USP30_1211翻译_灭菌和无菌保证

---1211STERILIZATIONANDSTERILITYASSURANCEOFCOMPENDIALARTICLES灭菌和无菌保证纲要条款Thisinformationalchapterprovidesageneraldescriptionoftheconceptsandprinciplesinvolvedinthequalitycontrolofarticlesthatmustbesterile.AnymodificationsoforvariationsinsterilitytestproceduresfromthosedescribedunderSterilityTests71shouldbevalidatedinthecontextoftheentiresterilityassuranceprogramandarenotintendedtobemethodsalternativetothosedescribedinthatchapter.报告章节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围和使用真实或可模拟的产品.证明加工是在给定协议围下执行,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的锅室功能.Itisusuallyappropriatetodevelopheatprofilerecords,i.e.,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围是±1.Theconfirmatorystageofthevalidationprogramistheactualsterilizationofmaterialsorarticles.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,i.e.,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(i.e.,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,Bacillusstearothermophilussporesis1.5minutesunderthetotalprocessparameters,e.g.,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1.5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;i.e.,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。TheDvaluefortheBacillusstearothermophiluspreparationdeterminedorverifiedfortheseconditionsshouldbereestablishedwhenaspecificprogramofvalidationischanged.Determinationofsurvivalcurves(seeBiologicalIndicators1035),orwhathasbeencalledthefractionalcycleapproach,maybeemployedtodeterminetheDvalueofthebiologicalindicatorpreferredforthespecificsterilizationprocedure.当确认的特效程序改变时为这些条件决定或校验对嗜热脂肪杆菌预备的D值应当是重建.Thefractionalcycleapproach,mayalsobeusedtoevaluatetheresistanceofthemicrobialburden.Fractionalcyclesarestudiedeitherformicrobialcount-reductionorforfractionnegativeachievement.部分时间方法也可以用来估计微生物担子抵抗力.Thesenumbersmaybeusedtodeterminethelethalityoftheprocessunderproductionconditions.在产品达到要求的情况下这些数字可以用来确定程序的致死量.Thedatacanbeusedinqualifiedproductionequipmenttoestablishappropriatesterilizationcycles.AsuitablebiologicalindicatorsuchastheBacillusstearothermophiluspreparationmaybeemployedalsoduringroutinesterilization.在具有资格的产品设备这数据能用来确定合适的灭菌时间.一个适当的微生物指示剂例如嗜热脂肪杆菌预备在常规的灭菌期间也可以使用.Anymicrobialburdenmethodforsterilityassurancerequiresadequatesurveillanceofthemicrobialresistanceofthearticletodetectanychanges,inadditiontoperiodicsurveillanceofotherattributes.除了定期监督其它品质,为无菌保证任何微生物担子方法要求适当物品微生物抗性监督探测任何改变.MethodsofSterilization灭菌方法Inthisinformationalchapter,fivemethodsofterminalsterilization,includingremovalofmicroorganismsbyfiltrationandguidelinesforasepticprocessing,aredescribed.在这报告的章节描述,终端灭菌的五种方法,包括微生物清除,通过过滤和无菌处理的指导.Moderntechnologicaldevelopments,however,haveledtotheuseofadditionalprocedures.Theseincludeblow-molding(athightemperatures),formsofmoistheatotherthansaturatedsteamandUVirradiation,aswellason-linecontinuousfillinginasepticprocessing.然而,现代科技的发展已经引导附加程序的运用.这些包括吹塑法(在高温)Thechoiceoftheappropriateprocessforagivendosageformorcomponentrequiresahighlevelofknowledgeofsterilizationtechniquesandinformationconcerninganyeffectsoftheprocessonthematerialbeingsterilized.1(​http:​/​​/​127.0.0.1:30251​/​uspnf​/​pub​/​data​/​v30251​/​usp30nf25s1_c1211.xml"\l"usp30nf25s1_c1s1211-f1​)对一个给定的配药形式或成份的合适的程序选择要求灭菌技术和有关影响原料灭菌程序的信息的较高的知识水平。SteamSterilization蒸汽灭菌Theprocessofthermalsterilizationemployingsaturatedsteamunderpressureiscarriedoutinachambercalledanautoclave利用饱和水蒸汽在锅室下由压力携带的热灭菌方法叫高压灭菌锅。Itisprobablythemostwidelyemployedsterilizationprocess.2(​http:​/​​/​127.0.0.1:30251​/​uspnf​/​pub​/​data​/​v30251​/​usp30nf25s1_c1211.xml"\l"usp30nf25s1_c2s1211-f2​)它是利用最广泛的灭菌程序。Thebasicprincipleofoperationisthattheairinthesterilizingchamberisdisplacedbythesaturatedsteam,achievedbyemployingventsortraps.工作的基本原理是在灭菌室通过通风孔和携带物由饱和水蒸汽取代空气。Inordertodisplaceairmoreeffectivelyfromthechamberandfromwithinarticles,thesterilizationcyclemayincludeairandsteamevacuationstages.为了更加有效率从锅室和物品里置换出空气，灭菌时间可以包括空气和水蒸汽排开时间。Thedesignorchoiceofacycleforgivenproductsorcomponentsdependsonanumberoffactors,includingtheheatlabilityofthematerial,knowledgeofheatpenetrationintothearticles,andotherfactorsdescribedunderthevalidationprogram(seeabove).给定的产品或成分的灭菌时间的设计或选择取决于很多因素，包括的热不稳定性，热渗透物品的知识，和在确认程序下描述的其它因素（参见上述）。Apartfromthatdescriptionofsterilizationcycleparameters,usingatemperatureof121,theF0conceptmaybeappropriate.除了灭菌时间参数描述外，使用温度为121，F0的概念可能是适合的。TheF0,ataparticulartemperatureotherthan121,isthetime(inminutes)requiredtoprovidethelethalityequivalenttothatprovidedat121forastatedtime.除了121,在特殊温度F0，是时间（分钟）要求在121适合即定时间提供使微生物带来致命性等同条件。Modernautoclavesg比enerallyoperatewithacontrolsystemthatissignificantlymoreresponsivethanthesteamreductionvalveofolderunitsthathavebeeninserviceformanyyears.现代化高压灭菌锅通常带有控制系统操作，比服务很多年的旧式蒸汽降低阀是引起值得注目地反响。Inorderfortheseolderunitstoachievetheprecisionandlevelofcontrolofthecyclediscussedinthischapter,itmaybenecessarytoupgradeormodifythecontrolequipmentandinstrumentationontheseunits.为了这些旧的单元达到精确和这章节讨论的时间控制水平，升级和修改控制装备以及这些单元的使用设备是必要的。Thismodificationiswarrantedonlyifthechamberandsteamjacketareintactforcontinuedsafeuseandifdepositsthatinterferewithheatdistributioncanberemoved.仅如果为了持续地安全利用和驱除存放物干扰热分配，锅室和蒸汽套是完整无缺，修改被批准。Dry-HeatSterilization干热灭菌TheprocessofthermalsterilizationofPharmacopeialarticlesbydryheatisusuallycarriedoutbyabatchprocessinanovendesignedexpresslyforthatpurpose.药典条款热灭菌程序通常通过在一个特别设计的烤炉进行干热来实现达到灭菌的目的。Amodernovenissuppliedwithheated,filteredair,distributeduniformlythroughoutthechamberbyconvectionorradiationandemployingablowersystemwithdevicesforsensing,monitoring,andcontrollingthecriticalparameters.一个现代烤箱提供热，过滤过的空气，均一分布在锅室，通过利用一个吹风机系统装置传送或发散适用于感知，监测和控制临界参数。Thevalidationofadry-heatsterilizationfacilityiscarriedoutinamannersimilartothatforasteamsterilizerdescribedearlier.Wheretheunitisemployedforsterilizingcomponentssuchascontainersintendedforintravenoussolutions,careshouldbetakentoavoidaccumulationofparticulatematterinthechamber.干热灭菌设备的确认通过与早期的蒸汽灭菌器相似的方式实现。为这灭菌成分例如用来盛装注射静脉溶液的容器，应当注意避免锅室颗粒物质的积聚。Atypicalacceptablerangeintemperatureintheemptychamberis±15whentheunitisoperatingatnotlessthan250.在空的锅室，一个典型可接受的温度围是±15，当它工作时，温度不小于250。Inadditiontothebatchprocessdescribedabove,acontinuousprocessisfrequentlyemployedtosterilizeanddepyrogenateglasswareaspartofanintegratedcontinuousasepticfillingandsealingsystem.除了以上描述的一炉程序外，一个连续的程序是频繁地使用灭菌和热原的玻璃器具作为一个综合的持续的无菌的添充物和密封系统的一部分。Heatdistributionmaybebyconvectionorbydirecttransferofheatfromanopenflame.热发送通过传送或从一个明火直接热传递。Thecontinuoussystemusuallyrequiresamuchhighertemperaturethancitedaboveforthebatchprocessbecauseofamuchshorterdwelltime.因为一个较短的保压时间，连续的系统对锅炉程序通常要求比以上引证的更高的温度。However,thetotaltemperatureinputduringthepassageoftheproductshouldbeequivalenttothatachievedduringthechamberprocess.然而，在产品通过期间总的温度输入应当与锅室程序取得等效。Thecontinuousprocessalsousuallynecessitatesarapidcoolingstagepriortotheasepticfillingoperation.持续的程序通常也是使一个快速冷却阶段先于无菌填充物实成为必要。Inthequalificationandvalidationprogram,inviewoftheshortdwelltime,parametersforuniformityofthetemperature,andparticularlythedwelltime,shouldbeestablished.在资格和确认程序，考虑到短的保压时间，温度的同样参数，特别是保压时间，应当确定。Amicrobialsurvivalprobabilityof10–12isconsideredachievableforheat-stablearticlesorcomponents.Anexampleofabiologicalindicatorforvalidatingandmonitoringdry-heatsterilizationisapreparationofBacillussubtilisspores.Sincedryheatisfrequentlyemployedtorenderglasswareorcontainersfreefrompyrogensaswellasviablemicrobes,apyrogenchallenge,wherenecessary,shouldbeanintegralpartofthevalidationprogram,e.g.,byinoculatingoneormoreofthearticlestobetreatedwith1000ormoreUSPUnitsofbacterialendotoxin.ThetestwithLimuluslysatecouldbeusedtodemonstratethattheendotoxicsubstancehasbeeninactivatedtonotmorethan1/1000oftheoriginalamount(3logcyclereduction).Forthetesttobevalid,boththeoriginalamountand,afteracceptableinactivation,theremainingamountofendotoxinshouldbemeasured.Foradditionalinformationontheendotoxinassay,seeBacterialEndotoxinsTest85.对热稳定物品或者成分，10–12的微生物的存活概率被认为可以实现。对于干热灭菌的确认和监测，一个生物指示剂的例子就是枯草芽孢杆菌孢子的制备。自从干热灭菌频繁地用于玻璃器具以及容器的的热原以及可活化的微生物的清除，除去热原是必要的，应当成为确认程序的主要部分，例如通过接种用1000或者更大USP单位的细菌毒素处理过的一种或更多物品。鲎试剂测试可以用于证明毒素物质已经活性丧失到不超过原来总量的1/1000（降低了3log数量级）。由于该测试被证明有效，不论是原始量还是可接受的失活量，毒素的残留量都应该测量。关于毒素的更多信息，参见细菌毒素测试85.GasSterilization气体灭菌法Thechoiceofgassterilizationasanalternativetoheatisfrequentlymadewhenthematerialtobesterilizedcannotwithstandthehightemperaturesobtainedinthesteamsterilizationordry-heatsterilizationprocesses.Theactiveagentgenerallyemployedingaseoussterilizationisethyleneoxideofacceptablesterilizingquality.Amongthedisadvantagesofthissterilizingagentareitshighlyflammablenatureunlessmixedwithsuitableinertgases,itsmutagenicproperties,andthepossibilityoftoxicresiduesintreatedmaterials,particularlythosecontainingchlorideions.Thesterilizationprocessisgenerallycarriedoutinapressurizedchamberdesignedsimilarlytoasteamautoclavebutwiththeadditionalfeatures(seebelow)uniquetosterilizersemployingthisgas.Facilitiesemployingthissterilizingagentshouldbedesignedtoprovideadequatepoststerilizationdegassing,toenablemicrobialsurvivormonitoring,andtominimizeexposureofoperatorstothepotentiallyharmfulgas.3(​http:​/​​/​127.0.0.1:30251​/​uspnf​/​pub​/​data​/​v30251​/​usp30nf25s1_c1211.xml"\l"usp30nf25s1_c4s1211-f3​)气体灭菌法作为一种替代在蒸汽和干热灭菌程序加热频繁地用于不能经受高温材料灭菌的方法。通常用于气体灭菌的活性剂是有合格消毒质量的环氧乙烷。这种灭菌作用剂的弊端有高度易燃的性质，除非混有适量的惰性气体，还有诱变特性，以及在处理过材料上的残留量引起中毒的可能性，特别是那些含有氯离子。灭菌程序是在一个如高压蒸汽灭菌器设计但又有独有的使用该气体灭菌特点（如下）的加压空间实现。使用这种灭菌作用剂的设备应当被设计成能提供足够的灭菌脱气，以确定残存微生物，并尽量减少设备操作人员对潜在有害气体的暴露。Qualificationofasterilizingprocessemployingethyleneoxidegasisaccomplishedalongthelinesdiscussedearlier.However,theprogramismorecomprehensivethanfortheothersterilizationprocedures,sinceinadditiontotemperature,thehumidity,vacuum/positivepressure,andethyleneoxideconcentrationalsorequirerigidcontrol.Animportantdeterminationistodemonstratethatallcriticalprocessparametersinthechamberareadequateduringtheentirecycle.Sincethesterilizationparametersappliedtothearticlestobesterilizedarecriticalvariables,itisfrequentlyadvisabletopreconditiontheloadtoachievetherequiredmoisturecontentinordertominimizethetimeofholdingattherequiredtemperaturebeforeplacementoftheloadintheethyleneoxidechamber.Thevalidationprocessisgenerallymadeemployingproductinoculatedwithappropriate(BIs)suchassporepreparationsofBacillussubtilis.Forvalidationtheymaybeusedinfullchamberloadsofproduct,orsimulatedproduct.Themonitoringofmoistureandgasconcentrationrequirestheutilizationofsophisticatedinstrumentationthatonlyknowledgeableandexperiencedindividualscancalibrate,operate,andmaintain.TheBImaybeemployedalsoinmonitoringroutineruns.Asisindicatedelsewhereinthischapter,theBImaybeemployedinafractionnegativemodetoestablishtheultimatemicrobiologicalsurvivorprobabilityindesigninganethyleneoxidesterilizationcycleusinginoculatedproductorinoculatedsimulatedproduct.使用环氧乙烷气体灭菌程序的条件通过使用前面讨论的方法得到完成。不过，相对于其他灭菌程序该方法更加广泛，因为在除了温度，湿度，真空/正压力，环氧乙烷的浓度需要更加严格的控制。一个重要的测定是要表明，在灭菌空间的所有关键的工艺参数在整个时间中都是恰当的。由于应用到物品灭菌的参数是至关重要的变数，预准备装载量，达到所需的水分含量以减少在装载环氧乙烷灭菌容器布置之前达到必需温度的保留时间是经常的可取的。Thevalidationprocessisgenerallymadeemployingproductinoculatedwithappropriate(BIs)suchassporepreparationsofBacillussubtilis.确认程序通常被用于灌输有适当(BIs的)产品，例如枯草芽孢杆菌的孢子的准备。为了确认，用于装满产品或模拟产品锅室。湿度和气体浓度的检测需要利用精密仪表，只有知识渊博、经验丰富的人才能够校准、操作和维护。Bl也可以用于常规的检测。正如在本文所指出，Bl可用于一个小的阴性模式，以确定在通过的预防注射产物或者模拟产物得方法设置好的环氧乙烷程序中的最终的微生物存活概率。Oneoftheprincipallimitationsoftheethyleneoxidesterilizationprocessisthelimitedabilityofthegastodiffusetotheinnermostproductareasthatrequiresterilization.Packagedesignandchamberloadingpatternsthereforemustbedeterminedsothatthereisminimalresistancetogasdiffusion.环氧乙烷的最重要的局限之一是气体扩散到需要灭菌的产品最里面的能力是有限的。因此必需决定包装设计和锅室装载模式从而对于气体扩散产生最小的阻力。SterilizationbyIonizingRadiation电离辐射灭菌法Therapidproliferationofmedicaldevicesunabletowithstandheatsterilizationandtheconcernsaboutthesafetyofethyleneoxidehaveresultedinincreasingapplicationsofradiationsterilization.Itisapplicablealsotodrugsubstancesandfinaldosageforms.Theadvantagesofsterilizationbyirradiationincludelowchemicalreactivity,lowmeasurableresidues,andthefactthattherearefewervariablestocontrol.Infact,radiationsterilizationisuniqueinthatthebasisofcontrolisessentiallythatoftheabsorbedradiationdose,whichcanbepreciselymeasured.Becauseofthischaracteristic,newprocedureshavebeendevelopedtodeterminethesterilizingdose.These,however,arestillunderreviewandappraisal,particularlywithregardtotheneed,orotherwise,foradditionalcontrolsandsafetymeasures.Irradiationcausesonlyaminimaltemperaturerisebutcanaffectcertaingradesandtypesofplasticsandglass.不能抗热力灭菌医疗用具的快速增加，还有环氧乙烷的安全性问题，使得辐射灭菌得到越来越多的应用。这种方法同样适合药品和最终剂型。辐射灭菌的优点包括：化学反应少、可测的残渣少和控制的变量少。事实上，辐射消毒之所以出众，是因为它的基础是控制辐射吸收剂量，而辐射吸收剂量能被精确测量。因为有此特征，已有新的程序