USP,EP、中国药典干热灭菌条件对照表1

1、EU,USP及ChP对干热灭菌/除热原条件对照表EP60USP32-NF27中国药典2010Dryheatsterilisation.（附件1-2）2.6.14.BACTERIALENDOTOXINS（附件1-2）1211STERILIZATIONANDSTERILITYASSURANCEOFCOMPENDIALARTICLES附件2-185BACTERIALENDOTOXINSTEST附件2-2灭菌方法内毒素检测方法ForthismethodofterminalApparatusAtypicalacceptablerangeAPPARATUS干热灭菌条件检测用玻璃器sterilisation

2、therefereneeintemperatureintheemptyAND一般为160皿去热原温度conditionsareaminimumDepyrogenateallGLASSWARE170Cx120min在250C,30of160Cforatleast2h.glasswareandotherchamberis15whenthe以上、170分钟以上。Othercombinationsoftimeheat-stableapparatusunitisoperatingatnotlessCommonly180Cx60minandtemperaturemaybeinahot-airovenusi

3、ngaC厂Cusedminimum以上或250Cusedprovidedthatithasvalidatedprocess.Athan250.timeandx45min以上，beencommonlyusedAmicrobialsurvivaltemperature也可采用其它satisfactorilydemonstratedminimumtimeandprobabilityof10-12issettingsare30温度和时间参thattheprocesschosentemperatureis30consideredachievableforminutesat数。总之，应deliversmi

4、nutesat250C.Ifheat-stablearticlesor250.保证灭菌后的anadequateandemployingplasticcomponents.Anexample产品其reproducibleleveloflethalityapparatus,suchasofabiologicalindicatorforSALS10-6。干whenmicrotitreplatesandvalidatingandmonitoring热过度杀灭后operatedroutinelywithinthepipettetipsfordry-heatsterilizationisa产品的SAL应e

5、stablishedtolerances.Theautomaticpipetters,usepreparationofBacillus10-12,proceduresandprecautionsapparatusshownsubtilisspores.Sincedry250C45minemployedaresuchastotobefreeofdetectableheatisfrequentlyemployed的干热灭菌也giveanendotoxinandoftorenderglasswareor可除去无菌产SALerferingeffectscontain

6、ersfreefrom品包装容器及Dryheatattemperaturesforthetest.pyrogensaswellasviable有关生产灌装greaterthan220CisNOTE:Inthischapter,microbes,apyrogen用具中的热原frequentlythetermtubeincludeschallenge,where物质。usedforsterilisationandalltypesofnecessary,shouldbeandepyrogenationofreceptacles,forintegralpartofthe细菌内毒glassware.In

7、examplemicrotitreplatevalidationprogram,e.g.,by素灭活验证试thiscasedemonstrationofawells.inoculatingoneormoreof验是证明除热3-logreductioninheatthearticlestobetreated原过程有效性resistantendotoxincanbewith1000ormoreUSP的试验。一般将usedasareplacementforUnitsofbacterial不小于1000单biologicalendotoxin.Thetestwith位的细菌内毒indicators(5

8、.1.2).Limuluslysatecouldbe素加入待去热usedtodemonstratethat原的物品中，证theendotoxicsubstanee明该去热原工hasbeeninactivatedtonot艺能使内毒素morethan1/1000ofthe至少下降3个originalamount(3logcycle对数单位。细菌reduction).内毒素灭活验证试验所用的细菌内毒素般为大肠杆菌内毒素(Escherichiacoliendoxin)。结论对去热原温度和时间组合没有明确要求，对温度下限有要求。对温度和时间有要求，同USP,ChP.对去热原温度和时间组合没有明确要求，

9、对温度下限有要求对温度和时间有要求，同EP,ChP.对去热原温度和时间组合有建议要求，没有强制要求。对温度和时间有要求，同EP，USP.EU,USP及ChP对干热灭菌/除热原条件对照表 /7附件1-1EP6.05.1.1.METHODSOFPREPARATIONOFSTERILEPRODUCTS)Dryheatsterilisation.Forthismethodofterminalsterilisationthereferenceconditionsareaminimumof160Cforatleast2h.Othercombinationsoftimeandtemperaturemaybe

10、usedprovidedthatithasbeensatisfactorilydemonstratedthattheprocesschosendeliversanadequateandreproducibleleveloflethalitywhenoperatedroutinelywithintheestablishedtolerances.TheproceduresandprecautionsemployedaresuchastogiveanSALof10-6orbetter.Dryheatsterilisationiscarriedoutinanovenequippedwithforced

11、aircirculationorotherequipmentspeciallydesignedforthepurpose.Thesteriliserisloadedinsuchawaythatauniformtemperatureisachievedthroughouttheload.Knowledgeofthetemperaturewithinthesteriliserduringthesterilisationprocedureisusuallyobtainedbymeansoftemperature-sensingelementsinsertedintorepresentativecon

12、tainerstogetherwithadditionalelementsatthepreviouslyestablishedcoolestpartoftheloadedsteriliser.Thetemperaturethroughouteachcycleissuitablyrecorded.Whereabiologicalassessmentiscarriedout,thisisobtainedusingasuitablebiologicalindicator(5.1.2).Dryheatattemperaturesgreaterthan220Cisfrequentlyusedforste

13、rilisationanddepyrogenationofglassware.Inthiscasedemonstrationofa3-logreductioninheatresistantendotoxincanbeusedasareplacementforbiologicalindicators(5.1.2)附件1-22.6.14.BACTERIALENDOTOXINSThetestforbacterialendotoxinsisusedtodetectorquantifyendotoxinsofgram-negativebacterialoriginusingamoebocytelysat

14、efromhorseshoecrab(LimuluspolyphemusorTachypleustridentatus).Thereare3techniquesforthistest:thegel-clottechnique,whichisbasedongelformation;theturbidimetrictechnique,basedonthedevelopmentofturbidityaftercleavageofanendogenoussubstrate;andthechromogenictechnique,basedonthedevelopmentofcolourafterclea

15、vageofasyntheticpeptide-chromogencomplex.Thefollowing6methodsaredescribedinthepresentchapter:MethodA.Gel-clotmethod:limittestMethodB.Gel-clotmethod:semi-quantitativetestMethodC.Turbidimetrickineticmethod182Seetheinformationsectionongeneralmonographs(coverpages)EUROPEANPHARMACOPOEIA6.02.6.14.Bacteria

16、lendotoxinsMethodD.ChromogenickineticmethodMethodE.Chromogenicend-pointmethodMethodF.Turbidimetricend-pointmethodProceedbyanyofthe6methodsforthetest.Intheeventofdoubtordispute,thefinaldecisionismadebaseduponmethodAunlessotherwiseindicatedinthemonograph.Thetestiscarriedoutinamannerthatavoidsendotoxin

17、contamination.ApparatusDepyrogenateallglasswareandotherheat-stableapparatusinahot-airovenusingavalidatedprocess.Acommonlyusedminimumtimeandtemperatureis30minutesat250C.Ifemployingplasticapparatus,suchasmicrotitreplatesandpipettetipsforautomaticpipetters,useapparatusshowntobefreeofdetectableendotoxin

18、andofinterferingeffectsforthetest.NOTE:Inthischapter,thetermtubeincludesalltypesofreceptacles,forexamplemicrotitreplatewells.indicators(5.1.2).附件2-11211STERILIZATIONANDSTERILITYASSURANCEOFCOMPENDIALARTICLESThisinformationalchapterprovidesageneraldescriptionoftheconceptsandprinciplesinvolvedinthequal

19、itycontrolofarticlesthatmustbesterile.AnymodificationsoforvariationsinsterilitytestproceduresfromthosedescribedunderSterilityTests71shouldbevalidatedinthecontextoftheentiresterilityassuranceprogramandarenotintendedtobemethodsalternativetothosedescribedinthatchapter.Withinthestrictestdefinitionofster

20、ility,aspecimenwouldbedeemedsterileonlywhenthereiscompleteabsenceofviablemicroorganismsfromit.However,thisabsolutedefinitioncannotcurrentlybeappliedtoanentirelotoffinishedcompendialarticlesbecauseoflimitationsintesting.Absolutesterilitycannotbepracticallydemonstratedwithoutcompletedestructionofevery

21、finishedarticle.ThesterilityofalotpurportedtobesterileisthereforedefinedEU,USP及ChP对干热灭菌/除热原条件对照表6/71inprobabilisticterms,wherethelikelihoodofacontaminatedunitorarticleisacceptablyremote.Suchastateofsterilityassurancecanbeestablishedonlythroughtheuseofadequatesterilizationcyclesandsubsequentasepticpr

22、ocessing,ifany,underappropriatecurrentgoodmanufacturingpractice,andnotbyreliancesolelyonsterilitytesting.Thebasicprinciplesforvalidationandcertificationofasterilizingprocessareenumeratedasfollows:Establishthattheprocessequipmenthascapabilityofoperatingwithintherequiredparameters.Demonstratethatthecr

23、iticalcontrolequipmentandinstrumentationarecapableofoperatingwithintheprescribedparametersfortheprocessequipment.Performreplicatecyclesrepresentingtherequiredoperationalrangeoftheequipmentandemployingactualorsimulatedproduct.Demonstratethattheprocesseshavebeencarriedoutwithintheprescribedprotocollim

24、itsandfinallythattheprobabilityofmicrobialsurvivalinthereplicateprocessescompletedisnotgreaterthantheprescribedlimits.Monitorthevalidatedprocessduringroutineoperation.Periodicallyasneeded,requalifyandrecertifytheequipment.Completetheprotocols,anddocumentsteps(1)through(4)above.METHODSOFSTERILIZATION

25、Inthisinformationalchapter,fivemethodsofterminalsterilization,includingremovalofmicroorganismsbyfiltrationandguidelinesforasepticprocessing,aredescribed.Moderntechnologicaldevelopments,however,haveledtotheuseofadditionalprocedures.Theseincludeblow-molding(athightemperatures),formsofmoistheatothertha

26、nsaturatedsteamandUVirradiation,aswellason-linecontinuousfillinginasepticprocessing.Thechoiceoftheappropriateprocessforagivendosageformorcomponentrequiresahighlevelofknowledgeofsterilizationtechniquesandinformationconcerninganyeffectsoftheprocessonthematerialbeingsterilized,Dry-HeatSterilizationThep

27、rocessofthermalsterilizationofPharmacopeialarticlesbydryheatisusuallycarriedoutbyabatchprocessinanovendesignedexpresslyforthatpurpose.Amodernovenissuppliedwithheated,filteredair,distributeduniformlythroughoutthechamberbyconvectionorradiationandemployingablowersystemwithdevicesforsensing,monitoring,a

28、ndcontrollingthecriticalparameters.Thevalidationofadry-heatsterilizationfacilityiscarriedoutinamannersimilartothatforasteamsterilizerdescribedearlier.Wheretheunitisemployedforsterilizingcomponentssuchascontainersintendedforintravenoussolutions,careshouldbetakentoavoidaccumulationofEU,USP及ChP对干热灭菌/除热

29、原条件对照表7/71particulatematterinthechamber.Atypicalacceptablerangeintemperatureintheemptychamberis15whentheunitisoperatingatnotlessthan250.Inadditiontothebatchprocessdescribedabove,acontinuousprocessisfrequentlyemployedtosterilizeanddepyrogenateglasswareaspartofanintegratedcontinuousasepticfillingandse

30、alingsystem.Heatdistributionmaybebyconvectionorbydirecttransferofheatfromanopenflame.Thecontinuoussystemusuallyrequiresamuchhighertemperaturethancitedaboveforthebatchprocessbecauseofamuchshorterdwelltime.However,thetotaltemperatureinputduringthepassageoftheproductshouldbeequivalenttothatachievedduri

31、ngthechamberprocess.Thecontinuousprocessalsousuallynecessitatesarapidcoolingstagepriortotheasepticfillingoperation.Inthequalificationandvalidationprogram,inviewoftheshortdwelltime,parametersforuniformityofthetemperature,andparticularlythedwelltime,shouldbeestablished.Amicrobialsurvivalprobabilityof10-12isconsideredachievableforheat-stablearticlesorcomponents.Anexampleofabiologicalindicatorforvalidatingandmonitoringdry-heatsterilizationisapreparationofBacillussubtilisspores.Sincedryh