《致我们终将逝去的青春》中人物的矛盾形象分析

无菌制剂GMP实施指南-吹灌封-隔离技术章节 20. 吹-灌-封技术 【法规要求】 《药品生产质量管理规范》2010 修订版: 第五章 吹灌封技术 第十七条 吹塑、灌装、密封(简称吹灌封)设备是一台可连续操作，将热塑性材料吹制成容器并完成灌装和密封的全自动机器。 第十八条 用于生产非最终灭菌产品的吹灌封设备本身应装有 A 级空气风淋装置，人员着装应符合 A/B 级区的式样，该设备可安装在洁净度至少为 C 级的环境中。在静态条件下，此环 境的悬浮粒子和微生物均应达到标准，在动态条件下，此环境的微生物应达到标准。 用于生产最终灭菌产品的吹灌封设备至少应安装在 D 级环境中。 第十九条 因吹灌封技术的特殊性，应特别注意设备的设计和验证、在线清洁和在线灭菌的验证及结果的重现性、设备所处的洁净区环境、操作人员的培训和着装，以及设备关键区域 内的操作，包括灌装开始前设备的无菌装配。 欧盟 GMP 中对吹灌封技术的表述: 吹气/灌装/密封系统(简称吹/灌/封)是一套专用的机械设备，连续操作，从一个热塑 性颗粒吹制成容器至灌装和密封，整个过程由一台全自动机器完成。用于无菌生产的吹/灌/ 封设备本身装有 A 级风淋装置，在操作人员按 A/B 级区要求着装的条件下，该设备可安装 在洁净度至少为 C 级的环境中。在静态条件下，此环境微粒和微生物均应达到标准，在动 态条件下，此环境的微生物应达到标准。用于生产最终灭菌产品的吹/灌/封设备至少应安装 在 D 级环境中。 因此项技术的特殊性，应特别注意以下几个方面:设备的设计及设备的验证、在线清洗 和在线灭菌的验证及结果的重现性、设备所处的洁净区环境、操作人员的培训和着装，以及 设备关键区域的操作，包括灌装开始前设备的无菌装配。 FDA 无菌制剂生产质量规范附录 2 中对吹灌封技术的表述: 吹灌封三合一(BFS)技术是 由机器自动以单一的工序完成容器的整个吹塑、产品的灌 装和封口的连续过程。 BFS 装置所在环境的空气等级应该达到 100，000 等级(ISO8)或更高标准，这取决于 BFS 机器的设计和房间的环境。在无菌产品或无菌原料暴露的过程中(例如:形成塑坯、塑 坯成型或灌装)，应使用高效来过滤空气或由膜过滤的无菌空气。在关键区域的空气质量应 该达到 100 级的微生物标准(ISO 5)，一个设计良好的 BFS 系统通常应达到 100 等级(ISO 5)的微粒子水平。人员经过培训后，穿上相应的洁净服才能进入 BFS 装置的相应区域。 【背景介绍】 吹塑、灌装、密封(简称吹灌封)设备是一台可连续操作，将热塑性材料吹制成容器并 完成灌装和密封的全自动机器。 strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality 20. 吹-灌-封技无菌制剂G MP 实施指南 术 该技术为先进的无菌处理技术之一，图 20-1 是此技术的简单过程示意图: 图 20-1 吹灌封技术过程示意图 吹-灌-封(Blow-Fill-Seal，BFS)设备可全自动运行，缩短了停机时间。整台设备的运 行设计理念是尽可能少地使用操作人员，从而减少管理成本，提高设备运行的稳定性。每台 设备一般都将在线清洁(CIP)和在线灭菌(SIP)整合在系统中，大大增加了设备的生产工 作时间，提高了机器运行效率，从而直接为用户节约了生产成本，增大了收益。 【技术要求】 用于生产非最终灭菌产品的吹灌封设备本身应装有 A 级空气风淋装置，人员着装应符 合 A/B 级区的式样，该设备可安装在洁净度至少为 C 级的环境中。在静态条件下，此环境 的悬浮粒子和微生物均应达到标准，在动态条件下，此环境的微生物应达到标准。 用于生产最终灭菌产品的吹灌封设备至少应安装在 D 级环境中。 因吹灌封技术的特殊 性，应特别注意设备的设计和验证、在线清洁和在线灭菌的验证及 结果的重现性、设备所处的洁净区环境、操作人员的培训和着装，以及设备关键区域内的操作，包括灌装开始前设备的无菌装配。 20.1 工艺流程 【实施指导】 A. 药液配置 B. 采用吹瓶-灌装-封口三合一设备进行无菌灌装; 这是整个生产过程的关键，其过程是将聚乙烯(PE)小瓶的吹瓶、灌装、封口三个步 骤集中在一个操作过程中完成。整个过程是在无菌条件下，也就是在 B 级背景的 A 级洁净 区内完成的。 要点有: , 设备应具有洁净空气系统，洁净空气主要用于塑坯的支撑空气、瓶体，成型空气、 药 液灌装系统等。设备带有时间压力定量灌装系统，用来保证装量准确; , 塑坯壁厚应控制系统，保证瓶壁均匀; strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality , 真空系统，保证灌装管路剩余药液的吸除，密封性完好; 另外，设备自身应配备 0.2um 除菌过滤器、管坯的空气过滤器及无菌空间的空气过滤器、 设 备能实现 CIP/SIP。 图 20-2 洁净空气系统——无菌风的全过程保护 图 20-3 时间压力定量灌装系统，保证装量准确 strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality 20. 吹-灌-封技无菌制剂G MP 实施指南 术 图 20-4 无菌灌装空间 C. 容器的快速切断及分离; 灌装完毕的塑料容器从吹瓶-灌装-封口三合一设备送出时，组成塑料瓶带，连续不断地 被送出三合一设备，进入快速分离系统后，进入后面的传送带上。这一过程称为“快速切断 及分离”。 D. 成品的漏液测试; 随后，成排的小瓶通过传送带的输送，进入检漏机，由检漏机对其进行是否存有泄漏部 位的完整性检测。 E. 贴签包装 没有明显的特殊要求，参见15.3 半成品的灯检、贴签和包装。 20.2 设备设计和气体质量 20.2.1 设备设计 【背景介绍】 吹灌封技术是在无菌状态下完成塑料容器的整个吹塑、灌装、封口过程，所以对设备的 要求较高。 设备一般包含以下几部分: , 液压系统:主要用于设备运行的驱动，例如主模具机构从挤出位置到灌装位置的传 送，主模具和头部成型模具的闭合和打开，尾部拉废料装置的提升和下降等机械运 动 , 气动系统(可分为子系统): : 通用空气系统:主要用于进行气缸、阀门的运作; strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality : 洁净空气系统:空气采用了无菌过滤，主要用于塑坯的支撑空气、瓶体成型空 气、药液灌装系统的空气 : 真空系统:用于瓶体成型和灌装管路剩余液滴的吸除; : 芯轴升降控制系统:采用了直线式电动机控制，避免了采用液压件出现的液压 渗漏危险 : 塑坯壁厚控制系统 : 模具机构 : 塑坯挤出系统 : 药液灌装定量系统:采用了药液的无菌过滤 : 在线灭菌 SIP 和在线清洗 CIP 系统 : 控制系统 另外，设备在注意无菌性的同时，应能满足产品的单 位重量差异要求。 【实施指导】 大多数 BFS 设备按以下步骤进行操作: , 加热塑料粒子 , 将其挤压形成塑坯(管形热树脂); , 高温切割塑坯; , 将塑坯传送到吹塑-灌装针下; , 用模具使塑坯成型; , 在成型的塑瓶中灌装液体药物; , 移开灌装针; , 封口。 在整个操作过程中，使用的均为无菌空气。在大多数操作中，切割塑坯、将塑坯传送到 灌装针下、灌装前针的移开这三个过程极有可能将塑坯暴露在空气，从而引入微粒子的污染。 BFS 机械装置和它周围的隔离装置可以防止可能的外源性污染。无菌操作过程的关键在 于产品表面应该是无菌的。使用经过验证的 SIP 系统或其它类似系统，来对管路进行灭菌。 对产品无菌有污染风险的其它部位，都应进行灭菌处理。 20.2.2 气体质量 【技术要求】 气体质量洁净度和各级别洁净度须符合下表要求。 表 20-1.各级别空气悬浮粒子的标准 悬浮粒子最大允许数/立方米 洁净度级 strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality 20. 吹-灌-封技无菌制剂G MP 实施指南 术 别静态 动态 ?0.5μm ?5μm ?0.5μm ?5μm A 级 3520 20 3520 20 B 级 3520 29 352000 2900 C 级 352000 2900 3520000 29000 D 级 不作规定 不作规定 3520000 29000 表 20-2. 各级微生物监测的动态标准 表面微生物 沉降菌( 90mm) 浮游菌 级 别 接触碟( 55mm) 5 指手套 cfu /4 小时 cfu/m3 cfu /碟 cfu /手套 A 级 1 1 1 1 B 级 10 5 5 5 C 级 , 100 50 25 D 级 , 200 100 50 【实施指导】 BFS 设备设计时，需要考虑预防周围可以减少与产品相接触表面微粒的装置。同非药品 生产相比，使用 BFS 装置生产无菌药品时，空气质量(如:微粒子)在该过程中起关键作 用，我们应该严格控制在塑坯挤出过程和封口过程中产生的微粒子。精确地控制空气流速不 仅能将生产过程中产生微粒有效排出，而且还阻止了周围环境中微粒子的引入。此外，将灌 装部分从周围环境阻隔的设计能有效的保护产品。研究表明，阻隔装置、负压保护、局部环 境和高速流动的无菌空气能有效防止产品污染。 除了合理的设计，建立一个适当的预防维护程序非常重要。例如，为了减少无菌药品的 污染， 需要对 BFS 装置中的的冷却、加热和其它系统进行日常维护和监测。 20. 3 验证和确认 【背景介绍】 因吹灌封技术的特殊性，应特别注意设备的设计和验证、在线清洁和在线灭菌的验证及 结果的重现性、设备所处的洁净区环境、操作人员的培训着装，以及设备关键区域内的操作， 包括灌装开始前设备的无菌装配。 【实施指导】 A. 环境监控和验证 对吹灌封技术的应用首先是环境的监控和验证，具体参见 18 环境监控。 strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality B. 人员验证 进入人员的要求:应当用头罩将头发以及胡须等相关部位全部遮盖住，头罩应塞进衣领 内，应戴口罩以防散发液滴。应戴经灭菌且未上滑石粉的橡胶或塑料手套，穿经灭菌或消毒 的脚套，裤管应当塞进脚套内，袖口应塞进手套内。同时，着装应不脱落纤维或粒子，并能 滞留身体散发的粒子。 人员能显著影响生产无菌产品所处环境的质量。应建立可以及时监控的和反馈的人员监 测计划。正常生产时，应每天监控生产操作人员手套上、以及其它重要部位的的表面微生物。 C. 设备验证 相应设备应灭菌后进行无菌性验证，同时对聚合物挤压成型、塑料产品相容性、成型、 单位重量差异、CIP、SIP 等重点项目，均应进行控制和验证。 根据 EU-GMP 指导中的关于仪器 IQ/OQ、PQ 要求如下: IQ 验证至少应该包括:设备及管路的安装，并检查设备、收集并整理仪器操作说明和 维护要求、校正仪器/确认部件清单、确认部件标示、确认与产品接触的表面是否光滑、确 认物质的特殊性、检查各部件技术性的文件、确认仪器的校准等，同时还应该根据设备 所置的具体环境增加验证项目。 OQ 包括:设备系统、运行过程的测试;苛刻工作环境下仪器运行的测试。 PQ 包括:用生产原辅料、合格的替代品或模拟产品来测试仪器、最差条件下的 CIP(3 次)、用微生物指示剂进行 SIP(3 次)、最差条件下的培养基灌装试验。 D. 容器的密封性验证 通过物理性测试和微生物挑战试验，来确认容器的密封性能是否良好。 容器密封性验证 常采用物理和微生物学检测手段。物理检测有许多优点，如灵敏度较高、 使用方便、检测迅速及低成本等。在产品有效期内，均可使用物理检测方法来确定包装完整性是否符合规定要求。进行包装完整性检测的一个重要原因是确保无菌产品始终保持无菌状 态。因此，在产品包装的研发阶段，应考虑采用微生物侵入试验，或采用经验证过的并且比 微生物检测更为有效的物理试验方法，来检测产品包装的完整性。但是，对效期内产品的稳 定性试验来说，因进行微生物侵入试验较为困难，故建议采用物理检测方法。微生物侵入试 验是对最终灭菌容器,密封系统完好性的挑战性试验。在验证试验中，在瓶中灌装入培养基， 然后，将容器密封面浸入高浓度运动性菌液中，取出、培养并检查是否有微生物侵入，确认 容器密封系统的完好性。同时，需作阳性对照试验，确认培养基的促菌生长能力。 20.4 批监测和控制 【实施指导】 生产过程中应对关键工艺进行监控(比如容器重量、灌装量、渗漏、气压等)。微生物 状况作为关键项目必须要监控，微粒的连续监控对吹-灌装-密封生产至关重要。取样应该具 有代表性。 strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality 20. 吹-灌-封技无菌制剂G MP 实施指南 术 容器密闭系统缺陷可能是 BFS 操作控制中的主要难题。样品检查技术必须可靠、灵敏， 对最终产品必须检验。 对于加热或机械问题引起的明显缺陷应进行调查。比如:容器的壁厚、容器或密闭系统 表 面缺陷、形成不良的密闭系统或其他缺陷。 strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality 21.隔离技术 本章将探讨以下问题: , 隔离器在设计应用时需考虑哪些方面, , 采用隔离器进行无菌生产，用户需从哪些角度考虑问题, , 隔离器的空气处理系统有没有什么特殊的要求, , 怎样对隔离器进行环境监测，环境监测结果的接受标准是什么, , 隔离器的验证需要考虑哪些问题, , 怎样对隔离器的无菌状态进行评价, 随着隔离系统在世界范围内的普及使用，隔离系统开始逐步代替传统的无菌洁净室成为一种发展趋势。例如，在一台经过正确验证的运行正常的隔离器中产生假阳性的试验结果的 概率是很低的，因此，隔离技术保证了试验结果的准确性，确保了药品生产时的无菌性。然 而作为一种新型的洁净系统，隔离系统的设计应用、验证和维护与普通的无菌洁净室相比有 一定的差异，因此该章节介绍隔离系统技术应用及验证技术方面的具体内容。 21.1 隔离技术的要求及应用 【法规要求】 《药品生产质量管理规范》2010 修订版: 附录 1:无菌药品 第十四条 采用隔离操作技术能最大限度降低操作人员的影响，并大大降低无菌生产中环境对产品微生物污染的风险。高污染风险的操作宜在隔离器中完成。隔离操作器及其所处环境 的设计，应能保证相应区域空气的质量达到设定标准。传输装置可设计成单门或双门、甚至 可以是同灭菌设备相连的全密封系统。 物品进出隔离操作器应特别注意防止污染。 隔离操作器所处环境的级别取决于其设计及应用。无菌生产的隔离操作器所处环境的级别至 少应为 D 级。 【背景介绍】 隔离系统的在药品制造业目前已经开始广泛应用，隔离系统代表了药品制造业生产的快 速发展技术，但是国内在这块领域工作中很少有技术指导。在“隔离时代”的开始阶段，隔 离系统总被认为仅仅是小型的洁净室，但经验告诉科学者和工程师们，隔离系统的功能需求 实际上根本不同于“传统的”洁净室。本节将介绍隔离技术的要求应用以及采用隔离技术进 行无菌生产的用户需求标准的具体要求。 strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality 21.隔离技术 无菌制剂G MP 实施指南 【技术要求】 应当设计合适的隔离器防止与周围环境发生交叉污染。 隔离器的设计及应用取决于隔 离器使用的性质，根据使用特性，设计隔离器的气流、压 差、构造材料、环境、类型等等。 在一般隔离器工艺应用中，需根据使用特性和需求制定用户需求标准(URS)，目的是 可靠地生产明确的产品，所有的 URS，都应在项目进程中被清晰地定义和及时归档。 URS 应作为控制文件，与其它 GMP 文件一样的方式批准。 【实施指导】 A. 洁净室的类型及特征(见图 21-1) (1)开放式洁净室(见图 21-2) , 背景房间 B 级，该环境允许操作人员进入。 , 关键区域为 A 级，无菌核心区域，操作人员需根据已定义的 SOP 从 B 级背景环境 打开设备，进行工艺操作和干预，这些动作高度依赖操作人员洁净服。 , 生物去污染方法为表面局部消毒或者某些情况下进行房间熏蒸(较少采用) , 操作者与无菌工艺核心需避免接触，例如通过聚碳酸酯门、屏风或垂帘等。 30 年前使用的开放式洁净室今天面临很多压力，例如胶塞料斗和胶塞振荡锅无灭菌操 作，在传动部件(例加胶塞机)运行和更换配件和部件等(如胶塞)时需要保持持续的 A 级环境，这些均是非常挑战的问题。 图 21-1 无菌完整性图谱 图 21-2 开放式洁净室原理 (2)“RABS” (Restricted Access Barrier System)限制进出隔离系统(见图21-3 ) , 背景房间 B 级，该环境允许操作人员进入。 , 关键区域为 A 级，无菌核心区域，操作者通过手套箱进行操作，密封的部件在背 景为 B 级的环境下处理。 strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality , 生物去污染方法与开放房间相同，表面局部消毒，某些情况下进行房间熏蒸(较少 采用)。 , 操作者与 A 级无菌核心工艺相隔离，具体方式如聚碳酸酯门，屏风带有手套箱和 部件传递口。 “RABS”限制进出隔离系统与传统的隔离装置不同的是，RABS 装置并不是完全密闭的， 而是一道由操作间正高压作用的空气力学屏障，它对无菌容器起保护作用。灌装的流通方向 为垂直单向流通，流通速度可以控制，使空气可以连续地循环和更新。通过两种技术的联合 使用，可以清除操作间里存在的颗粒物，预防来自外部的污染。在避免了完全密闭的同时， 持续的空气循环延长了无菌条件的时间，中间不必停工进行清除污染的作业。 无菌区的四周是屏障区，而屏障区也处在单向流通的控制之下。屏障区就像处在操作间 和车间其它地方之间的一个辅助的保护屏障，方便了机器的清洁和维护作业。 无菌操作期 间，在生产时只能通过在灌装机关键部位设的手套箱进入。本章对限制进出隔离系统不做详 细介绍。 (3)隔离器(见图 21-4) , 小的封闭空间，操作者不进入。关键工艺核心区(A 级)位于 D 级背景环境下。 , 操作者只在停产期间打开设备。人通过手套箱进行操作。 , 生物去污染方式为隔离器内部表面局部消毒，或者更经常地在隔离器内部进行喷雾 或蒸汽消毒。 , 操作者与无菌工艺核心相互隔离，隔离方式为通过隔离罩、隔离窗、隔离手套箱或 者 部件传递口。 由于人是无菌生产过程中最大的污染源，隔离器技术是将人与生产工艺完全分离开的一 A 级，背景环境可以在 D 级区的环境下。 种方法，并且隔离器不需要在 图 21-3 RABS 原理 图 21-4 隔离器原理 B. 隔离器的类型 (1)封闭式隔离器 strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality 21.隔离技术 无菌制剂G MP 实施指南 封闭式隔离器运行时，与周围环境换气必须通过高效过滤器。封闭式隔离器有两种类型:无菌用途和生物安全式。无菌用途的隔离器是将污染排除在隔离器外，生物安全式隔离器是 防止隔离器内有毒物料释放到隔离器外。类型及要求见图 21-5 所示。 ?无菌用途的隔离器 设备通常在正压下运行，在使用前需按规程有效地进行去污染。一般用 于处理无菌物料 的隔离器需遵循以下原则: , 在隔离器内所有工作和物料的处理必须远程控制完成，在运行时不能有人员或身体 部位直接进入隔离器的操作。 , 所有进入隔离器的物料必须被去污染或灭菌，并且必须直接经过去污染或灭菌系统 进入，或经过快速转移舱进入。 , 去污染方式必须是可重复和可量化的。 ?生物安全式隔离器 设备通常在负压下运行，在敞开前需清除所有潜在的有害物料。生物安 全式隔离器应用 需遵循以下原则: , 在隔离器内所有工作和物料的处理必须远程控制完成，在运行时不能有人员或身体 部位直接进入隔离器的操作。 , 隔离器中的所有物料必须被清洁，或按相关流程保证有害物不被释放到周围环境中 去。 , 清洁方式必须是以可重复和量化的。 ?兼有无菌用途的和生物安全式功能的封闭式隔离器 通常在正压下运行，有额外的安全措施 例如负压锁。在人员操作附近，需考虑附加的人 员保护设备。 strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality 图 21-5 隔离器类型及要求 (2)敞开式隔离器 敞开式隔离器不同于封闭式隔离器，在设备运行时，物料的进出是连续的或 是半连续的， 因此需维持高于内部环境一个级别的保护。敞开式隔离器不与周围环境交换未过滤的空气，敞开式隔离器在封闭时去污染，然后在生产时开启。 ?无菌用途的隔离器 除了在生产过程中存在的开口外，敞开式隔离器和以上封闭式隔离器满 足同样的总则。 需设计容器部件的进出，防止来自周围环境的污染。 ?兼有无菌用途的和生物安全式功能的敞开隔离器 这些隔离器和普通的敞开式隔离器以及 生物安全式隔离器相似，需设计清洁程序，确保 有毒污染在离开隔离器之前被去除。为了保持内部环境的无菌性，设计应预防空气的进入。 C. 隔离器的构造材料 隔离器可以用任何合适的材料制造，只要使得隔离器满足它的功能需要，并且材料要充 分结实以抵抗刺穿或损坏以确保系统完整性。一般而言，隔离器的外部结构被称为“柔性墙” (flexible wall，见图 21-6)或“刚性墙”( rigid wall，见图 21-7)。用于生物安全用途的隔离 器通常是刚性墙结构，因为这些系统要考虑到较强的表面清洁。常用的构造材料聚氯乙烯 (PVC)用于柔性墙，不锈钢用于刚性墙。 strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality 21.隔离技术 无菌制剂G MP 实施指南 图 21-6 柔性墙 图 21-7 刚性墙 D. 物料传递 隔离器的优点之一是可以直接和传递式灭菌器相连，这样可以在灭菌结束后直接向隔离 系统内传递物料，例如无菌培养基、无菌稀释液和无菌试验器具等，可避免实验用品外表面 的再污染;隔离器也可以和一种带有特殊设计的双门快速传递口(RTPs—Rapid Transfer Ports)的物料容器(物料舱)相连(DPTE—Double Port de Transfer Etanche)。双门快速传 递口中双门之间的非无菌表面设计成可连锁的垫圈或法兰连接，在对接时垫圈组件之间受挤 压 连形成了气封，将非无菌表面封从而阻止微生物的侵入。应引起注意的是但是当双门的法兰 接成一个气封阀时，垫圈有一道狭窄的箍会保留下来而可能有菌。在连接完成后的传递物 料前，应用杀孢子试剂立即处理连接后尚暴露的垫圈部分。传递物料时需要有熟练的无菌技 术，并且注意不要让物料或带手套的手接触垫圈。 一般情况下，使用者应根据快速传递口(RTPs)生产厂商的建议，对装在法兰上的垫 圈组件进行预防性维护和添加润滑油;并根据供应商推荐的频率更换和定期检查 RTP 的垫 圈是否损坏，因为断裂和磨损的垫圈不能实现完全气封。 在隔离器中，一般情况下，物料在隔离器间的传递是通过双门快速传递口进行的(具体 操作见图 21-8)，而物料在隔离器系统与外界环境之间的传递则是通过物料进出口来完成 的(具体操作见图 21-9)，当隔离器灭菌和保持无菌状态时，该进出口必须处于密封状态。 strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality 图 21-8 隔离器的 DPTE 系统 图 21-9 隔离器的 RTPs 系统 E. 空气处理系统 以无菌试验用隔离器为例，用于无菌试验的隔离器装有截菌过滤器(要求为 HEPA 高 效过滤器)。静态时，隔离器符合 ISO14644 中确定的 A 级洁净室空气悬浮粒子的要求，参 见 18.2 洁净区级别的划分。然而，隔离器在动态时无需达到A 级的条件，对空气流速或换 气率也无要求。尽管隔离系统是防泄漏的，但它仍需与周围环境进行气体交换，当存在直接 与外界环境相通的开口时，隔离器内的无菌状态是通过保持对外界持续的空气正压来维持 的。用于无菌试验的隔离器的气流既可为单向流，也可为乱流。 strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality 21.隔离技术 无菌制剂G MP 实施指南 压差是用来维持环境间的独立，以防止和其它环境发生交叉污染。敞开式隔离器，需要评估在使用过程中维持压差的能力，通常隔离器的压差设计不超过 100Pa。隔离器内部和外 部的压差应被连续监测，并应设计有警报装置(见图 21-10、11)。可以使用后备电池和紧 急发电器来维持关键区域的压差。 图 21-10 隔离器的压力警报装置 图 21-11 隔离器的监控装 置 F. 背景环 境 对于隔离器的背景环境，在新版中国 GMP 中，用于无菌生产的隔离器应被安置在 D 级 环境中，但没有明确规定用于无菌试验隔离器的背景环境的洁净要求，一般建议使用和无菌 生产同等的背景环境。 G. 隔离器的操作方 式 隔离器是用于防止密闭的工作环境和周围人员存在的背景环境间的交叉污染，因此在隔 离器内的物料处理必须经过手套、套装或自动操作。隔离器基本系统的设计应尽量使用自动 化操作来减少隔离器操作;当人员操作不可避免，需进行系统评估并谨慎执行;设备应被设 计在不破坏隔离器环境就能发现故障，并能进行应急维修以及进行常规检查维修。 (1)手套(见图 21-12) 在手套材料的设计中应该考虑使用的频率，以及化学耐受性。普遍 使用的材料包括氯丁 二烯橡胶和 Hypalon 橡胶。很多溶剂及其蒸汽对手套有化学腐蚀性。手套应定期进行更换， 手套应在使用前和使用中都经常进行检查。 (2)套装或半套装(见图 21-13) 一些隔离器使用中采用套装或半套装，这种方式相比手 套/袖子，在隔离器内有更广泛 的活动空间。大部分半套装都是安装在水平的或是略有倾斜的，并且与隔离器整合在一起的 金属板上。 半套装是典型绝缘结构，因此经空气的调节可在套装层间进行控制，在设计中应考虑合 适的温度和舒适度。半套装与手套有很多相同的特征，包括弹性塑料材料固有的弱点。操作 者在半套装内可以戴常规的防护用品(比如呼吸器，一种独立的吸气装置或其它装置)。由 于操作者可以较快地进出半套装，他们可以只在关键步骤穿上这种额外保护装置。全套装也 是strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality 尽量将用脐带装置供应空气给操作者。 strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality 21.隔离技术 无菌制剂G MP 实施指南 图 21-12 手套型操作方式 图 21-13 套装型操作方式 H. 设施要求 在设施方面没有强制新的或额外的要求，但需设计防止出现污染。 过滤器使用点应和 压缩空气或惰性气体一起使用，阀门和控制仪表的连接应没有清洁死 角。隔离器的设备连接点需是密封的，并且所有密封件和垫圈需经过检查确保无泄漏和磨损。 一般使用的 6-D 直径的卫生管道对隔离器系统来说是不够的，隔离器使用的某些气体 或蒸汽去污染方法不能完全到达管道死角，除非有其他方法帮助气体分配。如果气体/蒸汽 穿透不能被去污染、定期灭菌，应采用其他替代方法。 某些隔离器会附有真空系统以便于清洁或其它目的，如果附有真空来源，应考虑预防出 现回流导致系统污染。 strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality 【实例分析】 A. 采用隔离器进行无菌生产的用户需求标准(URS) (1)无菌性保证 隔离器作为无菌产品的生产和试验，是因为它被认为是可以提高产品或过程 的无菌性保 证，因此无菌性保证是隔离器的常规 URS 的最重要的一条。隔离器是通过将关键区域和操 作人员隔离开，通过微生物截流过滤器过滤进来的空气，通过隔离器、过程设备和物料的去 污染和灭菌来维持一个无菌的环境。 图 21-14 隔离器进行无菌生产的工艺流程 ?1 产品物料、成分、容器和设备的灭菌 和传统洁净室的无菌装置要求一致，液体产品通常是 通过过滤来去污染的，产品及物料 准备采用蒸汽、干热、辐照和气体灭菌。对于这些灭菌方法的研发、验证和使用，读者可参考行业指南。 2 ?产品传送管的灭菌 -6 产品传送管，就像所有和产品接触的设备一样，应被灭菌至 10的灭菌量。隔离器内管 路和设备的灭菌通常使用湿热灭菌，并且必须考虑热分布和冷点。另外，使用时必须考虑管 路和仪器的灭菌以及系统的产热，不影响隔离器的完整性。 3 ?不和产品接触的设备的去污染 隔离器及其内容物(如管道系统)在去污染后，隔离器将一 直处于运行状态中，直到维 修时隔离器内的无菌环境被破坏。因此在运行时，隔离器相比于去污染规程，更依赖于空气过滤器系统以及罩子(特别是手套，袖子等)的完整性。应考虑以下因素: , 气体/蒸汽去污染过程只在某一时间点内进行，并不是定义整个运行过程。 , 很多隔离器包含可动部分和保护区域，在去污染中很难去处理。在如此受限制的通 strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality 21.隔离技术 无菌制剂G MP 实施指南 道区域来接触产品的可能性是很小的。更重要的是，因为隔离器是干燥的环境，没 有有机原料，细胞在隔离器内存活的能力是受到限制的，即时有可能存活，也不可 能 在没有营养支持下增殖生长。 , 气体/蒸汽接触时间和浓度通常是在去污染效力和物料相容性之间取得平衡的。过 长的接触时间可能导致更大的问题，因为会增加软性部位的脆碎性和减少它们的使 用寿命。 4 ?包装好的物品或含无菌物料的容器表面的去污染 在很多隔离器使用中，多层包装的无菌 物料会被传递进隔离器或隔离器系统，在很多情 况下，其容器会是双层或是三层包装。可以采用辐照灭菌或紫外灯系统的方式在传递过程对塑料包装进行去污染。 去污染测试的目的是消除物料包装最外层或容器表面的任何微生物污染水平。外包装和 容器是不和产品接触的，且在传递过程中，因此不需要达到灭菌级别。 另外，还必须考虑到应用于在隔离器中的包装物品和容器的去污染的残留浓度:气体/ 蒸汽的残余浓度必须用通气来达到安全水平，一般这个范围在 1ppm 或低于 1ppm(去污染 八小时以上的平均值)。 5 ?去污染方法 隔离器去污染使用的气体/蒸汽包括过氧化氢，臭氧，过氧乙酸和二氧化氯。 用户应该 证明去污染剂流通状态良好，在灭菌中达到有效的充分均一的杀灭浓度，来保证作用到所有表面。任何符合之前推荐的方法都适用于隔离器的灭菌。 使用每立方米内放置 5-10 个生物指示剂，对只包含操作设备的隔离器来说通常足够了。 生物指示剂应该被很好地分布在隔离器表面，以便充分均匀地接触气体。生物指示剂应当下 降至少三个 log 值。 (2)密封性 1 ?封闭 封闭的关键问题是保护操作者免受毒性或活性物料的伤害。这在隔离器内通过手套和 半 套装的使用、泄漏的控制、隔离器的清洁和内外部压差的维持来完成。 2 ?隔离器清洁 隔离器的清洁可通过适当的隔离器设计来提高。考虑的方面包括:清洁是手动 完成还是 自动完成;不和产品接触的表面是否要清洁，以及清洁到什么程度;在清洁过程中如何保护 过滤器;如何更换可能污染的过滤器;如何清洁非一次性物件;以及清洁不和产品接触的表 面。在设计隔离器的清洁能力时，普通设计点包括: , 可用清洁剂的光滑表面 , 在各低点的带排水管的倾斜地面 , 没有平坦的凸起和表面 , 尽少使用易吸收的物料 , 有保护过滤器的设计 strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality , 容易进入所有要清洁的场所 , 在不暴露的情况下可以检查内表面的清洁度 在生物安全式隔离器使用中，与无菌用途的隔离器相比，在系统使用上关键过程方面是 不同的。例如，在生物安全式隔离器中，关键步骤是隔离器的运行、之后的清洁;而在无菌 用途的隔离器中，更强调的是系统使用前的去污染。以下描述的是隔离器的使用与隔离器的 去污染和清洁之间的关系: , 无菌用途的:准备(预清洁)，去污染，使用，清洁 , 生物安全式:准备(预清洁)，使用，清洁 , 无菌和生物安全式:准备(预清洁)，去污染，使用，清洁 3 ?无菌的细胞毒素物料 隔离器广泛应用在无菌的、对操作者有重大风险的物料生产中，例如 细胞毒素药物，激 素和放射性物料的生产。在这些情况中，必须进行合适的设计和指定相应的运行要求。建议在正压下运行隔离器，并且为操作者提供额外的保护设施(如加固的手套等形式)。 这些系统相比对操作人员无毒性的隔离器，泄漏结果更应该被关注。应该评估终端使用 者的安全和隔离器运行的安全，并放置合适的安全装置。例如在关键步骤使用人员保护设施; 通过使用自动化降低人工干预的次数;设计报警装置，防故障装置和后备能源补充装置。 (3)环境控制 隔离器无菌操作的环境必须控制在较高水平，才能维持一个无菌环境。可考虑以下几个规程: 1 ?无菌处理 隔离器技术提供一个较安全的环境，但容易导致用户对细节的不注意和无菌处理步骤执 行的不谨慎。用户绝不能忽视以下事实:操作者将继续很多在隔离器内部的操作(整个隔离 器内部都是关键区域)。如损坏的手套接触了无菌的表面，手套上的洞或缝隙会破坏无菌性。 隔离器技术使用者应认识到，任何时候人员在隔离器内必须有良好的无菌操作技术。尽 管手套表面和操作设施的所有其它表面在隔离器去污染中被处理过，但达不到无菌水平，因 此仍需要进行最大限度控制。在良好的无菌技术中，非无菌表面必须永远不会与无菌物品进 行直接接触，而且必须不得通过气流移动到无菌区域(产品和容器，盖子或暴露的无菌部件)。 基本上，所有用手套/袖子或手套/袖子/半套装系统的操作，都必须以在任何时候本质上和传 统洁净室相同的方式来进行。 2 ?空气处理系统 污染可以通过空气处理系统进入隔离器，因此空气处理系统必须被设计为带 有合适的防 故障装置，例如，不间断电源供应，紧急发电器，后备电池和失灵安全阀。 3 ?环境的物理监测 实时监测无菌环境的质量是不可能的，而且用户不应该只依靠环境监测的 结果来确保隔 离器的无菌性。但是可以通过物理监测来发现问题，比如设计空气处理系统失控的情况下立 即提供报警信息。考虑到异常情况的即时检测，物理监测相比活性监测在隔离器设置中会是 更有用的。 strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality 21.隔离技术 无菌制剂G MP 实施指南 (4)泄漏测试 不管是在无菌生产还是试验中，任何隔离器操作中需重要评估手套、袖子和半套装的泄 漏。最好的以及最明确的方法是通过频繁的测试保证这些设施的完整性。压力保持测试和较 灵敏的气体检漏测试，可以给用户提供关于这些组件和完整性的重要信息。泄漏测试应在活 动中进行，不管隔离器室清洁的还是去污染过的。根据手套的使用数量，手套的泄漏测试甚 至可以更为频繁一点。如果用户要用手套来进行重型操作会导致磨损、穿刺或变形，应考虑 进行更频繁的泄漏测试和手套更换。用户也必须注意灭菌试剂对手套和其它组件的影响。一 些灭菌试剂能导致手套变脆及容易破裂。 (5)监测系统 隔离器应被测量、控制和设计报警装置来保证足够的开口处向外气流，能源供 应以及温 度和湿度。 (6)环境的微生物监测 微生物监测是确认无菌操作隔离器在去污染周期中维持无菌环境的 能力。尽管它是一个 非常有用的工具，但监测还是有较大的限制，它不能提供环境控制的即时信息，必须在 2 至 5 天后才能知道结果。 很多微生物监测式要求将培养基带入隔离器。虽然培养基可被安全带入隔离器，但是应 该要谨慎操作，并且有足够的规程来防止促生长培养基的残留。 微生物监测常由三个或四个不同但相关的活动组成。以下监测类型会在隔离器中使用: 1 ?主动空气取样 主动空气取样应以不破坏气流的方式来进行，并且要求最少的处理步骤以避 免假阳性的 产生。 2被动空气取样 取样器由螺旋盖瓶、容器中的液体培养基或传统的沉降碟组成。这些取样有? 允许 2-4 小 时的长时间的暴露(含液体培养基的沉降瓶可比固体琼脂暴露更长时间)，然而，它们与主动空气取样灵敏度相似。沉降碟和沉降瓶为不破坏使用中的隔离器的内部环境提供了充实的 有利条件。 3 ?表面取样 表面取样可采用接触碟或擦拭法，但这两种方式都会留下残留，这两种方式的灵 敏度都 有局限。表面监测不应对生产线带来干扰，如果必须对关键表面或和产品接触的表面进行检 测，该检测应在生产结束后进行。 4 ?手套检测 手套可通过手指擦拭法来进行检测，这种方式的灵敏度不高，并且该方法存在物 质残留 的风险。手指擦拭应在隔离器的清洁和再次去污染之前进行，所有培养基残留必须被清除， 而且必须在手套上使用消毒剂以抑制微生物的生长。可以采用手套定期监测完整性测试的方 法，这将更好地来检测手套表面的微生物。 5 ?培养基选择 strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality 常规的广谱微生物生长培养基如 TSB，TSA 等。必须证明含培养基的取样设施被传递到隔离器中，且不影响培养基促生长的能力。没有经过去污染消毒的培养基不得进入隔离器， 而且培养基和取样设备的传递必须根据验证过的步骤来操作。 6 ?特殊取样 一般不需要对特殊类型的微生物(“厌氧菌”)进行取样，除非隔离器内的条件 利于特 殊微生物的生长。 7 ?可接受标准 不论什么什么类型的检测方式，结果均为无污 染检出。 8 ?过程模拟 应做一系列恰当的模拟试验来验证生产型隔离器的操作。通常包含传统培养基灌装测试 模拟最终灭菌产品的生产过程。 隔离器的过程模拟试验或培养基灌装试验的 URS 是:不论灌装量的数量为多少，污染 率必须为零。 B. 隔离器的清洁 目的及要求: 隔离器的清洁需要考虑可能造成的污染，隔离器的清洁应该有序地进行以最大 限度地减少污染的释放。 清洁顺序(示例): , 将所有产品物料和一次性物品保存在封闭容器中 , 清洁操作设备，将任何要清洁的部件保存在容器中 , 在隔离器关闭状态下清洁隔离器内表面和容器外表面 , 将容器移走 , 额外的内部清洁 , 重新安装已清洁的设备和部件 【要点备忘】 在隔离器的设计应用中可以考虑以下问题: , 隔离技术洁净室的类型和特征有哪些, , 怎样选择隔离器的类型，不同类型隔离器的应用要求是什么, , 隔离器的构造材料应采用什么样的, , 隔离器的传递口的设计有哪些，具体要求是什么, , 隔离器应采用何种空气处理系统, , 隔离器的背景环境的洁净等级应该是什么要求, , 隔离器有哪些操作方式，分别有哪些特性, , 隔离器有没有其它的设施要求, strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality 21.隔离技术 无菌制剂G MP 实施指南 采用隔离器进行无菌生产的用户需求标准可以考虑以下问题: , 隔离器从哪几点考虑无菌性, , 隔离器的密封性包括那些要求, , 隔离器需进行哪些环境控制, , 隔离器的泄漏测试要点是什么, , 隔离器的监测系统是什么, , 隔离器环境的微生物监测有哪些要点, 21.2 隔离系统的验证 【法规要求】 《药品生产质量管理规范》2010 修订版: 附录 1:无菌药品 第十五条 隔离操作器只有经过适当的验证后方可投入使用。验证时应当考虑隔离技术的所有关键因素，如隔离系统内部和外部所处环境的空气质量、隔离操作器的消毒、传递操作以 及隔离系统的完整性。 【背景介绍】 无菌生产或试验是批产品放行程序的一部分，隔离系统用于无菌生产和试验之前必须得 到验证。目前，美、欧药典的无菌检查法均已收载隔离系统及其验证方法，中国药典 2005 年版无菌检查法也已经收载了无菌隔离系统。本节介绍隔离器验证方面的内容。 【技术要求】 确认隔离系统以及所有相关设备适用于无菌试验的验证分三个阶段进行:安装确认 (IQ)，运行确认(OQ)和性能确认(PQ)。 对用于无菌试验的隔离系统进行验证时所需 考虑的内容，验证时进行的性能测试归结为 哪个验证阶段(如 IQ，OQ 或 PQ)本身并不重要，只要这些测试能证明隔离器在用于产品 分析前，其性能已得到验证并且有文件记录。 【实施指导】 A. 安装确认(IQ) 安装确认的结果总结在安装确认报告中。以下详细列出安装确认过程中需要检查的项目: , 合同和相关文件——检查购买合同和相关文件，确认设备和合同上签订的条款一致 , 供应商提供的文件--检查供应商提供的文件，并把它们详细记录下来，编号后妥善 保存以便日后查阅; strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality , 构造材料--检查关键系统部件的构造材料与设计要求是否一致，核实要用的灭菌方 法和构造材料的兼容性; , 内部结构--据供应商提供的设备图纸，检查设备的尺寸和内部结构是否和图纸上的 一致，内部结构完全能够适应以后将要进行的工作 , 装的介质, 包括电源和压缩空气--根据操作手册、程序及仪器图解中的说明，检查 系统运行所需的公用介质是否完备，是否与设计要求一致。检查公用系统与隔离系 统的所有连接，如灭菌器与压缩空气之间的连接、隔离器舱体和灭菌气体管道之间 的连接，以及隔离器舱体和通风管道之间的连接等等都已正确连接并确认这些连接 符合要求。电源和压缩空气均应按要求供给。 , 零配件--检查零配件的数量和种类。 , 过滤器确认-- 过滤器包括高效过滤器和其它除菌滤器两个部份，如:前过滤器， 对高效过滤器和其它除菌过滤器均应经过测试，确认其性能符合要求，测试结果和 证书的复印件应包括在安装确认的总结中。同时还要核实空气过滤系统的性能符合 要求。 , 隔离器体，袖子和手套(或半身操作服)以及更换检查隔离器体，袖子和手套是否 有 可见破损，袖子和手套(或半身操作服)是否能按要求更换; , 电脑软件--列出所有与隔离系统相关的电脑软件的名称、数量和版本号。原版的电 脑磁盘应妥善标记并安全保存。 B. 运行确认(OQ) 该阶段主要包括以下几个部份: (1)悬浮粒子水平测试 该测试的目的在于检查隔离器内的悬浮粒子水平。一般仅在静态下 进行悬浮粒子计数。 测试点和取样体积可根据供应商的建议或洁净室的相关标准确定，但结果应符合静态 100 级区的要求。 (2)性能检查 该检查的目的在于确认提醒和警报功能符合其性能要求。确认系统运行能够遵 从所有设 定值和可调参数。方法一般为在报警设置点增加或降低参数值使其高于或低于报警设置点的上限或下限以检查报警器是否能报警。 (3)隔离器的完整性测试 (隔离器体和手套) 该测试的目的在于确认隔离器在日常运行中能维持其完整性。以确保隔离器在使用灭菌 化学试剂时的安全性。隔离器完整性包括隔离器舱体和手套或半身操作服的完整性。测试原 理一般都是通过测试系统的泄漏性来反映完整性。其中一个简单易行的方法就是压力下降试 验。该方法是预先在隔离器系统中保持一定的压力，然后快速关闭系统中所有的进气口与出 气口，包括隔离器自身的空气处理系统也应关闭，让该状态持续一段时间，如 10 分钟，假 如隔离器系统完整性完好，在这特定时间内，压力下降值应在一定的要求范围内(如:16Pa); strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality 21.隔离技术 无菌制剂G MP 实施指南 反之，则不符合规定。该试验简单易行并且灵敏度高，但是它只能反映出隔离系统完整性是否有破损，却不能指示破损处的具体位置，因此还应辅助以其它的测试以进一步确定破损处。 手套的完整性是隔离器完整性测试中的另一个重要部份，因为手套既接触无菌试验材料 又接触测试样品，然而在使用过程中有时即使压降试验合格，手套上也有可能存在着难以发 现的极微小的破洞，这样就有必要定期专门检查手套的完整性了。现在国外市场上有几种手 套测漏仪出售，操作人员应确保在最接近实际使用情况的条件下用测漏仪测试手套;这里需 要指出的是标准的“手印试验”的灵敏度可能并不足以查出手套上极低水平的污染及破损。 另外，隔离器在正常运行时需维持 20-50pa 或以上的正压，以防止可能发生的污染。如 果需要维持恒定的正压，验证时必须证明隔离器能维持和控制设定的正压值。 (4)灭菌器的功能，灭菌过程参数 该测试确认灭菌器的功能符合既定要求。这些参数包括 灭菌剂每小时的消耗量，灭菌剂 升温至所需温度所需的时间等，还包括厂商提供的反应灭菌器功能的其它参数。 (5)灭菌程序确认 该过程目的在于确认所执行的灭菌程序各步骤正常，运行值和设定值相 符。 在隔离系统中，可以使用不同的灭菌方法来对系统及试验用品进行灭菌，目前用于 隔离 器灭菌的化学试剂有:过氧乙酸、二氧化氯、臭氧和过氧化氢，每一种试剂对于暴露条件、过程控制都有不同的要求。因些应严格遵从生产厂商的使用要求选择合适的灭菌方法，并在 性能要求中对该方法进行详细描述。例如当过氧化氢蒸汽被用作灭菌剂时，控制房间的温度 和湿度以及隔离器内的温度就很重要。因为要在冷凝点下保持一定的气体浓度，温度是关键。 而其它一些灭菌化学试剂，例如二氧化氯和臭氧，则需要在灭菌前增加隔离器内的湿度。如 果需要较高的相对湿度，那么在运行确认中必须对相对湿度的控制能力进行确认。 确认灭菌化学试剂的浓度与分布是 OQ 阶段中的另一个重要部份。对于灭菌剂的气体或 蒸汽形式，其浓度可用化学指示剂、光谱分析或电子传感器测量来测量，分布情况也可以用 化学指示剂进行测试，但是必需明确的是化学指示剂仅能提供定性的而不是定量的信息。气 体和蒸汽灭菌的过程中，一般都会由风扇使隔离器内的灭菌试剂分布均匀。由于在隔离器舱 体中的架子、设备、手套和袖子以及半身操作服对气体分布有影响，所以应调整这些风扇的 位置及方向以获得最佳的气体分布状态。并且必须在隔离器满载设备和试验器具时进行灭菌 气体分布检查，由此确定待灭菌器具的装载方式并进行记录。 许多隔离系统中，把较小的可移动的传递隔离器作为物品灭菌装置，测试样品和试验器 具先在这些传递隔离器中用灭菌化学试剂去除表面微生物，再通过双门快速传递口 RTP 传 递到试验隔离器中进行试验。因此在对这样的隔离系统进行运行确认时，还应确定传递隔离 器的物料装载方式，并画出或拍下装载的放置图。由于隔离器中的灭菌试剂仅在物体的表面 起作用，因此，任何不能完全暴露在灭菌气体中的表面就会得不到处理，从而可能会有残存 的活的微生物。应当把物料放入传递隔离器之前用灭菌剂充分擦试待灭菌物品表面，(前提 条件是该表面不会渗透灭菌剂)尤其是有皱折或是有覆盖物的表面。 灭菌程序完成后，要将灭菌试剂从隔离器中排除，使隔离器内的残留灭菌试剂量为安全 浓度。排除过程可通过由灭菌器或其它方法提供(如:隔离器自身的空气处理系统)的新鲜 无菌空气进行替换来完成。排 出的灭菌气体既可以通过开放式管道由排气孔直接排向大气， strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality 也可以在密闭程序管道中，由灭菌设备将灭菌试剂去除和破坏后再排出。假如排风系统中使用了开放式管道结构，还应检查排风系统的气流与安全性。 当灭菌程序的确认完成以后，就可以根据确认好的灭菌程序进行下一步工作，即灭菌程 序的开发过程了。 (6)灭菌程序的开发 灭菌程序开发的目的在于确定日常灭菌程序中所必需的过程控制参数 (见图 21-15)。任 何用于灭菌过程验证的常用方法，包括阴性分数法和过量杀灭法，都可使用。在这个过程中， 生物指示剂被用来挑战灭菌过程，生物指示剂的孢子数和对灭菌条件的耐受力应是已知的。 灭菌程序开发的目的在于确定日常灭菌程序中所必需的过程控制参数。任何用于灭菌过程验 证的常用方法，包括阴性分数法和过量杀灭法，都可使用。在这个过程中，生物指示剂被用 来挑战灭菌过程，生物指示剂的孢子数和对灭菌条件的耐受力应是已知的。开发测试项目至 少包括以下几个方面，隔离器中灭菌试剂的分布以及灭菌时间和灭菌程序完成以后的灭菌试 剂排空时间;假如有传递隔离器，还应测试传递隔离器在满载状态下的上述项目。只有当 OQ 测试结束并获得批准之后，才能进行 PQ 阶段的测试。 图 21-15 灭菌程序的开发 C. 性能确认(PQ) 在性能确认中主要应确认灭菌程序的效力以及灭菌化学试剂的充分排放两个方面。整个 过程类似于 OQ 阶段中 “灭菌程序的开发”中所述，但是，为了达到足够的无菌保证值，PQ 阶段的灭菌时间将会长于 OQ 阶段中的灭菌时间;生物指示剂的数量也将增加，以证明在统 计学上有重现性以及灭菌试剂的充分分布;对于那些可能影响灭菌试剂浓度分布的区域应特 别加以注意，在满载设备和试验材料的隔离器内应使用更多数量的生物指示剂以确定灭菌过 程的有效性。当经过校验的传感器不能直接用于测量灭菌试剂的浓度时，应考虑放置更多的 生物指示剂在隔离器内，同时最好能在隔离器的结构示意简图上标出生物指示剂的放置位置 以利于当试验失败时易于查找原因。所有的 PQ 测试项目，包括灭菌程序的验证和灭菌试剂 strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality 21.隔离技术 无菌制剂G MP 实施指南 的排除程序，都应进行至少三次连续的验证过程以确认结果的重现性，即灭菌程序能重现5-6 个对数单位致死率的能力及排除程序的重现能证明排除灭菌试剂至安全浓度的能力。 灭 菌过程完成以后，隔离器内的无菌状态主要通过隔离器自身的空气处理系统，适当的 物料传递操作，还有最重要的是通过保证无菌操作手套的完整性来维持的。 最后把所有的性能确认数据应适当总结、评价和存档。 清洁确认是 PQ 确认阶段另一项内容，一般说来清洁对无菌试验来说并不是非常重要。 但是，假如在同一隔离器中进行多种产品的无菌试验时，那么产品的残留就是一个值得考虑 的问题了，尤其当试验产品是抗菌剂时，它的残留可能会影响随后进行的试验中检出低水平 污染的能力。当产品为抗菌粉末时，残留污染则更加是一个值得重视的问题，因为粉末更容 易扩散。然而对于无菌试验隔离系统来说，清洁到无可见污染的程度已足够了，这对操作人 员也是一个较适合的要求。隔离器的清洁方法、频率、设备和材料都应有文件记录。 D. 再验 证 隔离器的再验证和附属设备可按照目前无菌生产的行业规则来进行。典型的过程模拟试 验每年两次，虽然方法是定义了对无菌最坏情况的风险，将操作污染对过程安全的影响最小 化方面也相当不同。当采用生产的操作方法时，再验证研究应该考虑最大操作持续时间。没 有理由可以相信微生物污染可以在隔离器内毫无合适的微生物生长条件下长时间增殖，但是 在典型的操作持续时间下评估隔离器系统的能力仍然是合理的。 去污染过程和相关设备的再验证通常是一年进行一次。如果气体/蒸汽的出现和分布可 它用化学方法确定，用生物指示剂来进行的再验证则是不需要的。根据选择的去污染方法，其 试验包括房间温度和湿度，以及生物指示剂评估会是必须的。 【实例分析】 A. 悬浮粒子水平测 试 测试目的及要求:该测试的目的在于检查隔离器内的悬浮粒子水平。一般仅在静态下进行悬 浮粒子计数。测试点和取样体积可根据供应商的建议或洁净室的相关标准确定，但结果应符 合静态 100 级区的要求。 3方法:选取 4 个取样点，取样体积为每次 1ft，每个取样点测试三次。取样头的位置高于台 面 20cm。最后计算所有取样点的95,置信上限。取样点的数量、取样体积以及取样点按照 ISO14644-1 中的要求进行计算。 3 接受标准(静态100 级):100/0 Counts/ft(>=0.5um/>=5um)，每个采样点的平均粒子浓 度和全部采样点的粒子浓度平均值的95,置信上限都应符合上述要求。 位置单个值平均值95置信上限 0/0 1 1.0 - 1/0 2/0 1/02 0.7 6.31 0/0 strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality 1/0 0/0 3 0.0 2.92 0/0 0/0 2/0 4 1.7 2.35 0/0 3/0 结论: 每个采样点的平均粒子浓度和全部采样点的粒子浓度平均值的 95,置信上限都应符 合上述要求，已确认隔离器内的洁净度可以达到无菌实验要求的 100 级。 B. 隔离器完整性试验 (隔离器体和手 套) 试验目的及要求:该方法是预先在隔离器系统中保持一定的压力，然后快速关闭系统中所有 的进气口与出气口，包括隔离器自身的空气处理系统也应关闭，让该状态持续一段时间，如 10 分钟，假如隔离器系统完整性完好，在这特定时间内，压力下降值应在一定的要求范围 内(如:16Pa);反之，则不符合规定。该试验简单易行并且灵敏度高，但是它只能反映出 隔离系统完整性是否有破损，却不能指示破损处的具体位置，因此还应该辅助以其它的测试 以进一步确定破损处。 参数设定 设定值=110pa 时间=10分钟 AL1=200pa AL2=10pa Pi=104pa Pf=100pa ,P/min=0.4pa/min 实验结果 Ti=22.8?C Tf=22.8?C ,T/min=0?C/min ,P=Pi-Pf和,P/min=,P/10 计算公式 ,T=Ti-Tf和,T/min=,T/10 合格标准 (,P/ min)低于1.6 Pa/min和,T/min低于0.05?C 结论:压力降低测试法，在温度变化< 0.05?C/分钟时，压力变化应<1.6 Pa/分钟，因此隔离 器完整性测试结果符合要求。 C. 灭菌器的功能，灭菌过程参数 试验目的及要求:该测试确认灭菌器的功能符合既定要求。这些参数包括灭菌剂每小时的消 耗量，灭菌剂升温至所需温度所需的时间等，还包括厂商提供的反应灭菌器功能的其它参数。 方法:在 1 小时时用过氧乙酸运行灭菌器以检查灭菌循环的参数:(1)过氧乙酸的每小时 消耗量;(2)过氧乙酸温度升至 45 ?所需的时间;(3)灭菌结束后到启动自动排风的平 均时间。 接受标准:(1)过氧乙酸平均每小时消耗量 50-60 ml/h;(2)过氧乙酸温度升至45 ?所 需的时间<=15min;(3)灭菌结束后到启动自动排风的平均时间<2min。 测试项目 接受标准 灭菌 1小时 消耗量strengthen the sense of responsibility, work to solve the lack of decent occupation explain away, conduct problems. To establish the overall concept, eliminate departmentalism. Strict assessment and accountability, to solve the spiritual slack, nianqingpazhong, status quo, and other issues. To establish and perfect the muddle along Bureau staff conduct work regulations, standardize the behavior of personnel. 2. To strengthen the responsibility system. One is the in-depth study and implement the "Hunan provincial Party and government leading cadres Interim Provisions on the work safety of a pair of > (Hunan Office issued 2013 No. 5)," Hunan province safety supervision and management responsibilities of the provisions on the production (Hunan Zhengban made 2013 No. 4) And resolutely implement the safety production of the party with responsibility, a pair of responsibility. "Two is issued safety production administration and inspection to promote the responsibilities bear safety production supervision departments strictly and effectively assumed responsibility. The three is to establish risk self correction self reporting system for safety in production enterprises, promote the enterprises to implement the main responsibility for production safety is introduced. Four strengthen the county safety production supervision ability construction work, promote safe production responsibility to the grassroots. 3, strict accountability and target management. Adhere to the" who is in charge, who is responsible for the pipe industry must be safe, Guan Sheng production and operation must be safe, pipe business must control security "principle, the implementation of safety The production of "cure." stagnation supervision and leadership responsible system. The safety production of key towns, key enterprises and key problems, by the township government and the Department responsible for the stagnation led the lump sum, to tackle tough. To further increase the production safety index assessment, strictly implement the safety production of the "one vote veto" and the reward system, strengthen the safety incentive and restraint mechanism. (six) the implementation of the work force is not strong. The documents, meeting, long work arrangement, check and supervise the implementation of small, poor implementation of the system, the work is not effective. Some leading cadres sense of purpose, consciousness of the masses is not strong, the ruling " For the people "," the interests of the masses no matter "concept understanding is not in place. The specific work treats with the deployment, a few leading cadres complain that work is too complicated, too much responsibility, the pressure is too large, too much emphasis on the difficulty of the work, such as underground mines to avoid the disaster of" six systems "construction and construction of mechanical ventilation to file the form, forwarding arrangements work, no in-depth mining enterprises to promote the specific work, the increase in the number of files, but the effect is not good, not according to the actual situation of non coal mines in the county, to engage in" across the board ", and the quality 50-60 ml/hr Qi= 460 ml (Cm= Qi?Qf/t ) 过氧乙酸每小时的平均消耗 Qi=起始数量 量 Qf=最终数量 Cm=55 ml/h Qf= 350 ml Cm=消耗量 t ? 15 min 过氧乙酸升温到 45?所Ti=起始温度 Ti= 45 ? t = 6分21秒 需 的时间 t =升温时间 t < 2 min 灭菌结束到自动通风开始所 t = 1分08秒 ------ t =等候时间 需的时间 结论:所有测试结果均符合要求，已确认灭菌器的功能符合要求。 D. 确认空载隔离器的灭菌试剂分 布 试验目的及要求:气体和蒸汽灭菌的过程中，一般都会由风扇使隔离器内的灭菌试剂分布均 匀。由于在隔离器舱体中的架子、设备、手套和袖子以及半身操作服对气体分布有影响，所 以应调整这些风扇的位置及方向以获得最佳的气体分布状态。并且必须在隔离器装载设备和 试验器具时进行灭菌气体分布检查，由此确定待灭菌器具的装载方式并进行记录。 方法:将 6 个化学指示剂放置于灭菌试剂较难达到的位置，计算化学指示剂变色的时间。指 示剂放置的位置是根据气流走向、腔体构造以及初始验证结果制定，具体原则如下:(1) 距离进气口最远的位置;(2)由于任何障碍气流难以达到的位置;(3)由于连接管路狭长 或弯曲气流难以达到的位置。 灭菌达到规定浓度(>50ppm)所需时间 位置 取样位置描述 评估意见 结果(时间) MD8取样口内 此位置为 MD8取样管路，较狭长 5分10秒 1 排水口内 此位置为排水管路，呈 90?弯曲 3分40秒 2 传递门中间 根据灭菌剂的气流走向，该位置远离进气口 4分35秒 3 架子底部 有架子障碍 5分 4 架子后部 有架子障碍 2分40秒 5 袖子下部 有袖子障碍 3分2秒 6 411 21.隔离技术 无菌制剂G MP 实施指南 结论: (1)空载时，运行约 6 分钟时，腔体内灭菌剂的浓度大于 50ppm (2)运行约 3 小时后，生物指示剂已全部杀灭 (3)自动通风 5 小时后，腔体内灭菌剂的浓度小于 5ppm (4)手动通风约 1 小时后，腔体内灭菌剂的浓度小于 5ppm 因此确认空载隔离器的灭菌试剂分布符合要求。 【要点备忘】 安装确认阶段的工作主要是确认系统已被正确安装，首先要审阅设备附带的所有文件， 确认其准确地反映了所安装系统的关键属性。这是隔离系统能符合设计和安装要求的基础。 然后应详细描述隔离系统的物理特征，例如尺寸、内部结构和建造材料等。设备的图纸应标 示出结合部位，其中传递系统也应清晰标明大小尺寸。应确认公用系统提供的介质，例如供 气、真空、外部排风、温度湿度控制等能符合隔离系统的设计要求。其它与隔离系统一起使 用的设备也要详细描述;如果对原设计有任何修改，这些改动应详细描述。将设备手册及复 印件编号存放在便于查阅之处，还应核实图纸是否与设计要求一致。所有的图纸、程序和仪 器图解应编号存放，便于查阅。 运行确认阶段的目的在于确认隔离器的操作和功能符合标准并适用于无菌试验。 再验证可由用户对故障和过程控制性能确认系统的性能是否符合操作者的要求。 的分析来决定合适的进度。 21.3 隔离系统的维护体系 【法规要求】 《药品生产质量管理规范》2010 修订版: 附录 1:无菌药品 第十六条 隔离操作器和隔离用袖管或手套系统应进行常规监测，包括经常进行必要的检漏试验。 【背景介绍】 必须有严格的无菌维持体系确保隔离器的无菌状态。 只有经过批准，经过专门培训的人员 方可进入无菌隔离器，无论何时均需遵守这个原则。 【技术要求】 隔离系统在规定的操作期限内维持无菌状态的能力必须得到验证。 412 在从事无菌工作之前，应对所有人员进行合适的培训并对他们的能力进行评估。 【实施指导】 A. 隔离器内无菌状态的维持 (1)微生物监测 对隔离器内的环境必须进行微生物监测，以检查隔离系统的故障或隔离器中 意外污染的 发生。微生物监测通常包括一个日常取样，例如可以在灭菌后运行的第一天取样以及在预定的无菌维护期的最后一天取样。无菌维护期间的取样用来证明隔离器内无菌状态的维护 情况。 (2)悬浮粒子监测 对隔离器内进行空气悬浮粒子的连续监控，因为这样可以快速发现过滤 器的故障。第二 选择是用便携式粒子计数仪进行定期监测。悬浮粒子的取样必须采用对隔离器内无菌状态的维持不产生风险的方式。 (3)完整性测试 定期进行检漏测试，可以给用户提供关于这些组件和完整性的重要信息，为 保证隔离器 的无菌性提供必要的依据。 (4)日常仪表校验 关键量具和仪器的日常维护和校验对整个隔离器验证维护规程是重要的， 因为任何制药 生产过程都需要的。隔离器技术使用没有在制药/生物制药GMP 之外强加新的或额外的维护 或校验要求。同样的，变更控制实施和要求在隔离器技术和 CGMP 生产系统上也没有不同。 B. 人员培训 与在传统的洁净室内进行的无菌试验相比，对操作人员的培训主要针对的是隔离器的操 作。所有的培训课程和对操作人员的考核都应记录在个人的培训记录中，隔离系统运行和维 护所必需的安全规程的培训也是必不可少的。 应对灭菌试剂使用过程中操作人员的安全性进行评估。灭菌试剂使用现场应有材料安全 数据表或相应的文件，遵从所有的储藏和安全注意事项。在投入使用前，应先对隔离器和相 关设备运行的安全性进行检查并有文件记录。 【实例分析】 日常仪表校验 要求:需根据隔离器系统维护的基本原则和零部件的使用特征 表 21-1 常规检查和零部件的更换频率表 名称 常规维护 更换频率 413 21.隔离技术 无菌制剂G MP 实施指南 沉降菌，表面微生物和空气浮 每次实验之后 --- 游菌的监测 空气悬浮粒子监测 每月一次 --- 压力下降实验 有实验操作时每周一次 --- 氨实验 每年一次或者是压降实验失败以后 --- 灭菌器 每次灭菌后清洁 --- 预过滤器 两年一次 --- 两年一次或 高效过滤器 每半年进行校验 DOP 测试失败以后 隔离器外罩 不能修复的损坏后 --- 手套和袖子 被损坏以后 --- 盛液缸的封口盖 发生泄漏以后 --- 盛液缸的加液密封圈 发生泄漏以后 --- 盛液缸的密封件 每年一次 --- 微过滤器 每年一次 --- 橡皮带 每季度目检 每年一次或发生损坏以后 O形圈 发生损坏以后 --- MD-8 过滤器 每三个月一次 --- 【要点备忘】 隔离器的无菌维持包括以下几点: , 微生物监测 , 悬浮粒子监测 , 完整性测试 , 日常仪表校验 人员应有合 适的培训及评 414 415