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1、1,1,Sterilization 灭菌,A General Discussion from CGMP Perspective 从CGMP角度的综合讨论,2,2,Outline 讨论纲要,PART I Terminology 专业用词的定义 GMP Requirements in The Manufacture of Sterile Pharmaceutical Products无菌药品生产过程中GMP的基本要求 PART II Facility Design 生产设施的设计 HVAC System 空调系统 Environmental Monitoring (EM) 环境的监视 Pharma
2、ceutical Water 制药用水 Cleaning/Sanitation 清洁消毒 Personnel 无菌区操作人员 PART III Methods of sterilization 灭菌方法 Sterile Production and validation 无菌生产和验证 The Trend of Sterile Production 无菌产品生产趋势,3,Presentation Outline概要,US Regulations 美国法规 Moist Heat Sterilization 湿热灭菌 Dry Heat/Depyrogenation 干热/去热原法 Steriliz
3、ation Process Validation 灭菌工艺验证 Other Sterilization Methods 其他灭菌方法,3,4,Code Federal Regulation美国联邦法规,211.84(c)(3) sterile equipment 灭菌设备 Sterile 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) sterilized (c) Drug product containers and clos
4、ures 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。 (d) Standards or specifications, methods of testing, and, where indicated,
5、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。,4,5,Code Federal Regulation美国联邦法规,211.113(a) and (b) sterilization 灭菌 (a) Appropriate written pr
6、ocedures, 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。 (b) Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, s
7、hall 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。,5,6,Code Federal Regulation美国联邦法规,211.167(a) testing （a）测试 For each batch of drug product purporting to be sterile and/or pyrogen-free, there shall
8、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。,6,7,Sterilization Methods灭菌方法,Moist Heat: 湿热 For drugs and devices. The mode of action is protein denatu
9、ration. 用于药品和设备。作用方式是使蛋白质变性 Dry 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 Ethylene 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 Radiation: 辐射 Primarily for dev
10、ices. The mode of action is DNA strand breakage 主要用于设备。作用方式是使DNA链破坏 Other methods? 其他方法？,7,8,Bioburden生物负荷,Definition: 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 Mixture of organisms 有机物混合 Indigenous microflora 地方微植物群 Needs to be inactivated by ste
11、rilization 需灭菌失活,8,9,Bioburden生物负荷,Bioburden Sources 生物负荷来源 Environment 环境 Product contact surface, personnel, air 产品接触表面，人员，空气 Materials 材料 Water, raw materials. plastic, paper 水，原材料，塑料，纸张 Characteristics of Bioburden 生物负荷特点 Types of microorganisms 微生物类型 Resistance to sterilization process 对无菌工艺的耐受
12、 Number of organisms 有机物数量,9,10,Biological Indicator (BI)生物指示剂,Microbiological 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。 A 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
13、某一特定灭菌工艺的抵抗性,10,11,Typical Biological Indicators典型生物指示剂,Moist heat sterilization 湿热灭菌 Geobacillus stearothermophilus Bacillus stearothermophilus Dry heat and EO sterilization 干热和环氧乙烷灭菌 Bacillus atrophaeus Bacillus subtilis var. niger,11,12,Forms of Biological Indicators生物指示剂形式,Strips/discs in glassi
14、ne envelopes 在透明纸信封里的条形板/光盘 Strips/discs 条/光盘 Self-contained 独立包装的 Ampoules 安瓶 Strips with medium 中号条形板 Liquid suspension 液体悬浮液 Metal 金属 Fiberglass 玻璃纤维,12,13,Choice of an Appropriate BI相关生物指示剂的选择,Sterilization process 灭菌工艺 Cycle design method 循环设计方法 Product bioburden 产品生物负荷 Population 数量 Resistance
15、 抵抗性,13,14,BIs Prepared by User生物指示剂的准备,Performance 性能 Resistance 抵抗性 Population 数量 Purity 纯度 D- value D 值 Recovery methods 恢复方法 Storage requirements 储存要求,14,15,Biological Indicator Use生物指示剂使用,Place BI within 把BI 放进 Product 产品 Package 包装 Sterilizer load to monitor process 灭菌器负荷以监视灭菌工艺 Expose to ster
16、ilizing conditions 暴露在灭菌状态 Remove BI and test 移除BI和测试 Count survivors 生存数量的计算 Growth/no growth response 生长/无生长反应,15,16,D-value D值,The 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。 Bacillus stearothermophilus has a D value: 嗜热脂肪芽胞杆菌的D值 2 min at 121oC 20 min at 110oC 0.2-0.3 min at 130oC Of all t
