灭菌的方法及注意事项

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1、整理ppt1 1Sterilization 灭菌灭菌A General Discussion from CGMP Perspective从从CGMP角度的综合讨论角度的综合讨论整理ppt2 2Outline 讨论纲要讨论纲要nPART InTerminology 专业用词的定义专业用词的定义nGMP Requirements in The Manufacture of Sterile Pharmaceutical Products无菌药品生产过程中无菌药品生产过程中GMP的基本要求的基本要求nPART IInFacility Design 生产设施的设计生产设施的设计nHVAC System

2、空调系统空调系统nEnvironmental Monitoring(EM)环境的监视环境的监视nPharmaceutical Water 制药用水制药用水nCleaning/Sanitation 清洁消毒清洁消毒nPersonnel 无菌区操作人员无菌区操作人员nPART IIInMethods of sterilization 灭菌方法灭菌方法 nSterile Production and validation 无菌生产和验证无菌生产和验证nThe Trend of Sterile Production 无菌产品生产趋势无菌产品生产趋势整理ppt3Presentation Outline概

3、要概要nUS Regulations 美国法规美国法规nMoist Heat Sterilization 湿热灭菌湿热灭菌nDry Heat/Depyrogenation 干热干热/去热原法去热原法nSterilization Process Validation 灭菌工艺验证灭菌工艺验证nOther Sterilization Methods 其他灭菌方法其他灭菌方法整理ppt4Code Federal Regulation美国联邦法规美国联邦法规211.84(c)(3)sterile equipment 灭菌设备灭菌设备nSterile equipment and aseptic samp

4、ling techniques shall be used when necessary 必要时应使用灭菌设备和无菌取样技术。必要时应使用灭菌设备和无菌取样技术。211.94(c)and(d)sterilizedn(c)Drug product containers and closures shall be clean and,where indicated by the nature of the drug,sterilized and processed to remove pyrogenic properties to assure that they are suitable for

5、 their intended use.药品容器和密封系统应清洁并根据药品的性质和要求，进行灭菌，除药品容器和密封系统应清洁并根据药品的性质和要求，进行灭菌，除热原过程以确保预期的用途。热原过程以确保预期的用途。n(d)Standards or specifications,methods of testing,and,where indicated,methods of cleaning,sterilizing,and processing to remove pyrogenic properties shall be written and followed for drug produc

6、t containers and closures.应建立并执行对药品容器和密封系统的规格或质量标准，测试方法，清应建立并执行对药品容器和密封系统的规格或质量标准，测试方法，清洁方法，灭菌和除热原过程的相关书面程序洁方法，灭菌和除热原过程的相关书面程序。整理ppt5Code Federal Regulation美国联邦法规美国联邦法规211.113(a)and(b)sterilization 灭菌灭菌n(a)Appropriate written procedures,designed to prevent objectionable microorganisms in drug produc

7、ts not required to be sterile,shall be established and followed.应该建立并执行用于防止非无菌药品被致病菌污染的相关书面程序。应该建立并执行用于防止非无菌药品被致病菌污染的相关书面程序。n(b)Appropriate written procedures,designed to prevent microbiological contamination of drug products purporting to be sterile,shall be established and followed.Such procedures

8、 shall include validation of any sterilization process.应该应该建立建立并执行用于阻止无菌药品并执行用于阻止无菌药品被致病菌污染被致病菌污染的相关书面程序。的相关书面程序。这些程序应包括任何无菌工艺的验证。这些程序应包括任何无菌工艺的验证。整理ppt6Code Federal Regulation美国联邦法规美国联邦法规211.167(a)testing（a）测试测试nFor each batch of drug product purporting to be sterile and/or pyrogen-free,there shall

9、 be appropriate laboratory testing to determine conformance to such requirements.The test procedures shall be in writing and shall be followed.对无菌和对无菌和/或无热原的每批药品应进行相应的实验室测试以确定或无热原的每批药品应进行相应的实验室测试以确定其与符合要求。测试程序应有书面文件并遵照执行。其与符合要求。测试程序应有书面文件并遵照执行。整理ppt7Sterilization Methods灭菌方法灭菌方法nMoist Heat:湿热湿热For d

10、rugs and devices.The mode of action is protein denaturation.用于药品和设备。作用方式是使蛋白质变性用于药品和设备。作用方式是使蛋白质变性nDry Heat:干热干热For depyrogenation and equipment sterilization.The mode of action is protein denaturation 用于去热原和设备灭菌。作用方式是使蛋白质变性用于去热原和设备灭菌。作用方式是使蛋白质变性nEthylene Oxide:氧化乙烯氧化乙烯 Primarily for devices.The mod

11、e of action is alkylation of nucleic acids.主要用于设备。作用方式是使核酸烷基化主要用于设备。作用方式是使核酸烷基化nRadiation:辐射辐射Primarily for devices.The mode of action is DNA strand breakage 主要用于设备。作用方式是使主要用于设备。作用方式是使DNA链破坏链破坏nOther methods?其他方法？其他方法？整理ppt8Bioburden生物负荷生物负荷nDefinition:定义定义Population of viable microorganisms on or i

12、n a product and/or a package 产品和产品和/包装上的活性微生物的数量和类型包装上的活性微生物的数量和类型nMixture of organisms 有机物混合有机物混合 nIndigenous microflora 地方微植物群地方微植物群 nNeeds to be inactivated by sterilization 需灭菌失活需灭菌失活整理ppt9Bioburden生物负荷生物负荷Bioburden Sources 生物负荷来源生物负荷来源nEnvironment 环境环境Product contact surface,personnel,air 产品接触表

13、面，人员，空气产品接触表面，人员，空气nMaterials 材料材料Water,raw materials.plastic,paper 水，原材料，塑料，纸张水，原材料，塑料，纸张Characteristics of Bioburden 生物负荷特点生物负荷特点nTypes of microorganisms 微生物类型微生物类型nResistance to sterilization process 对无菌工艺的耐受对无菌工艺的耐受nNumber of organisms 有机物数量有机物数量整理ppt10Biological Indicator(BI)生物指示剂生物指示剂nMicrobio

14、logical test system providing a defined resistance to a specific sterilization process 微生物测试系统对指定灭菌工艺有明确抵抗性微生物测试系统对指定灭菌工艺有明确抵抗性。nA characterized preparation of specific microorganisms resistant to a particular sterilization process某一确定的微生物某一确定的微生物(指示剂指示剂)应具有对某一特定灭菌工艺的抵应具有对某一特定灭菌工艺的抵抗性抗性整理ppt11Typica

15、l Biological Indicators典型生物指示剂典型生物指示剂nMoist heat sterilization 湿热灭菌湿热灭菌nGeobacillus stearothermophilusnBacillus stearothermophilusnDry heat and EO sterilization 干热和环氧乙烷灭菌干热和环氧乙烷灭菌nBacillus atrophaeusnBacillus subtilis var.niger整理ppt12Forms of Biological Indicators生物指示剂形式生物指示剂形式nStrips/discs in glass

16、ine envelopes 在透明纸信封里的条形板在透明纸信封里的条形板/光盘光盘nStrips/discs 条条/光盘光盘nSelf-contained 独立包装的独立包装的nAmpoules 安瓶安瓶nStrips with medium 中号条形板中号条形板nLiquid suspension 液体悬浮液液体悬浮液nMetal 金属金属nFiberglass 玻璃纤维玻璃纤维整理ppt13Choice of an Appropriate BI相关生物指示剂的选择相关生物指示剂的选择nSterilization process 灭菌工艺灭菌工艺nCycle design method 循环

17、设计方法循环设计方法nProduct bioburden 产品生物负荷产品生物负荷nPopulation 数量数量nResistance 抵抗性抵抗性整理ppt14BIs Prepared by User生物指示剂的准备生物指示剂的准备nPerformance 性能性能nResistance 抵抗性抵抗性nPopulation 数量数量nPurity 纯度纯度nD-value D 值值nRecovery methods 恢复方法恢复方法nStorage requirements 储存要求储存要求整理ppt15Biological Indicator Use生物指示剂使用生物指示剂使用nPlac

18、e BI within 把把BI 放进放进nProduct 产品产品nPackage 包装包装nSterilizer load to monitor process 灭菌器负荷以监视灭菌工艺灭菌器负荷以监视灭菌工艺nExpose to sterilizing conditions 暴露在灭菌状态暴露在灭菌状态nRemove BI and test 移除移除BI和测试和测试nCount survivors 生存数量的计算生存数量的计算nGrowth/no growth response 生长生长/无生长反应无生长反应整理ppt16D-value D值值nThe D value is the ti

19、me,usually in minutes,required to achieve inactivation of 90%(or one logarithm)of a population of the test microorganism at specified conditions.D值是在特定条件下微生物数量降低的值是在特定条件下微生物数量降低的90%（或一对数）所用的时间，通（或一对数）所用的时间，通常是以分钟为单位的。常是以分钟为单位的。nBacillus stearothermophilus has a D value:嗜热脂肪芽胞杆菌的D值2 min at 121oC 20 m

20、in at 110oC 0.2-0.3 min at 130oCnOf all the aspects of sterilization validation,the D value is perhaps the most important.Validating a process without consideration of the D value is largely ineffective and is not acceptable from CGMP perspective 灭菌验证中，灭菌验证中，D值可能是最重要的。不考虑值可能是最重要的。不考虑D值的验证过程多半是无效值的验证

21、过程多半是无效的且不被的且不被CGMP接受。接受。整理ppt17Z-value Z值值nZ-value:number of degrees of temperature required for a 1 logarithm change in the D-value Z值：值：D值值1对数改变需要的温度数对数改变需要的温度数nZ=-1/slope of the thermal resistance curve Z=-1/热阻力曲线斜率热阻力曲线斜率 whereSlope=logarithmic change in D-value/change in temperature 斜率斜率=D值上对数

22、的改变值上对数的改变/温度的改变温度的改变整理ppt18Impact of Z-value Z值的影响值的影响nWhen z-value is small,considerably less inactivation will result below reference temperature and considerably more above the reference temperature 当当Z值较小时，较低程度的失活将导致温度低于参考温度，较大程度的失活将导值较小时，较低程度的失活将导致温度低于参考温度，较大程度的失活将导致温度高于参考温度致温度高于参考温度。0.010.111

23、0114116118120122124126128TemperatureD-valueStrain 1Strain 2整理ppt19Typical Temperature Profiles典型温度分布典型温度分布整理ppt20Type of Sterilization灭菌类型灭菌类型Moist Heat Sterilization湿热灭菌湿热灭菌整理ppt21Moist Heat Sterilization湿热灭菌湿热灭菌Characteristics:特征特征nWell understood and well characterized process,first validated pro

24、cess in pharm industry湿热灭菌是一已被很好地理解并描述灭菌工艺，也是在制药工业中第一个湿热灭菌是一已被很好地理解并描述灭菌工艺，也是在制药工业中第一个被验证的灭菌工艺被验证的灭菌工艺nSuitable for a wide variety of applications 适合于较大应用范围适合于较大应用范围nEquipment is readily available 设备很容易从市场购买到设备很容易从市场购买到nCost on a per use basis is low 每次使用基准花费低每次使用基准花费低整理ppt22Moist Heat Sterilization

25、湿热灭菌湿热灭菌Applications:应用应用nTerminal sterilization of parental product 注射剂的终端灭菌注射剂的终端灭菌nSterilization of equipment and components for use in aseptic filling 无菌灌装线上设备和配件的灭菌无菌灌装线上设备和配件的灭菌nSterilization of laboratory materials 实验室用材料的灭菌实验室用材料的灭菌nIn-situ sterilization of process piping and equipment(SIP)工

26、艺管道和设备在线灭菌工艺管道和设备在线灭菌 整理ppt23Basic Types of Moist Heat Sterilization湿热灭菌基本类型湿热灭菌基本类型nSaturated steam 饱和蒸汽饱和蒸汽nAutoclaves(self-closing)高压灭菌柜（半封闭）高压灭菌柜（半封闭）nSIP 在线灭菌在线灭菌nSuper heated water 过热水过热水nSpray 喷雾喷雾nSubmerged 浸没的浸没的nSIP 在线灭菌在线灭菌nSteam-air-mixture(SAM)水蒸气空气混合物水蒸气空气混合物整理ppt24Basic Elements of St

27、erilization Process Validation 灭菌工艺验证的基本元素灭菌工艺验证的基本元素nEmpty vessel heat distribution 空容器热分布空容器热分布nHeat distribution and penetration 热分布和渗透热分布和渗透3.Microbiological challenges 微生物挑战微生物挑战整理ppt25Steam Sterilization Validation:Prerequisites 蒸汽灭菌验证：前提蒸汽灭菌验证：前提nOQ for an autoclave:高压灭菌柜运行确认高压灭菌柜运行确认nEmpty c

28、hamber temperature mapping within 1.0oC of the mean 空腔体温度分布图在平均值的空腔体温度分布图在平均值的1.0oC 内内nChamber integrity test(no leaking)腔体完整性测试腔体完整性测试 nCertification of HEPA filtration on the air used to break vacuum or integrity testing of the vent filter 用于隔断真空或通气过滤器完整性测试的空气用于隔断真空或通气过滤器完整性测试的空气HEPA过滤认证过滤认证nRequi

29、rements for SIP 在线灭菌要求在线灭菌要求nTemperature mapping 温度分布图温度分布图nAn integrity test,where appropriate 相关完整性测试相关完整性测试nUse of BI 生物指示剂的使用生物指示剂的使用nAll critical instruments must be calibrated 所有关键仪器需校验所有关键仪器需校验整理ppt26Steam Sterilization Validation:Prerequisites 蒸蒸汽灭菌验证：前提汽灭菌验证：前提nAcceptable test results for n

30、on-condensable gases,super-heated steam and dryness should be obtained for the clean steam used for the autoclave/SIP 应获得用于高压灭菌柜应获得用于高压灭菌柜/SIP的洁净蒸汽中的不凝气体，过热的洁净蒸汽中的不凝气体，过热蒸汽及干燥度的可接受测试结果蒸汽及干燥度的可接受测试结果5.Tools for the conduct of the PQ study:进行进行PQ研究的工具研究的工具oBI with 106 spores and known D and Z values B

31、I 有有106个孢子，已知个孢子，已知D值和值和Z值值oTemperature sensors 温度传感器温度传感器oRecording device capable of supporting 12 temp sensors with an accuracy of 0.5 oC,recording data every minute or less 记录设备能支撑记录设备能支撑 12温度传感器，精度温度传感器，精度 0.5 oC，每分，每分钟或间隔更短时间记录数据钟或间隔更短时间记录数据oMeans of introducing temp sensors into the autoclave

32、/SIP 将温度传将温度传感器导入高压灭菌柜感器导入高压灭菌柜/SIP的方法的方法整理ppt27Steam Sterilization Validation:Preparation of PQ protocol 蒸汽灭菌验证：蒸汽灭菌验证：PQ方案的准备方案的准备nA protocol shall be prepared for:对于下列各项应建立方案：对于下列各项应建立方案：nNew autoclave/SIP 新高压灭菌柜新高压灭菌柜/SIPnNew loading patterns or product configurations 新装料方式或产品配置新装料方式或产品配置nChange

33、s to existing patterns 对现有装料方式的变更对现有装料方式的变更nChanges to operation cycle parameters 对运行周期参数的变更对运行周期参数的变更nMajor change to equipment as directed by change control 变更控制要求的设备主要变更变更控制要求的设备主要变更整理ppt28Steam Sterilization Validation:Preparation of PQ protocol 蒸汽灭菌验证：蒸汽灭菌验证：PQ方案的准备方案的准备nThe protocol may includ

34、e:方案可能包括：方案可能包括：nObjectives of the validation study 验证研究的目的验证研究的目的nIdentification and description of the sterilizer and its process controls 灭菌器的识别和说明及工艺控制灭菌器的识别和说明及工艺控制nIdentification of SOPs for the process equipment 工艺设备工艺设备SOP的识别的识别nDescription of or SOP reference for instrument calibration proc

35、edures 仪器校验程序的说明或仪器校验程序的说明或SOP参考参考nIdentification of calibration procedures for temp-monitoring equipment,which include a two point pre-run calibration and a post-run verification for each run 温度监测设备校验程序的识别，包括一个两点预运行校验和每次运温度监测设备校验程序的识别，包括一个两点预运行校验和每次运行后的确认行后的确认nProcess parameter acceptance criteria

36、工艺参数的验收标准工艺参数的验收标准整理ppt29Steam Sterilization Validation:Preparation of PQ protocol 蒸汽灭菌验证：蒸汽灭菌验证：PQ方案的准备方案的准备nA description of the following:以下说明以下说明nBiodurden determination studies 生物负荷确认研究生物负荷确认研究nEmpty chamber heat distribution studies(1 oC)空腔体热分布研究（空腔体热分布研究（1 oC）nLoaded chamber(including Load co

37、nfiguration,max lading and min loading)heat penetration studies 满载腔体（包括装载配置满载腔体（包括装载配置,最大和最少）热穿透研究最大和最少）热穿透研究nContainer mapping studies(may not needed if 100mL)容器分布图研究（如果容量容器分布图研究（如果容量100mL，可能不需要），可能不需要）nMicrobiological challenge studies 微生物挑战研究微生物挑战研究nEvaluation of drug product cooling water(where

38、applicable)药品冷却水评估（若适用）药品冷却水评估（若适用）nEvaluation of vent filter membranes associated with the sterilizer 与灭菌器相关的通气过滤膜的评估与灭菌器相关的通气过滤膜的评估整理ppt30Steam Sterilization Validation:Preparation of PQ protocol 蒸汽灭菌验证：蒸汽灭菌验证：PQ方案的准备方案的准备4.Description of the temp sensor placement within the load 在负荷范围内温度传感器位置的说明在

39、负荷范围内温度传感器位置的说明nOne next to the temp controlling sensor for autoclave.一一1个接近高压灭菌柜的温度控制传感器个接近高压灭菌柜的温度控制传感器nNLT 12 sensors for autoclave 不少于不少于12 个传感器用于高压灭菌柜个传感器用于高压灭菌柜nNLT 3 sensors for SIP不少于不少于3传感器用于在线灭菌传感器用于在线灭菌 If the temp controlling sensor is not in the drain,an additional sensor shall be place

40、d in the drain 如果温度控制传感器不在排水口中，应置另一个传感器于排水口中如果温度控制传感器不在排水口中，应置另一个传感器于排水口中i.A minimum#of sensors meeting the calibration and verification shall be established.Any sensor that fail at the end of the study shall be investigated.Any sensor located next to the temp controlling sensor or in the drain shal

41、l meet the pre and post calibration as part of the acceptance criteria for a successful run 应建立符合校验和验证的最少应建立符合校验和验证的最少#传感器。最终任何传感器的失败应调查研传感器。最终任何传感器的失败应调查研究。任何临近温度控制传感器或在排水口的传感器应符合预校验和后校验，究。任何临近温度控制传感器或在排水口的传感器应符合预校验和后校验，这是成功运行的验收标准的一部分。这是成功运行的验收标准的一部分。整理ppt31Steam Sterilization Validation:Preparati

42、on of PQ protocol 蒸汽灭菌验证：蒸汽灭菌验证：PQ方案的准备方案的准备5.Acceptance criteria for temp.pressure,Fo where appropriate,vacuum and destructions of BIs 温度压力，相关温度压力，相关Fo，真空及生物指示剂灭活的验收标准，真空及生物指示剂灭活的验收标准6.A requirement for 3 consecutive,successful runs 3次连续成功运行的要求次连续成功运行的要求The drain is the coldest point and is outside

43、 of the sterilization zone,not included in the calculation of mean chamber temperature and not subject to chamber distribution requirement.排水口是最冷点，在灭菌区外，且不包括在平均腔体温度计算内，不受限于腔体排水口是最冷点，在灭菌区外，且不包括在平均腔体温度计算内，不受限于腔体分布要求分布要求Thermocouples should be placed at the same location for empty chamber and loaded ch

44、amber heat distribution studies.热电偶应置于相同位置，进行空腔体和满载腔体热分布研究热电偶应置于相同位置，进行空腔体和满载腔体热分布研究Uniformity is expected only at the steady state.仅在稳定状态下要求均一性仅在稳定状态下要求均一性整理ppt32Steam Sterilization Validation:Execution of PQ 蒸汽灭菌验证：蒸汽灭菌验证：PQ执行执行1.Temperature sensor shall:温度传感器应温度传感器应：nFor heat penetration data,be

45、located such that they penetrate the equipment,or the product container and are immersed in the product 对于热穿透数据，应置于能穿透设备或产品容器处，并包对于热穿透数据，应置于能穿透设备或产品容器处，并包含在产品中含在产品中nFor heat distribution data,be evenly distributed within the load or system and shall not contact metal surface 对于热分布数据，平均分布在负荷范围内或系统中，且

46、不能接触金属面对于热分布数据，平均分布在负荷范围内或系统中，且不能接触金属面2.The BI shall:生物指示剂应生物指示剂应：nBe placed near the tip of the temperature sensor used for penetration 置于靠近用于穿透的温度传感器的顶端置于靠近用于穿透的温度传感器的顶端nInclude the identification that links to the number of the appropriate temperature sensor of the BI 包括与相关包括与相关BI温度传感器数量有关的识别温度传感

47、器数量有关的识别nThe D value of the BI shall be determined in the product BI的的D值应在生产中确定值应在生产中确定整理ppt33Steam Sterilization Validation:Execution of PQ 蒸汽灭菌验证：蒸汽灭菌验证：PQ执行执行nThe autoclave shall be loaded and operated in accordance with SOP 高压灭菌器应按照高压灭菌器应按照SOP进行装载并运行进行装载并运行nUsing 121.1 oC as the base temperature

48、 and 10 oC as the Z-value,Fo shall be calculated 121.1 oC 作为基底温度，作为基底温度，10 oC 作为作为Z值，值，Fo应为计算值应为计算值nAcceptance criteria shall be based on no growth on exposed BIs and growth on the positive control BI 验收标准应依据暴露的验收标准应依据暴露的BI上未生长和阳性控制上未生长和阳性控制BI上的生长上的生长nFailure to meet acceptance criteria shall requir

49、e cycle parameter modifications,load pattern modification and/or equipment repairs/corrections 未达到验收标准应要求周期参数变更，负荷曲线图变更和未达到验收标准应要求周期参数变更，负荷曲线图变更和/或设备修或设备修理理/修正修正整理ppt34Case Study 实例分析实例分析Autoclave Sterilization Validation 高压蒸汽灭菌验证高压蒸汽灭菌验证Table 1 Acceptance Criteria of Empty Chamber Heat Distribution

50、表表1 空腔体热分布验收标准空腔体热分布验收标准No.Acceptance Criteria验收标准验收标准1The 12 TCs distributed throughout the chamber must be within 1C of the mean thermocouple temperature each minute after stabilization throughout the duration of the sterilization phase.整个灭菌阶段，稳定后，每分钟分布在腔体内的12个 TC必须在平均热电偶温度的1C 2Dwell time not less

51、 than the pre-set sterilization time of 40 minutes.停留时间不少于预设定的灭菌时间40分钟3The TCs monitoring the drain and chamber RTDs may not fail post check calibration.Ten of the twelve TCs must be functional at the end of the cycle.监测排水和腔体RTD的TC不应在实验后校验失败。循环结束时，12个TC中的10个必须在实验后校验时功能完好整理ppt35Case Study 实例分析实例分析Aut

52、oclave Sterilization Validation 高压蒸汽灭菌验证高压蒸汽灭菌验证Table 2 Acceptance Criteria for Heat Distribution表表2 热分布验收标准热分布验收标准No.Acceptance Criteria验收标准验收标准1Dwell time must be not less than the pre-set sterilization time of 15 minutes 停留时间不得少于预设定的灭菌时间15分钟2The drain PT-100 and TC in the drain must be within 1.0

53、C of each other during the stabilized sterilization period.在稳定灭菌期间，排水管PT-100和排水管中TC之间温差必须在1.0oC 之内3The temperature deviation during holding times does not exceed-1C and+2C from the set point(during the stabilization period)停留时间的温度偏差不超过-1oC及设定点的+2oC（在稳定阶段）4At least 10 TCs of 12 thermocouples must be

54、functional at the end of the run循环结束时，12个TC中的10个必须功能完好整理ppt36Case Study 实例分析实例分析Autoclave Sterilization Validation 高压蒸汽灭菌验证高压蒸汽灭菌验证Table 3Acceptance Criteria for Heat Penetration表表3热分布验收标准热分布验收标准No.Acceptance Criteria 验收标准验收标准1F0 must be not less than preset time of 15 minutes F0不得低于预设定的15分钟2The dra

55、in PT-100 and TC in the drain must be within 1.0C of each other during the stabilized sterilization period.在稳定灭菌期间，排水管PT-100和排水管中TC之间温差必须在1.0C 之内3The temperature sensors remained in position at the end of cycle 循环结束时温度传感器仍然在位4The items containing sensors are intact;bottles have not leaked,burst or b

56、roken 装传感器的器具完整；瓶子不漏，爆裂或破碎5No more than 1%of the bottles has burst or broken 爆裂或破碎的瓶不超过1%6The temperature measured in any fluid containers is not greater than 80 C at the end of the cycle 循环结束时，任何液体容器中测量的温度不超过80 C 7The temperature deviation during holding time does not exceed-1C and+2C from the setp

57、oint during the stabilized sterilization period 停留时间的温度偏差不超过-1C及稳定灭菌阶段设定点的+2C 8No spore survival of the biological indicators 生物指示器上无孢子生存9At least 10 TCs of 12 thermocouples are functional at the end of the run for themaximum&minimum load configurations,respectively 每次最大&最小装载配置结束时，12个热电偶中至少10个TC起作用1

58、0Autoclave and validation timers must be synchronized 高压灭菌柜和确认计时器必须同步整理ppt37Dry Heat Sterilization 干热灭菌干热灭菌 Depyrogenation去热原去热原整理ppt38Terminology and Definitions 术语和定义术语和定义nPyrogen:Fever producing substance:endotoxin,viruses,fungi,toxin from gram(+)and gram(-)bacterials,peptiglycan 热原：热产生的物质：内毒素，病毒

59、，真菌，革兰氏阳性和阴性细菌产热原：热产生的物质：内毒素，病毒，真菌，革兰氏阳性和阴性细菌产生的毒素，肽糖生的毒素，肽糖nEndotoxin:Component from outer membrane of gram(-)bacterial,most potent pyrogens,LPS in structure 内毒素：革兰氏阴性细菌外膜的成分，大多数有效热原，结构中的内毒素：革兰氏阴性细菌外膜的成分，大多数有效热原，结构中的LPSnEnvironmental:complex of protein,carbohydrate&lipid.环境：复合蛋白质，环境：复合蛋白质，碳水化合物碳水化合

60、物&脂类脂类 nPurified:lipopolysacchride,used in endotoxin standards 提纯后：脂多糖，用于内毒素标准提纯后：脂多糖，用于内毒素标准整理ppt39Sources of Pyrogen in Parenterals注射用药热原的来源注射用药热原的来源nWater systems and resin columns 水系统和树脂交换柱水系统和树脂交换柱nAPIs produced without endotoxin removal 生产生产API而未除内毒素而未除内毒素nAPI&excipients from natural sources 来

61、自自然源的来自自然源的API&赋形剂赋形剂nManufacturing equipment 生产设备生产设备nAnywhere gram(-)microbes are growing or have been growing 革兰氏阴性细菌生长或曾生长的任何地方革兰氏阴性细菌生长或曾生长的任何地方整理ppt40Depyrogenation去热原去热原nA process to remove or destroy Endotoxin 除去或破坏内毒素的一种工艺除去或破坏内毒素的一种工艺n 3 log reduction per USP 按照按照USP，3对数减少值对数减少值nDepyrogena

62、tion requires:去热原要求去热原要求：nDistillation or ultrafiltration of water 对水进行蒸馏或超滤对水进行蒸馏或超滤nDry heat incineration 干热焚烧干热焚烧nDestruction by strong alkali or oxidation with peroxide 用强碱或过氧化物进行氧化来破坏用强碱或过氧化物进行氧化来破坏整理ppt41Types of Dry Heat Sterilizers干热灭菌器的种类干热灭菌器的种类nCommon 常用常用nForced-convection batch steriliz

63、ers:utensils,glassware,stainless steel equipment,product 强制对流批灭菌器：器具，玻璃器皿，不锈钢设备，产品强制对流批灭菌器：器具，玻璃器皿，不锈钢设备，产品nTunnel:glassware 烘箱：玻璃器皿烘箱：玻璃器皿nFlame:ampoule sealing 火焰：安瓿封口火焰：安瓿封口nLess common 不常用不常用nMicrowave 微波微波nLaser plasma 激光等离子体激光等离子体整理ppt42Components for Aseptic Processing 无菌工艺元件无菌工艺元件Component部件

64、部件Endotoxin内毒素内毒素Method方法方法LRV*Water 水Most likely 很可能Distillation,RO 蒸馏，RO4Lg.Containers 容器Possible 可能Chemicals,CIP 化学品，CIP2Excipients 赋形剂Possible 可能Purification 提纯 NDGlass vials 玻璃瓶Never seen 未见过Dry heat 干热4Closures 塞子Unlikely 不可能Wash/sterilize清洗/灭菌3Lubricant 润滑油Never seen 未见过Dry heat 干热ND整理ppt43Dr

65、y Heat Depyrogenation:Glass干热除热原：玻璃干热除热原：玻璃nTemp.range:200-350 oC 温度范围：温度范围：200-350 oC nHeat tolerant materials,glassware,metal parts,scissors,oils,inorganic salts 耐热材料，玻璃器皿，金属部件，剪刀，油，无机盐耐热材料，玻璃器皿，金属部件，剪刀，油，无机盐nProcess:heated,HEPA filtered air,uniformly distributed by convection&fan 工艺：加热，工艺：加热，HEPA

66、 过滤空气，通过对流过滤空气，通过对流&风扇进行均匀分布风扇进行均匀分布nLethal effect:oxidation of proteins and denaturation 致命效应：蛋白质氧化和变性致命效应：蛋白质氧化和变性nUSP:3 log reduction 大于大于3个对数减少值个对数减少值整理ppt44Advantages of Dry-heat Depyrogenation干热去热原的优点干热去热原的优点nInactivates pyrogens while sterilization 灭菌时使热原失活灭菌时使热原失活 nMaterials dry at the end of cycle 循环结束时物料干燥循环结束时物料干燥nCorrosive effects are minimal 腐蚀性最小腐蚀性最小nConveyor systems allow for higher temps and shorter dwell time 传送系统允许更高温度和更短的停留时间传送系统允许更高温度和更短的停留时间 整理ppt45Disadvantages of Dry-heat