無菌生產(chǎn)GMP檢查中的常見缺陷

MostfrequentGMPdeficienciesobservedinsterileproductionfacilities無菌生產(chǎn)GMP檢查中的常見缺陷

IanThrussell,MHRA,UKManufactureofsterilemedicines–AdvancedworkshopforSFDAGMPinspectors,Nanjing,November2009SessionOutline

主要內(nèi)容InspectionFindings-AsepticProcessing

檢查中發(fā)現(xiàn)的缺陷-無菌工藝產(chǎn)品InspectionFindings–TerminallysterilisedProducts

檢查中發(fā)現(xiàn)的缺陷–最終滅菌產(chǎn)品Questions

提問原料人員程序驗(yàn)證的工藝設(shè)備廠房環(huán)境包裝材料Poorlydesignedprocesses

工藝設(shè)計(jì)欠佳

MaterialstransferredintoAsepticareawithinsufficientsterilityassurance物料進(jìn)入無菌區(qū)的程序缺乏無菌保證Poortransferofpartiallystopperedvialstolyophiliser半壓塞西林瓶進(jìn)凍干箱的轉(zhuǎn)移程序不恰當(dāng)Excessiveholdingtimesforsterileequipmentorfilteredsolutions滅菌設(shè)備或過濾后藥液的儲(chǔ)存時(shí)間過長(zhǎng)原料人員程序驗(yàn)證的工藝設(shè)備廠房環(huán)境包裝材料Poorlydesignedprocesses

工藝設(shè)計(jì)欠佳

Singlefiltration單級(jí)過濾Filtrationnotperformedascloseaspracticabletothefillingpoint過濾操作未盡可能靠近灌裝點(diǎn)Inadequateresponsetoleakingcontainers–nolimitssettopromptaninvestigation對(duì)產(chǎn)品容器泄漏沒有及時(shí)反應(yīng)–沒有設(shè)定啟動(dòng)調(diào)查的限度Whathappenedwhenthesefiltersarevented!

當(dāng)這些濾器排空時(shí)會(huì)發(fā)生什么情況Poorlydesignedprocesses

工藝設(shè)計(jì)欠佳

Rawmaterialsuppliersnotauditedbutacceptanceofsidesamplese.g.sterileAPIsidesamplesacceptedwithnojustification原料供應(yīng)商沒有經(jīng)過審計(jì)，就接受了邊緣樣品，例如：未經(jīng)評(píng)估就接受了無菌原料藥的邊緣樣品Prefilledsyringeassemblysterilisationsitesneveraudited從未審計(jì)預(yù)充填注射器配件的滅菌承包商原料人員程序驗(yàn)證的工藝設(shè)備廠房環(huán)境包裝材料Poorcleanroomandasepticpractices

不良的潔凈區(qū)行為和無菌操作行為

Fillingneedlesinstalled&leftunprotectedwhileremainderoflinesetupstilltakingplaceNotroutinelyrecorded/documented部分生產(chǎn)線還沒有安裝完成，灌裝針頭已安裝好而且沒有保護(hù)，該情況未記錄下來Nomonitoringduringequipmentsetup設(shè)備安裝設(shè)置期間沒有監(jiān)控Allowedinterventionsintoasepticzonearenotderivedfromriskbasedprocessreview允許在無菌區(qū)域內(nèi)出現(xiàn)的干擾未經(jīng)過基于風(fēng)險(xiǎn)分析的工藝評(píng)估Systems/Proceduresnotclearwhattodouponintervention遇到干擾時(shí)的處理系統(tǒng)/程序不明確Interventionsnotlinkedtobatchreleaseprocess批放行程序沒有考慮已發(fā)生的干擾原料人員程序驗(yàn)證的工藝設(shè)備廠房環(huán)境包裝材料Poorcleanroomandasepticpractices

不良的潔凈區(qū)行為和無菌操作行為Interventionsnotlinkedtobatchreleaseprocess批放行程序未考慮已發(fā)生的干擾Excessivenumbersofmanipulations動(dòng)作過多Excessivenumbersofpeople人數(shù)過多PeopleroutinelylocatedintheclassAzone操作人員經(jīng)常待在A級(jí)潔凈區(qū)Failuretouseisolationandclosedtechniques隔離或密閉技術(shù)運(yùn)用失敗原料人員程序驗(yàn)證的工藝設(shè)備廠房環(huán)境包裝材料

Poorcleanroomandasepticpractices

不良的潔凈區(qū)行為和無菌操作行為“Anyinterventionorstoppageduringanasepticprocesscanincreasetheriskofcontamination.

Thedesignofequipmentusedinasepticprocessingshouldlimitthenumberandcomplexityofasepticinterventionsbypersonnel.”

無菌工藝過程中任何干擾或停機(jī)都會(huì)增加污染的風(fēng)險(xiǎn)。無菌工藝設(shè)備的設(shè)計(jì)應(yīng)該限制由于人員引起的干擾的次數(shù)和復(fù)雜程度“Evensuccessfullyqualifiedsystemscanbecompromisedbypooroperational,maintenance,orpersonnelpractices.”甚至確認(rèn)成功的系統(tǒng)也會(huì)被拙劣的操作、維護(hù)或人員行為破壞Poorcleanroomandasepticpractices

不良的潔凈區(qū)行為和無菌操作行為Asepticprocessingoperatortouchesfloorwhenpickingupsettleplates,sanitizeshands,andthenperformsinterventionimmediatelyafterward

無菌工藝操作人員在取沉降碟時(shí)接觸到了地板，進(jìn)行手消毒，然后立即實(shí)施了干擾操作Operatorremovessterileforcepsfromasepticprocessingzone(Class100),carriesthemthroughthesurroundingClass10,000area,andplacesthemonatrolleyintheclass10,000room.Theseweretheonlysterileforcepssterilizedandavailableforasepticmanipulations.Later,theoperatorretrievesforcepsandusesthemagainattheasepticprocessinglinetomanipulatesterileproduct.

操作人員將無菌鑷子拿出無菌區(qū)（100級(jí)），帶入10000級(jí)背景區(qū)域，放在10000級(jí)房間的推車上。這是無菌操作僅有的滅菌鑷子。然后，操作人員又在無菌工藝生產(chǎn)線上再次使用這把鑷子處理無菌產(chǎn)品。Poorlydesignedormaintainedequipment

設(shè)備設(shè)計(jì)欠佳或維護(hù)保養(yǎng)不善Viewingportsonsterilisingtunnelsnotadequatelysealed滅菌隧道的觀察窗密封不夠Lyophilisersnotsterilisableornotsterilisedsufficientlyfrequently凍干機(jī)無法滅菌或經(jīng)常滅菌不充分Vialcappingperformedunderuncontrolledconditions在非控制區(qū)進(jìn)行軋蓋操作原料人員程序驗(yàn)證的工藝設(shè)備廠房環(huán)境包裝材料Constructionactivities

施工活動(dòng)Majorconstructionincleanroomnexttopersonnelentryairlock(e.g.,gowning).與人員入口氣鎖相鄰的潔凈區(qū)內(nèi)有施工活動(dòng)Constructionoccurredoverapproximatelyone-monthperiodandcoincidedwithcontinuedproduction

每隔一個(gè)月就要進(jìn)行施工，同時(shí)生產(chǎn)不停MediaFillFailure2weekslater兩星期后培養(yǎng)基灌裝驗(yàn)證失敗Constructionnotconsideredtobethecause.Rootcausesidentifiedbyinvestigationconsideredcorrected.施工活動(dòng)沒有被認(rèn)為是影響因素，糾正了調(diào)查中發(fā)現(xiàn)的根本影響因素。NewMediaFillperformed

進(jìn)行新的培養(yǎng)基灌裝驗(yàn)證SecondMediaFillFailureOccurred

第二次培養(yǎng)基灌裝批失敗Contaminationattributedtoconstruction

污染是由施工活動(dòng)引起的Examplesofmisplacedstoppersfromrealcaselines壓蓋錯(cuò)位示例Visionsystemsforraisedstopperdetection

凸起膠塞檢測(cè)的目檢系統(tǒng)Poorlydesignedormaintainedequipment設(shè)備設(shè)計(jì)欠佳或維護(hù)保養(yǎng)不善

Blowfillsealmachine吹灌封設(shè)備Coolingwater冷卻水Chillsmoldplatesusedtoformthecontainer-closureintowhichthesteriledrugisfilled.

冷卻吹制無菌藥品灌裝后密封用塞子的模具Demineralizedpotablewater.Heldintank,chilled(whensampled,yieldsveryhighmicrobialcounts)罐內(nèi)儲(chǔ)存的冷去礦物質(zhì)飲用水（取樣檢測(cè)發(fā)現(xiàn)有大量微生物）Sterilityfailureandmediafillfailure產(chǎn)品無菌不合格和培養(yǎng)基灌裝驗(yàn)證不合格Pseudomonas,sp.and

Acinetobacter,sp.foundinmediafill

培養(yǎng)基灌裝驗(yàn)證中發(fā)現(xiàn)Pseudomonas,sp.假單胞菌和不動(dòng)桿菌Stenotrophomonas

maltophiliaidentifiedasSterilityFailureisolate

培養(yǎng)基灌裝驗(yàn)證陽性樣品中分離出嗜麥芽寡食單胞菌Severallotsrejected

多批產(chǎn)品報(bào)廢Boththesterilityfailureandmediafillfailureattributedtocoolingwatercontamination

產(chǎn)品無菌不合格和培養(yǎng)基灌裝失敗都是由冷卻水污染引起的Rootcauseofnon-sterilitywasleak/s/inasepticfillingmachine’smoldplates.Coolingwaterdirectlycontaminatedproduct.根本原因是無菌灌裝設(shè)備的模具泄漏，冷卻水直接污染了產(chǎn)品CAPAIssue:Exactdateofproblemoccurrenceunknown.

糾正與預(yù)防問題：不知道出現(xiàn)該問題的確切時(shí)間原料人員程序驗(yàn)證的工藝設(shè)備廠房環(huán)境包裝材料PoorlydesignedorexecutedPMmonitoring

懸浮粒子監(jiān)測(cè)的設(shè)計(jì)和執(zhí)行欠佳

Samplespointsinappropriatelypositioned取樣點(diǎn)位置不合適Alarmsystemsdonotfeedbacktofillingoperators.警報(bào)系統(tǒng)不能反饋給灌裝操作人員Alarmsandproceduresunclearandconfused警報(bào)和程序不清楚，易混淆原料人員程序驗(yàn)證的工藝設(shè)備廠房環(huán)境包裝材料PoorlydesignedorexecutedPMmonitoring

懸浮粒子監(jiān)測(cè)的設(shè)計(jì)和執(zhí)行欠佳

Lengthoftubingtoparticlecountertoolong&evenkinked!粒子計(jì)數(shù)器的取樣管過長(zhǎng),甚至彎曲PMSdatanotreviewedaspartofbatchreleaseprocess懸浮粒子監(jiān)測(cè)數(shù)據(jù)沒有作為批放行程序的一部份進(jìn)行審核Overseas-useofmanifoldsystemsandno5micronmonitoring遠(yuǎn)程使用多支管系統(tǒng)并且不監(jiān)控5um的粒子原料人員程序驗(yàn)證的工藝設(shè)備廠房環(huán)境包裝材料PoorlydesignedorexecutedPMmonitoring

懸浮粒子監(jiān)測(cè)的設(shè)計(jì)和執(zhí)行欠佳Relianceontheuseofcontactplatesandnouseofswabs依賴于使用接觸碟，并且不使用棉簽Relianceonactiveairmonitoringandinadequateuseofsettleplates依賴于浮游菌監(jiān)測(cè)并且不能正確使用沉降碟“Averagingintocompliance”–inadequateattentiontotheindividualhighcount“通過取平均值來符合標(biāo)準(zhǔn)”-沒有適當(dāng)關(guān)注個(gè)別過高的數(shù)據(jù)Acceptanceof“goodpattern”ofverylowcontaminationandfailuretoevaluatewhethertheprogrammeiseffective.接受“好的結(jié)果”-污染較低，而監(jiān)控程序本身的有效性評(píng)估失敗。原料人員程序驗(yàn)證的工藝設(shè)備廠房環(huán)境包裝材料Poorlydesignedorexecutedmicromonitoring

微生物監(jiān)測(cè)的設(shè)計(jì)和執(zhí)行欠佳

Viablesamplepointsnotclosetopointoffill微生物監(jiān)控取樣點(diǎn)不靠近灌裝點(diǎn)Thewholeprocessisnotmonitored整個(gè)生產(chǎn)過程沒有監(jiān)測(cè)ViablesamplingdoesnotcoverallkeyareasunderGradeAe.g.vialturntable,stopperhopper微生物監(jiān)控取樣點(diǎn)沒有覆蓋整個(gè)A級(jí)關(guān)鍵區(qū)例如：西林平轉(zhuǎn)盤、膠塞斗Monitoringisnotriskedbasedand“tooroutine”監(jiān)測(cè)不是基于風(fēng)險(xiǎn)考慮的，并且“過于常規(guī)“Highpre-filtrationbioburdennotadequatelyinvestigatedandbioburdenlimits>>10cfu/100mlandnojustification過濾前生物負(fù)荷過高沒有經(jīng)過適當(dāng)?shù)恼{(diào)查，并且對(duì)于遠(yuǎn)遠(yuǎn)大于10cfu/100ml的限度沒有合理的解釋原料人員程序驗(yàn)證的工藝設(shè)備廠房環(huán)境包裝材料Mediafills!

培養(yǎng)基灌裝驗(yàn)證ThebeliefthatsomecontaminationisOK!相信個(gè)別污染是可以接受的AcceptancecriteriadoesnotmeetAnnex1&allows1failuretobeacceptedwithnoeffectiveinvestigation可接受標(biāo)準(zhǔn)不符合附錄1，并且允許出現(xiàn)1瓶污染后不調(diào)查原因Poorpracticesacceptedascovered&justifiedby“passing”MediaFills!用“通過培養(yǎng)基灌裝驗(yàn)證”作為標(biāo)準(zhǔn)來解釋和判斷某些不良操作情況是可以接受的Goodhistorydoesnotmeanfailures/growthneednotbeinvestigated良好的歷史不能意味著失敗/陽性結(jié)果可以不調(diào)查Implicationstobatchesonthemarketorinstocksubsequenttofailuresarenotalwaysconsideredfully對(duì)于牽涉到市場(chǎng)上的或仍在倉庫內(nèi)的不合格批次考慮不周全原料人員程序驗(yàn)證的工藝設(shè)備廠房環(huán)境包裝材料Mediafills!

培養(yǎng)基灌裝驗(yàn)證Interventionsallowedinproceduresbutnotcoveredbysimulations程序中允許的干擾沒有在培養(yǎng)基灌裝驗(yàn)證中進(jìn)行模擬Excessiveinterventionsnotprohibited沒有禁止過度的干擾原料人員程序驗(yàn)證的工藝設(shè)備廠房環(huán)境包裝材料SteamSterilisation!

蒸汽滅菌Leaktest/BowieDicktestnotperformedsufficientlyfrequentlyonequipmentsterilisersandfailuresfullyinvestigated.泄漏測(cè)試/BowieDick測(cè)試多次執(zhí)行不充分，失敗的調(diào)查也不充分Poorcontrolofcheckingacceptabilityofautoclavecycles不能有效地控制濕熱滅菌批次放行的審核過程Engineeringworknotrecorded工程部門工作沒有記錄Notrialrunsaftermajorbreakdownstoshowautoclavestillmeetsvalidatedparameters在大故障修復(fù)后沒有通過試運(yùn)行來確定滅菌釜仍然能滿足驗(yàn)證參數(shù)。原料人員程序驗(yàn)證的工藝設(shè)備廠房環(huán)境包裝材料SteamSterilisation!

蒸汽滅菌Longheattimesduringvalidationnotinvestigatedasnolimitsforheatuptimes=potentialsterilityissues因?yàn)闆]有設(shè)置升溫時(shí)間限度，所以沒有對(duì)驗(yàn)證中過長(zhǎng)的加熱時(shí)間進(jìn)行調(diào)查=潛在的滅菌問題原料人員程序驗(yàn)證的工藝設(shè)備廠房環(huán)境包裝材料Whensterilisingequipmentandcomponents-thereisjustoneobjective

當(dāng)對(duì)設(shè)備和組件進(jìn)行滅菌時(shí)-只有一個(gè)目標(biāo)

TOKNOWUNEQUIVOCALLYTHATALLPARTSOFTHELOADARESUBJECTTODRYSATURATEDSTEAMATTHEREQUIREDTEMPERATUREFORTHEREQUIREDTIME.

明確確認(rèn)在規(guī)定的時(shí)間內(nèi)，裝載中所有部分都充滿了規(guī)定溫度下干飽和蒸汽Asterilizationprocessbasedontheprinciplethatcoldairwithinthechamberisheavierthanthesteamenteringandwillsinktothebottomofthechamber.Assteamentersthechamber,airispushedoutthebottomdrainandexits,withthecondensate,throughasteamtrap.根據(jù)腔體內(nèi)冷空氣比進(jìn)入的蒸汽中而沉在腔體底部，當(dāng)蒸汽進(jìn)入滅菌釜時(shí)，空氣被推至底部并與冷凝水一起排出的原理設(shè)計(jì)的滅菌過程。GravityDisplacementProcess重力置換過程EquilibrationTime

平衡時(shí)間Theequilibrationtimeistheperiodthatelapsesbetweenattainmentoftheminimumspecifiedsterilizingtemperatureinthechamber(chamberreferencetemperature-typicallyinthedrain)andattainmentoftheminimumspecifiedsterilizationtemperatureintheload,asmeasuredbytheslowest-to-heatpenetrationprobe.Thisperiodisanindicationoftheabilitytoproperlyconditiontheloadthroughairremovalandloadheating.

平衡時(shí)間是指腔體內(nèi)溫度達(dá)到最低滅菌溫度（腔體參考溫度-通常在排水口測(cè)得）到滅菌裝載內(nèi)部達(dá)到最低滅菌溫度時(shí)的時(shí)間間隔，該溫度由升溫最慢處的熱穿透探頭測(cè)得。這段時(shí)間顯示了滅菌釜通過去除空氣和加熱來平衡滅菌裝載的能力。SterilizationProcessDevelopment滅菌工藝開發(fā)EquilibrationTime

1Prevacuum-TyvekWrapped

Materials1次預(yù)真空-采用Tyvek紙包裝的物料lShortequilibrationtimescanbeachievedwithappropriatepre-vacuumstopre-condition(removeairandheat)theload.

通過采用適當(dāng)?shù)念A(yù)真空（去除空氣并加熱）來平衡滅菌裝載可以獲得較短的平衡時(shí)間Withappropriateloadpreconditioning,anysurfacetemperaturemeasurementmethodshouldyieldacceptableresults.

滅菌裝載經(jīng)過適當(dāng)?shù)念A(yù)平衡，采用任何表面溫度測(cè)量方法測(cè)量都可以得到可接受的結(jié)果Withminimalloadpre-conditioning,theheatpenetrationprobescoveredwithautoclavetapewereinfluencedthemost.

滅菌裝載預(yù)平衡做的最少，用滅菌釜指示帶包裹的熱穿透探頭受影響最大。Pre-vacuumProcess

預(yù)真空過程Asterilizationprocessinwhichairisremovedfromthechamberusingavacuumpumporothermechanicalsystembeforetheexposurephasebegins.

Thismethodisparticularlysuitedtoloaditemsthatcantrapairsuchastubing,filtersandfillingmachineassemblies.

在滅菌開始前，采用真空泵或其它機(jī)械系統(tǒng)去除滅菌釜內(nèi)空氣的滅菌過程。該方法尤其適用于富含空氣的滅菌裝載，例如：軟管、過濾器和灌裝配件。SteamSterilisation&SIPsystems!

蒸汽滅菌和在線滅菌系統(tǒng)Airremovalfromequipmentnotadequatelyconsidered沒有考慮去除設(shè)備中的空氣Steamqualitynotassessedadequately蒸汽質(zhì)量沒有正確的評(píng)價(jià)Non-condensablegases非冷凝性氣體Wetsteam(Drynessfraction)濕蒸汽（干燥度）SuperheatCleansteamqualitytestsarenotperformedatdistalpointsofthedistributionsystem.Steamqualitytestnotperformedfollowingmodifications在分配系統(tǒng)的遠(yuǎn)端沒有測(cè)試過熱清潔蒸汽的質(zhì)量。蒸汽質(zhì)量的測(cè)試沒有根據(jù)以下修改項(xiàng)進(jìn)行原料人員程序驗(yàn)證的工藝設(shè)備廠房環(huán)境包裝材料Ovendesigns!

烘箱設(shè)計(jì)Nooverpressureinhotairovens在烘箱中沒有過壓NoHEPAfiltersontheexhaustsideoftheoven烘箱的排氣側(cè)沒有高效過濾器原料人員程序驗(yàn)證的工藝設(shè)備廠房環(huán)境包裝材料Packagingandpoststerilisationdamage!

包裝以及滅菌后的損傷FailuretomeetGMP:

不符合GMP Roughhandlingofbulkfinishedvialsresultedindifficulttodetectandhairlinecracksinbottle.“Washdown”ofvialswithpotablewaterwasapparentcontaminationsource.粗野地搬運(yùn)成品瓶導(dǎo)致瓶子出現(xiàn)很難發(fā)現(xiàn)的頭發(fā)狀細(xì)小的裂紋，采用飲用水洗滌西林瓶顯然是污染原因。PatientsInfected:multiplebloodculturesyieldEnterobactercloacae.病人感染：多人血液培養(yǎng)發(fā)現(xiàn)有陰溝腸桿菌污染Atleastonelot“directlyimplicated”insepticemia至少一批直接牽涉到了敗血癥Over25SepticemiaReportsnamingthelotor“unknown”

超過25例敗血癥報(bào)告指向這批或“未知”Class1Recall:ElevenLots(“stronglikelihoodthatproductwillcauseseriousadversehealthconsequencesordeath”)1級(jí)召回：11批（“產(chǎn)品很有可能導(dǎo)致嚴(yán)重的健康傷害或死亡）CulturesofunopenedvialsgrewEnterobactercloacae

未開封的產(chǎn)品培養(yǎng)出了陰溝腸桿菌Severalwatersamplescollectedatfirmfromthewaterhose/sink