USP30_1211翻译_灭菌和无菌保证

1211 STERILIZATION AND STERILITY ASSURANCE OF COMPENDIAL ARTICLES 灭菌和无菌保证纲要条款灭菌和无菌保证纲要条款 This informational chapter provides a general description of the concepts and principles involved in the quality control of articles that must be sterile Any modifications of or variations in sterility test procedures from those described under Sterility Tests 71 should be validated in the context of the entire sterility assurance program and are not intended to be methods alternative to those described in that chapter 报告章节规定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 Within the strictest definition of sterility a specimen would be deemed sterile only when there is complete absence of viable microorganisms from it However this absolute definition cannot currently be applied to an entire lot of finished compendial articles because of limitations in testing Absolute sterility cannot be practically demonstrated without complete destruction of every finished article 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 The sterility of a lot purported to be sterile is therefore defined in probabilistic terms where the likelihood of a contaminated unit or article is acceptably remote Such a state of sterility assurance can be established only through the use of adequate sterilization cycles and subsequent aseptic processing if any under appropriate current good manufacturing practice and not by reliance solely on sterility testing The basic principles for validation and certification of a sterilizing process are enumerated as follows 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范围的 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 Establish that the process equipment has capability of operating within the required parameters 确定加工设备的操作性能处在正确的参数 2 Demonstrate that the critical control equipment and instrumentation are capable of operating within the prescribed parameters for the process equipment 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 Perform replicate cycles representing the required operational range of the equipment and employing actual or simulated product Demonstrate that the processes have been carried out within the prescribed protocol limits and finally that the probability of microbial survival in the replicate processes completed is not greater than the prescribed limits 执行可重复的循环表现在设备必需的操作范围和使 用真实或可模拟的产品 证明加工是在给定协议范围下执行 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范围 4 Monitor the validated process during routine operation Periodically as needed requalify and recertify the equipment 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 Complete the protocols and document steps 1 through 4 above 完 善协议 证明以上步骤 1 4 The principles and implementation of a program to validate an aseptic processing procedure are similar to the validation of a sterilization process In aseptic processing the components of the final dosage form are sterilized separately and the finished article is assembled in an aseptic manner 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 Proper validation of the sterilization process or the aseptic process requires a high level of knowledge of the field of sterilization and clean room technology In order to comply with currently acceptable and achievable limits in sterilization parameters it is necessary to employ appropriate instrumentation and equipment to control the critical parameters such as temperature and time humidity and sterilizing gas concentration or absorbed radiation 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 An important aspect of the validation program in many sterilization procedures involves the employment of biological indicators see Biological Indicators 1035 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 The validated and certified process should be revalidated periodically however the revalidation program need not necessarily be as extensive as the original program 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 A typical validation program as outlined below is one designed for the steam autoclave but the principles are applicable to the other sterilization procedures discussed in this informational chapter The program comprises several stages 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 The installation qualification stage is intended to establish that controls and other instrumentation are properly designed and calibrated Documentation should be on file demonstrating the quality of the required utilities such as steam water and air 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 The operational qualification stage is intended to confirm that the empty chamber functions within the parameters of temperature at all of the key chamber locations prescribed in the protocol 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内的锅室功能 It is usually appropriate to develop heat profile records i e simultaneous temperatures in the chamber employing multiple temperature sensing devices 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 A typical acceptable range of temperature in the empty chamber is 1 when the chamber temperature is not less than 121 当锅室温度不少于 121 一个典型的可接受 的锅室温度幅度范围是 1 The confirmatory stage of the validation program is the actual sterilization of materials or articles 确认程序的确认时期是原料或物 品实际灭菌期 This determination requires the employment of temperature sensing devices inserted into samples of the articles as well as either samples of the articles to which appropriate concentrations of suitable test microorganisms have been added or separate BIs in operationally fully loaded autoclave configurations 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 The effectiveness of heat delivery or penetration into the actual articles and the time of the exposure are the two main factors that determine the lethality of the sterilization process The final stage of the validation program requires the documentation of the supporting data developed in executing the program 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 It is generally accepted that terminally sterilized injectable articles or critical devices purporting to be sterile when processed in the autoclave attain a 10 6 microbial survivor probability i e assurance of less than 1 chance in 1 million that viable microorganisms are present in the sterilized article or dosage form 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 With heat stable articles the approach often is to considerably exceed the critical time necessary to achieve the 10 6 microbial survivor probability 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 with an article where extensive heat exposure may have a damaging effect it may not be feasible to employ this overkill approach 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 In this latter instance the development of the sterilization cycle depends heavily on knowledge of the microbial burden of the product based on examination over a suitable time period of a substantial number of lots of the presterilized product 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 The D value is the time in minutes required to reduce the microbial population by 90 or 1 log cycle i e to a surviving fraction of 1 10 at a specific temperature 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 or log1 周期 也就是 1 10 存活部分 Therefore where the D value of a BI preparation of for example Bacillus stearothermophilus spores is 1 5 minutes under the total process parameters e g at 121 if it is treated for 12 minutes under the same conditions it can be stated that the lethality input is 8D 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 The effect of applying this input to the product would depend on the initial microbial burden 应用这个输入产品的效果依靠最初的微生物耐热负荷 Assuming that its resistance to sterilization is equivalent to that of the BI if the microbial burden of the product in question is 102 microorganisms a lethality input of 2D yields a microbial burden of 1 10 theoretical and a further 6D yields a calculated microbial survivor probability of 10 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 Under the same conditions a lethality input of 12D may be used in a typical 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 the survivor probability achieved for the article under the validated sterilization cycle is not completely correlated with what may occur with the BI For valid use therefore it is essential that the resistance of the BI be greater than that of the natural microbial burden of the article sterilized 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 It is then appropriate to make a worst case assumption and treat the microbial burden as though its heat resistance were equivalent to that of the BI although it is not likely that the most resistant of a typical microbial burden isolates will demonstrate a heat resistance of the magnitude shown by this species frequently employed as a BI for steam sterilization 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 In the above example a 12 minute cycle is considered adequate for sterilization if the product had a microbial burden of 102 microorganisms 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 if the indicator originally had 106 microorganisms content actually a 10 2 probability of survival could be expected i e 1 in 100 BIs may yield positive results 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 100 BIs 有 1 个 产生阳性结果 This type of situation may be avoided by selection of the appropriate BI Alternatively high content indicators may be used on the basis of a predetermined acceptable count reduction 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 The D value for the Bacillus stearothermophilus preparation determined or verified for these conditions should be reestablished when a specific program of validation is changed Determination of survival curves see Biological Indicators 1035 or what has been called the fractional cycle approach may be employed to determine the D value of the biological indicator preferred for the specific sterilization procedure 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 The fractional cycle approach may also be used to evaluate the resistance of the microbial burden Fractional cycles are studied either for microbial count reduction or for fraction negative achievement 部分时间方法也可以用来估计微生物担子抵 抗力 These numbers may be used to determine the lethality of the process under production conditions 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 The data can be used in qualified production equipment to establish appropriate sterilization cycles A suitable biological indicator such as the Bacillus stearothermophilus preparation may be employed also during routine sterilization 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 Any microbial burden method for sterility assurance requires adequate surveillance of the microbial resistance of the article to detect any changes in addition to periodic surveillance of other attributes 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 METHODS OF STERILIZATION 灭菌方法灭菌方法 In this informational chapter five methods of terminal sterilization including removal of microorganisms by filtration and guidelines for aseptic processing are described 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 Modern technological developments however have led to the use of additional procedures These include blow molding at high temperatures forms of moist heat other than saturated steam and UV irradiation as well as on line continuous filling in aseptic processing 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 The choice of the appropriate process for a given dosage form or component requires a high level of knowledge of sterilization techniques and information concerning any effects of the process on the material being sterilized 1 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 Steam Sterilization 蒸汽灭菌 The process of thermal sterilization employing saturated steam under pressure is carried out in a chamber called an autoclave 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 It is probably the most widely employed sterilization process 2 它是利用最广泛的灭菌程序 The basic principle of operation is that the air in the sterilizing chamber is displaced by the saturated steam achieved by employing vents or traps 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 In order to displace air more effectively from the chamber and from within articles the sterilization cycle may include air and steam evacuation stages 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 The design or choice of a cycle for given products or components depends on a number of factors including the heat lability of the material knowledge of heat penetration into the articles and other factors described under the validation program see above 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 包括材料的热不稳定性 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 Apart from that description of sterilization cycle parameters using a temperature of 121 the F0 concept may be appropriate 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 The F0 at a particular temperature other than 121 is the time in minutes required to provide the lethality equivalent to that provided at 121 for a stated time 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 Modern autoclaves g 比 enerally operate with a control system that is significantly more responsive than the steam reduction valve of older units that have been in service for many years 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 In order for these older units to achieve the precision and level of control of the cycle discussed in this chapter it may be necessary to upgrade or modify the control equipment and instrumentation on these units 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 This modification is warranted only if the chamber and steam jacket are intact for continued safe use and if deposits that interfere with heat distribution can be removed 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 Heat Sterilization 干热灭菌 The process of thermal sterilization of Pharmacopeial articles by dry heat is usually carried out by a batch process in an oven designed expressly for that purpose 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 A modern oven is supplied with heated filtered air distributed uniformly throughout the chamber by convection or radiation and employing a blower system with devices for sensing monitoring and controlling the critical parameters 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 The validation of a dry heat sterilization facility is carried out in a manner similar to that for a steam sterilizer described earlier Where the unit is employed for sterilizing components such as containers intended for intravenous solutions care should be taken to avoid accumulation of particulate matter in the chamber 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内溶液的容器 应当 注意避免锅室颗粒物质的积聚 A typical acceptable range in temperature in the empty chamber is 15 when the unit is operating at not less than 250 在 空的锅室 一个典型可接受的温度范围是 15 当它工作时 温度不小于 250 In addition to the batch process described above a continuous process is frequently employed to sterilize and depyrogenate glassware as part of an integrated continuous aseptic filling and sealing system 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 Heat distribution may be by convection or by direct transfer of heat from an open flame 热发送通过传送 或从一个明火直接热传递 The continuous system usually requires a much higher temperature than cited above for the batch process because of a much shorter dwell time 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 the total temperature input during the passage of the product should be equivalent to that achieved during the chamber process 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 The continuous process also usually necessitates a rapid cooling stage prior to the aseptic filling operation 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 In the qualification and validation program in view of the short dwell time parameters for uniformity of the temperature and particularly the dwell time should be established 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 A microbial survival probability of 10 12 is considered achievable for heat stable articles or components An example of a biological indicator for validating and monitoring dry heat sterilization is a preparation of Bacillus subtilis spores Since dry heat is frequently employed to render glassware or containers free from pyrogens as well as viable microbes a pyrogen challenge where necessary should be an integral part of the validation program e g by inoculating one or more of the articles to be treated with 1000 or more USP Units of bacterial endotoxin The test with Limulus lysate could be used to demonstrate that the endotoxic substance has been inactivated to not more than 1 1000 of the original amount 3 log cycle reduction For the test to be valid both the original amount and after acceptable inactivation the remaining amount of endotoxin should be measured For additional information on the endotoxin assay see Bacterial Endotoxins Test 85 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 单位的细菌内毒素处理过的一种或更多物品 鲎试剂测试可以用 于证明内毒素物质已经活性丧失到不超过原来总量的 1 1000 降低了 3 log 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 内毒素 的残留量都应该测量 关于内毒素分析的更多信息 参见细菌内毒素测试 85 Gas Sterilization 气体灭菌法 The choice of gas sterilization as an alternative to heat is frequently made when the material to be sterilized cannot withstand the high temperatures obtained in the steam sterilization or dry heat sterilization processes The active agent generally employed in gaseous sterilization is ethylene oxide of acceptable sterilizing quality Among the disadvantages of this sterilizing agent are its highly flammable nature unless mixed with suitable inert gases its mutagenic properties and the possibility of toxic residues in treated