓶不应该储存于冰箱或超低温冰箱中以免使样品中微生物受损或阻碍生长。微生物样品应当被放置在受控的环境中排除任何对样品有害的影响；否则，分析人员应当立即进行测试。Finishedproductsorin-processsamplesthatareundergoingsterilitytestinginaClass100cleanroom(o

26、risolator)shouldbedisinfectedusinganantimicrobialsolutionandavalidatedcontacttime.Disinfectantvaporsorsolutionpassingthroughtheproductpackagingorcontainer-closureandintoorontotheproductpriortosampleanalysismaypreventorkillmicrobesinthemedia-enrichmenttestenvironment,whichmayinhibitrecoveryofproductc

27、ontaminants.Forexample,iftheproductsamplewascontaminatedpriortothepackagedisinfectionstep,avulnerablecontainer-closuresystempreparedwithexcessivedisinfectantwouldlikelyresultinfalsenegativedata.Thesamplecontainerdisinfectionprocessshouldbeincludedinlaboratoryqualificationstudiesandthesuitabilitytest

28、edtoensurethatresidualdisinfectionsolutiondoesnotaltertheintegrityofthesampleresults.100级房间（或隔离器）中进行成品或中间产品的无菌测试，应当使用消毒剂及经验证的接触时间对样品表面进行消毒。在样品检验前消毒剂喷雾或溶液如果穿透待检品包装或容器密封系统进入或覆盖在包装外则会阻止或杀灭充满培养基的环境，从而阻碍产品中微生物生长。例如，在包装消毒步骤前产品取样遭到污染，那么过度的消毒将容易透过容器密封系统产生假阴性的结果。样品包装容器消毒程序应当包含在实验室确认研究工作以及方法适用性监测中，确保残留的消毒剂不会改

29、变样品微生物结果的完整性。Becausemicrobiologicalresultsarenotcapturedinachromatograph,aswithHPLCorGCanalysis,opportunitiestodirectlyreviewanyanomaliesbetweentherawandrecordeddataarefew.Onewaytoverifytheaccuracyofthetestdatadocumentationistosetasideallavailablemicrobialpetriplates,broths,identificationstrips,etc.

30、,inasecureareaorrefrigeratorjustaftertheyhavebeenremovedfromtheincubatorandanalysisiscomplete.AcarefulreviewoftherawdataagainsttheanalyticalworksheetsorLIMSdataentriesshouldrevealanydiscrepanciesandprovideanopportunitytocatchanyproblemswitheitherpersonneltrainingorequipmentrecording,andthusimprove,l

31、aboratoryprocedures.由于微生物测试不像高效液相和气相测试那样通过色谱仪进行分析，因此能够直接审核出原始数据和所记录的数据之间异常情况的几率很小。确认测试数据准确性的一种方法是，在待检验工作完成后将用于测试的微生物培养皿、营养肉汤、鉴定条等从培养箱中取出，将它们放在安全区域或冰箱中，然后仔细核对检验工作表或UMS数据。可以发现任何不符之处，并提供机会发现人员培训或设备记录方面的任何问题，从而改进实验室程序。Anothertechniquemayproveeffectiveincheckingdatafromsamplesstoredinrefrigeratorsandfree

32、zers.Theordinaltestvesselsfromcompletedanalysesofallpositivesamples（in-processorfinishedproductbioburdentestresults,sterilitytestresults,watertesting,EM,personnel,etc.）usuallycontainmicrobialisolates.Conductinganinventoryofthestoredsamplescanprovideastartingpointtodetermineiftherearedifferencesbetwe

33、enwhatwasactuallyrecoveredduringsampleanalysisandthedatarecordedonworksheetsorintheLIMS.Whiletakinginventoryofsamplesstoredinfreezersandrefrigerators,besuretonotetheproductname,lotnumbers,trackingnumbers,microbialidentification,etc.,markedontheexterioroftesttubesandpetridishes.Thiscollectedinformati

34、onwillprovidealistthatcanlaterbecomparedtotheresultsrecordedonbatchrecords,worksheets,andLIMS.TheinformationgatheredfromreviewingthestoredsampleplatesandtubescanindicatewhetheracompanySOPsareeffectiveoriftheanalystsarefollowingproceduresrrectlywhenthereareobjectionablemicroorganismsthatneedtobeinves

35、tigated.Ifthenumberandtypesofactualmicrobialisolatesfoundfromthestoredsamplesdonotmatchthoseinthecompanysqualitycontrolrecords,thesedataintegrityissuesmaybeduetointentionalmisreportingofthedata.另一个可能证明有效的手段是检查储存在冰箱或超低温冰箱中的样品数据。保存所有原始的阳性测试结果的测试容器（中间产品或成品的微生物限度测试、无菌检查、水测试，环境测试，人员表面微生物测试等）通常都包含微生物菌落。检查

36、被存储的阳性样品可以从最开始的数据检查检验记录单或LlMS系统与实际数值之间是否存在差异。如果要将阳性样品储存起来，应当确保在试管壁和培养皿外表面注明产品名称，批号，追踪号，微生物鉴定结果等信息。收集这些信息是用于提供足够信息用于与检验记录结果，批记录，表格和LlMS系统中的数据核对。对于这些搜集信息的审核是为了考察公司SC）P规定的是否完善以及分析人员是否正确按照规程执行操作，对有任何可疑菌落生长发起必要的调查。如果被储存起来的冻存管，培养皿等观察到的信息与QC报告的数据不一致，则显示有故意为之的嫌疑而造成微生物数据完整性不符合要求。5.1.3 WorksheetReview检验记录的审核M

37、icrobiologydataoftenreliesonlessautomatedrecordkeepingthatcanbemanipulated,oftenwithoutcleartraceabilitytotheoriginalrecord,whenrecordingformsandworksheetsarenotwellcontrolledorreconciled.Inordertocross-checkandconfirmdatainworksheets,entriesinlinkeddocumentationshouldbereviewed(e.g.1logbooksofequip

38、ment,batchrecords).Controlovertheissuanceoforiginalpaperrecords,formsorworksheetsshouldprovidemechanismsthatallowtheoriginalrecordstobedistinguishedfromcopiesandreconciled.Anexpertmicrobiologistrecommendsreviewinganalyticalworksheetscarefullyduringaninspectionforthefollowingindicationsofpossiblefals

39、ification:(a)labreportscontainingmoreteststhancanreasonablyberunperdayorperweekorbyanindividualanalyst;(b)backloggedsampleworksheetsreviewedandapprovedasabatchattheendofthemonth;(c)worksheetscompletedbypersonnelnotpresentinthelabthedayofthetests;(d)worksheetsreviewedandapprovedbysomeotherthananautho

40、rizedreviewer/approver;(e)changesinhandwritingsignatures;(f)changesinreportingformat,e.g,1CFUbeingreplacedbyzero;(g)resultswithcountsreportedasmerelymeetingspecifications;(h)achangeinfrequencyofOOSresultreporting;(i)perfectlyfilled-outworksheets,indicatingariskthattheyareasecondcopy;(j)useofmediabef

41、oreitpassesgrowthpromotion;(k)missingworksheetsorworksheetsoutofnumericalorder;(I)discrepanciesbetweeninvestigationreportsandworksheets;and(m)resultsfromasinglebatchreportedtwice(31)微生物数据记录通常无自动记录装置依靠手工操作，如果记录本和台账未良好受控或管理，这样通常会导致很难可清晰追溯至原始记录数据。为了能够对记录表格中原始数据进行交叉审核，在录入相关文件记录时应当对其录入的数据进行审核(例如：设备使用日志，批

42、记录)。实验室原始记录和表格应当有受控发放机制，以区分原始记录和复印件及受控件的区别。一位微生物学专家建议在审核实验员检验记录时应当关注以下可能出现的数据造假：(a)实验室某个实验员出具的检验记录数量远远超过理论上一个单独实验员一天或一周正常的数量；(b)月底开始集中审核和批准积压的一批次样品检验记录：(C)检测记录上签字的人员在检测当天并未在岗：(d)未授权的记录审核员；(e)书写或签名处有涂改；(f)报告形式变更，例如用。替代VlCfu；(g)报告的结果几乎接近标准值：(h)OOS结果报告周期的变更：(!)刚好填满一整张记录，可能显示为重新替抄的记录：(j)在培养基适用性检查之前就使用该培

43、养基：(k)记录表格丢失或表格编号不连续；(I)记录表和调查报告之间存在差异；以及(m)同一批次报告2次结论(31)o5.1.4 ContractLaboratories合同实验室Companiesthatdonothavethelaboratoryspace,specializedequipment,orcapacitytoconducthighvolumemicrobiologicalanalysesmayoutsourcethistypeoftestingtocontractlaboratories.Insuchcases,thecompanyisresponsibleforthorou

44、ghlyinvestigatingthereputationandqualitycontrolperformanceofanyneworunfamiliarcontractlaboratorywithwhichtheyengageinaqualityagreement.Beforesigninganagreement,itisrecommendedthatamanufacture(a)confirmthatthecontractlaboratorycomplieswithCGMPregulationsregardinglaboratoryqualificationsandcanperformt

45、herequiredcompendialtestingformicrobialrecoveryandbacterialendotoxins(30,3234);(b)conductanon-siteaudit;and(c)submitasamplebatchfortestingtoensurethequalityoftestinganddataintegrity.ThecompanymaywishtosubmitablindedchallengeoftestsamplesthatshouldproduceOOSresults.Documentationthatthelaboratorymanag

46、ementisqualifiedtointerpretmicrobiologicalsampleresultsisrequired,especiallyifthoseindividualswillbeusedassubjectmatterexpertsfordatarevieworintheeventthelabmanagementneedstoconductalaboratoryinvestigationforquestionablesampleresults.若公司内部没有实验场地，特殊实验设备或缺乏足够的实验能力完成大量的微生物测试，则会寻求将微生物测试外包给合同实验室。这种情况下，寻求

47、合同实验室的公司将负责彻底调查任何新的或不熟悉的合同实验室的名声和质量控制能力，并将审计结论签署在双方质量协议中。在签署协议之前，建议委托方(a)确认合同实验室严格遵守CGMP法规中实验室确认的要求以及能按照药典要求进行微生物测试和细菌内毒素测试(30,32-34):(b)进行现场审计；(C)以及提供给合同实验室一些样品进行测试判断其测试水平和数据完整性。委托方甚至可以提供一个阳性挑战对照样品以判断其是否能产生OOS结果。实验室管理文件应确认在有需求的时候能够解释样品结果，特别是如果这些人将被用作数据审查的主题专家或实验室管理人员需要对可疑样品结果进行实验室调查的情况下。Reportswrit

48、tenbasedonsamplestestedbyacontractlaboratoryshouldincludecompleteanalyticalworksheetsfromtheanalysisperformed(e.g.,rawmaterial,in-processproductintermediates,EMsamples,water,finishedproducts).AJ1oftheoriginaldata(includingcalculations)andallofthepositive(growthpromotionresults)andnegativecontrolsuse

49、dduringanalysisshouldbeincludedintheresponsereportastheyareequallyimportanttothefinalproductanalysisresults.ThefullinvestigationreportofanyOOSmustalsobeprovided.Acertificateofanalysiswithasummaryoftheanalyticalresultsdoesnotprovidealloftheinformationneededtoverifysampletestdataortosatisfyaregulatoryaudit.合同实验室的实验报告应当基于合同实验室测试员执行的全部分析测试表格(例如