灭菌的方法及注意事项.ppt

1 1Sterilization 灭菌A General Discussion from CGMP Perspective 从CGMP角度的综合讨论2 2Outline 讨论纲要nPART InTerminology 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GMP的基本要求 nPART IInFacility Design 生产设施的设计nHVAC System 空调系统nEnvironmental Monitoring (EM) 环境的监视nPharmaceutical Water 制药用水nCleaning/Sanitation 清洁消毒nPersonnel 无菌区操作人员 nPART IIInMethods of sterilization 灭菌方法 nSterile Production and validation 无菌生产和验证nThe Trend of Sterile Production 无菌产品生产趋势3Presentation Outline 概要nUS Regulations 美国法规nMoist Heat Sterilization 湿热灭菌nDry Heat/Depyrogenation 干热/去热原法nSterilization Process Validation 灭菌工艺验证nOther Sterilization Methods 其他灭菌方法4Code Federal Regulation 美国联邦法规211.84(c)(3) sterile equipment 灭菌设备 nSterile equipment and aseptic sampling techniques shall be used when necessary 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 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 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 product 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 洁方法，灭菌和除热原过程的相关书面程序。

5Code Federal Regulation 美国联邦法规211.113(a) and (b) sterilization 灭菌n(a) Appropriate written procedures, designed to prevent objectionable microorganisms in drug products 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n(b) Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization process.应该建立并执行用于阻止无菌药品被致病菌污染的相关书面程序 。

这些程序应包括任何无菌工艺的验证6Code Federal Regulation 美国联邦法规211.167(a) testing （a）测试nFor each batch of drug product purporting to be sterile and/or pyrogen-free, there shall 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/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7Sterilization Methods 灭菌方法nMoist Heat: 湿热 For drugs 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 nDry Heat: 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 nEthylene Oxide: 氧化乙烯 Primarily for devices. The mode of action is alkylation of nucleic acids. 主要用于设备作用方式是使核酸烷基化 nRadiation: 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DNA链破坏 nOther methods? 其他方法？8Bioburden 生物负荷nDefinition: 定义 Population of viable microorganisms on or in a product and/or a package产品和/包装上的活性微生物的数量和类型nMixture of organisms 有机物混合nIndigenous microflora 地方微植物群 nNeeds to be inactivated by sterilization 需灭菌失活9Bioburden 生物负荷Bioburden Sources 生物负荷来源 nEnvironment 环境 Product contact surface, personnel, air产品接触表面，人员，空气 nMaterials 材料 Water, raw materials. plastic, paper水，原材料，塑料，纸张Characteristics of Bioburden 生物负荷特点 nTypes of microorganisms 微生物类型 nResistance to sterilization process 对无菌工艺的耐受 nNumber of organisms 有机物数量10Biological Indicator (BI) 生物指示剂nMicrobiological 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。

nA characterized preparation of specific microorganisms resistant to a particular sterilization process某一确定的微生物(指示剂)应具有对某一特定灭菌工艺的抵抗 性11Typical Biological Indicators 典型生物指示剂nMoist heat sterilization 湿热灭菌nGeobacillus stearothermophilusnBacillus stearothermophilusnDry heat and EO sterilization 干热和环氧乙烷灭菌nBacillus atrophaeusnBacillus subtilis var. niger12Forms of Biological Indicators 生物指示剂形式nStrips/discs in glassine envelopes 在透明纸信封里的条形板/光盘nStrips/discs 条/光盘nSelf-contained 独立包装的nAmpoules 安瓶nStrips with medium 中号条形板nLiquid suspension 液体悬浮液nMetal 金属nFiberglass 玻璃纤维13Choice of an Appropriate BI 相关生物指示剂的选择nSterilization process 灭菌工艺nCycle design method 循环设计方法nProduct bioburden 产品生物负荷nPopulation 数量nResistance 抵抗性14BIs Prepared by User 生物指示剂的准备nPerformance 性能nResistance 抵抗性nPopulation 数量nPurity 纯度nD- value D 值nRecovery methods 恢复方法nStorage requirements 储存要求15Biological Indicator Use 生物指示剂使用nPlace BI within 把BI 放进nProduct 产品nPackage 包装nSterilizer load to monitor process灭菌器负荷以监视灭菌工艺nExpose to sterilizing conditions 暴露在灭菌状态nRemove BI and test 移除BI和测试nCount survivors 生存数量的计算nGrowth/no growth response 生长/无生长反应16D-value D值nThe D value is the time, 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90%（或一对数）所用的时间，通 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。