USP301211翻译灭菌和无菌保证.docx

USP301211翻译灭菌和无菌保证.docx

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USP301211翻译灭菌和无菌保证

灭菌和无菌保证纲要条款

Thisinformationalchapterprovidesageneraldescriptionoftheconceptsandprinciplesinvolvedinthequalitycontrolofarticlesthatmustbesterile.AnymodificationsoforvariationsinsterilitytestproceduresfromthosedescribedunderSterilityTests71shouldbevalidatedinthecontextoftheentiresterilityassuranceprogramandarenotintendedtobemethodsalternativetothosedescribedinthatchapter.

报告章节规定涉及到条款质量控制总的概念描述和原则是必须是无菌的.从无菌测试<71>的章节描述中,无菌保证程序的整个上下文中规定没有可选择的方法,任何有关无菌测试程序变更或修改应该得到验证.

Withinthestrictestdefinitionofsterility,aspecimenwouldbedeemedsterileonlywhenthereiscompleteabsenceofviablemicroorganismsfromit.However,thisabsolutedefinitioncannotcurrentlybeappliedtoanentirelotoffinishedcompendialarticlesbecauseoflimitationsintesting.Absolutesterilitycannotbepracticallydemonstratedwithoutcompletedestructionofeveryfinishedarticle.

在最严格的无菌定义里,仅当它不含有任何可存的微生物,样品才被认为无菌.然而,因为测试的局限性，这个绝对的定义不能普遍应用到整个纲要条款中。

实际上每个灭菌的物品没有完全的破坏，绝对无菌性不能得到论证。

Thesterilityofalotpurportedtobesterileisthereforedefinedinprobabilisticterms,wherethelikelihoodofacontaminatedunitorarticleisacceptablyremote.Suchastateofsterilityassurancecanbeestablishedonlythroughtheuseofadequatesterilizationcyclesandsubsequentasepticprocessing,ifany,underappropriatecurrentgoodmanufacturingpractice,andnotbyreliancesolelyonsterilitytesting.Thebasicprinciplesforvalidationandcertificationofasterilizingprocessareenumeratedasfollows:

许多无菌状态据说是消过毒的,因此是或然论的定义污染的个体和物品可能性是在可以接受的细小范围的.这样一个无菌状态保证,仅能通过适当的灭菌周期和无菌的后续加工,即便要,在当前合适的GMP程序下,无菌测试也不可靠.一个无菌过程验证的基本原理如下:

1.Establishthattheprocessequipmenthascapabilityofoperatingwithintherequiredparameters.确定加工设备的操作性能处在正确的参数.

2.Demonstratethatthecriticalcontrolequipmentandinstrumentationarecapableofoperatingwithintheprescribedparametersfortheprocessequipment.证明关键控制设备和使用仪器是能够在具有效力参数下操作.

3.Performreplicatecyclesrepresentingtherequiredoperationalrangeoftheequipmentandemployingactualorsimulatedproduct.Demonstratethattheprocesseshavebeencarriedoutwithintheprescribedprotocollimitsandfinallythattheprobabilityofmicrobialsurvivalinthereplicateprocessescompletedisnotgreaterthantheprescribedlimits.执行可重复的循环表现在设备必需的操作范围和使用真实或可模拟的产品.证明加工是在给定协议范围下执行,而且最后在可重复的加工完成下微生物存活的可能性不能超过给定协议范围.

4.Monitorthevalidatedprocessduringroutineoperation.Periodicallyasneeded,requalifyandrecertifytheequipment.在常规的操作期间监控验证程序.根据需要定期,重新证明和保证设备正常.

5.Completetheprotocols,anddocumentsteps

（1）through（4）above.完善协议,证明以上步骤1-4.

Theprinciplesandimplementationofaprogramtovalidateanasepticprocessingprocedurearesimilartothevalidationofasterilizationprocess.Inasepticprocessing,thecomponentsofthefinaldosageformaresterilizedseparatelyandthefinishedarticleisassembledinanasepticmanner.

验证一个无菌处理程序的法则和执行和灭菌过程的确认是相似的.在无菌处理中,最终剂量组成成分是分别灭菌的,最后物品的组装是在无菌方式完成的.

Propervalidationofthesterilizationprocessortheasepticprocessrequiresahighlevelofknowledgeofthefieldofsterilizationandcleanroomtechnology.Inordertocomplywithcurrentlyacceptableandachievablelimitsinsterilizationparameters,itisnecessarytoemployappropriateinstrumentationandequipmenttocontrolthecriticalparameterssuchastemperatureandtime,humidity,andsterilizinggasconcentration,orabsorbedradiation.灭菌过程或无菌程序正确确认要求较高的灭菌和绝对无尘室技术领域的知识水平.Animportantaspectofthevalidationprograminmanysterilizationproceduresinvolvestheemploymentofbiologicalindicators（seeBiologicalIndicators1035）.在许多灭菌程序一个重要的确认纲要方面包括生物指示剂的使用（参见生物指示剂<1035>-）.Thevalidatedandcertifiedprocessshouldberevalidatedperiodically;however,therevalidationprogramneednotnecessarilybeasextensiveastheoriginalprogram.验证和鉴定的程序应当定时性地重新生效,然而,重新生效程序不必像原始文件那样广泛.

Atypicalvalidationprogram,asoutlinedbelow,isonedesignedforthesteamautoclave,buttheprinciplesareapplicabletotheothersterilizationproceduresdiscussedinthisinformationalchapter.Theprogramcomprisesseveralstages.一个典型的确认程序如下列大纲,一个蒸汽高压灭菌锅设计而作,但原理也是适用于其它的灭菌程序,将在报告章节讨论.

Theinstallationqualificationstageisintendedtoestablishthatcontrolsandotherinstrumentationareproperlydesignedandcalibrated.Documentationshouldbeonfiledemonstratingthequalityoftherequiredutilitiessuchassteam,water,andair.限定时期安装目的建立调节装置和其它的使用仪器能够得到适当设计和校准.文件能够记录下来备查证明要求效用的质量像蒸汽,水,空气.Theoperationalqualificationstageisintendedtoconfirmthattheemptychamberfunctionswithintheparametersoftemperatureatallofthekeychamberlocationsprescribedintheprotocol.可操作资格的时期是打算确认在协议规定的所有关键锅室区域在温度参数以内的锅室功能.Itisusuallyappropriatetodevelopheatprofilerecords,.,simultaneoustemperaturesinthechamberemployingmultipletemperature-sensingdevices.它通常适用于显示压力剖面的记录也就是在锅室使用多种温度敏感装置Atypicalacceptablerangeoftemperatureintheemptychamberis±1whenthechambertemperatureisnotlessthan121.当锅室温度不少于121,一个典型的可接受的锅室温度幅度范围是±confirmatorystageofthevalidationprogramistheactualsterilizationofmaterialsorarticles.确认程序的确认时期是原料或物品实际灭菌期.Thisdeterminationrequirestheemploymentoftemperature-sensingdevicesinsertedintosamplesofthearticles,aswellaseithersamplesofthearticlestowhichappropriateconcentrationsofsuitabletestmicroorganismshavebeenadded,orseparateBIsinoperationallyfullyloadedautoclaveconfigurations.决定要求温度敏感装置嵌入到物品样本中,除了添加微生物测试需要的适当的物品浓度,或在操作上二度单独的装满物品的高压灭菌锅装置.Theeffectivenessofheatdeliveryorpenetrationintotheactualarticlesandthetimeoftheexposurearethetwomainfactorsthatdeterminethelethalityofthesterilizationprocess.Thefinalstageofthevalidationprogramrequiresthedocumentationofthesupportingdatadevelopedinexecutingtheprogram.热传递或穿透实际物品的效力和曝光时间是两个主要的因素决定灭菌程序的破坏性.确认的最终阶段需要执行程序的数据支持文件发展更新.

Itisgenerallyacceptedthatterminallysterilizedinjectablearticlesorcriticaldevicespurportingtobesterile,whenprocessedintheautoclave,attaina10–6microbialsurvivorprobability,.,assuranceoflessthan1chancein1millionthatviablemicroorganismsarepresentinthesterilizedarticleordosageform.一般公认的是末尾已灭菌的可注射的商品或关键设备声明是无菌的.在高压灭菌锅程序达到10–6细菌存活率也就是说保证在已灭菌的物品或配药形式上可存活的微生物一百万个不超过一个的几率.Withheat-stablearticles,theapproachoftenistoconsiderablyexceedthecriticaltimenecessarytoachievethe10–6microbialsurvivorprobability（overkill）.随着热稳定的物品,方法通常是相当超越需要的临界温度达到10–6细菌存活率（过度杀灭）.However,withanarticlewhereextensiveheatexposuremayhaveadamagingeffect,itmaynotbefeasibletoemploythisoverkillapproach.然而随着物品曝露在过度压力下可能有一个破坏性的作用.Inthislatterinstance,thedevelopmentofthesterilizationcycledependsheavilyonknowledgeofthemicrobialburdenoftheproduct,basedonexamination,overasuitabletimeperiod,ofasubstantialnumberoflotsofthepresterilizedproduct.在后面的例子,灭菌周期的发展很大程度上依靠基于检验,适当的时间周期,许多实质预先消毒的产品微生物负担的知识.

TheDvalueisthetime（inminutes）requiredtoreducethemicrobialpopulationby90%or1logcycle.,toasurvivingfractionof1/10）,ataspecifictemperature.D-值是在特效的温度下需要的时间（分钟）减少微生物群体,或大约90%orlog1周期（也就是1/10存活部分）.Therefore,wheretheDvalueofaBIpreparationof,forexample,Bacillusstearothermophilussporesisminutesunderthetotalprocessparameters,.,at121,ifitistreatedfor12minutesunderthesameconditions,itcanbestatedthatthelethalityinputis8D.然而一个BI,D值的地方,例如嗜热脂肪杆菌孢子在总的程序参数下为分钟,举例来说,在121.下相同的条件下如果加热12分钟,规定的致命性的输入是8D.Theeffectofapplyingthisinputtotheproductwoulddependontheinitialmicrobialburden.应用这个输入产品的效果依靠最初的微生物耐热负荷.AssumingthatitsresistancetosterilizationisequivalenttothatoftheBI,ifthemicrobialburdenoftheproductinquestionis102microorganisms,alethalityinputof2Dyieldsamicrobialburdenof1（10theoretical）,andafurther6Dyieldsacalculatedmicrobialsurvivorprobabilityof10–6.假设它抵抗灭菌等同BI耐热能力,如果产品的微生物负担BI可商榷的是102微生物,一个2D产量致命输入一个微生物1担子（理论上是10）,进一步的6D产量一个计算出的存活几率是10–6.（Underthesameconditions,alethalityinputof12Dmaybeusedinatypical“overkill”approach.）（在相同的条件下,一个12D致死输入量可能是在一个典型的过度杀伤方法）Generally,thesurvivorprobabilityachievedforthearticleunderthevalidatedsterilizationcycleisnotcompletelycorrelatedwithwhatmayoccurwiththeBI.Forvaliduse,therefore,itisessentialthattheresistanceoftheBIbegreaterthanthatofthenaturalmicrobialburdenofthearticlesterilized.通常,有效的灭菌时间对物品而言存活概率取得，不能完全和BI联系起来。

为有效利用，因此BI的抗性是比已灭菌物品上的自然界微生物大。

Itisthenappropriatetomakeaworst-caseassumptionandtreatthemicrobialburdenasthoughitsheatresistancewereequivalenttothatoftheBI,althoughitisnotlikelythatthemostresistantofatypicalmicrobialburdenisolateswilldemonstrateaheatresistanceofthemagnitudeshownbythisspecies,frequentlyemployedasaBIforsteamsterilization.于是进行最差的假设和测试微生物负担是合适的好象它的热抵抗力等同于BI，尽管不是类似于大多数典型微生物担子隔离证明一个物种显示的巨大热抵抗。

对蒸汽灭菌而言，经常作为一个BI。

Intheaboveexample,a12-minutecycleisconsideredadequateforsterilizationiftheproducthadamicrobialburdenof102microorganisms.在上面的例子如果产品有一个102微生物担子，12分钟的时间被认为是合适的灭菌时间。

However,iftheindicatororiginallyhad106microorganismscontent,actuallya10–2probabilityofsurvivalcouldbeexpected;.,1in100BIsmayyieldpositiveresults.然而，如果最初的指示剂有106微生物含量，实际上，预期10–2存活率，也就是说100BIs有1个，产生阳性结果。

ThistypeofsituationmaybeavoidedbyselectionoftheappropriateBI.Alternatively,highcontentindicatorsmaybeusedonthebasisofapredeterminedacceptablecountreduction.通过适当的BI选择，这个典型情况可以避免。

择二为一，高容量的指示剂可用于以预定的可接受的数量减少为基础。

TheDvaluefortheBacillusstearothermophiluspreparationdeterminedorverifiedfortheseconditionsshouldbereestablishedwhenaspeci