欧盟GMP(中英文对照).doc

（The words that are in the green background are new standards） (绿色背景下的内容为新标准)ANNEX 1MANUFACTURE OF STERILE MEDICINAL PRODUCTS附录1 无菌医药产品的生产Principle总则The manufacture of sterile products is subject to special requirements in order to minimize risks of microbiological contamination, and of particulate and pyrogen contamination. Much depends on the skill, training and attitudes of the personnel involved. Quality Assurance is particularly important, and this type of manufacture must strictly follow carefully established and validated methods of preparation and procedure. Sole reliance for sterility or other quality aspects must not be placed on any terminal process or finished product test.无菌药品的生产，必须符合一些特殊的要求，以防止微生物、微粒和热源的污染。这很大程度上依赖与工作人员的技术水平、培训和工作态度。在这方面质量保证显得特别重要，这种类型的生产，必须严格按照完善的和经过验证的生产方法和工作程序。仅靠产品的最终灭菌和某一方面的质量控制是不允许的。Note:This guidance does not lay down detailed methods for determining the microbiological and particulate cleanliness of air, surfaces etc. Reference should be made to other documents such as the EN/ISO Standards.注：本规范没有详述测定空气、表面等微生物和微粒洁净度的详细方法，请参阅EN/ISO中相关标准。General 概要1. The manufacture of sterile products should be carried out in clean areas entry to which should be through airlocks for personnel and/or for equipment and materials. Clean areas should be maintained to an appropriate cleanliness standard and supplied with air which has passed through filters of an appropriate efficiency.无菌产品的生产要在洁净区域内进行，进入这些区域内的人员、设备和物料，必须通过缓冲间。洁净区必须保持一定的洁净级别，空气必须通过规定的过滤器。2. The various operations of component preparation, product preparation and filling should be carried out in separate areas within the clean area. Manufacturing operations are divided into two categories; firstly those where the product is terminally sterilised, and secondly those which are conducted aseptically at some or all stages.各种原料的准备、产品的准备和灌装，必须在洁净区的不同区域进行，生产操作分为两类，一是最终灭菌型，二是部分过程或全过程的无菌操作。3. Clean areas for the manufacture of sterile products are classified according to the required characteristics of the environment. Each manufacturing operation requires an appropriate environmental cleanliness level in the operational state in order to minimise the risks of particulate or microbial contamination of the product or materials being handled.无菌生产的洁净区，按照产品对环境的要求分级。每一步生产操作，其操作状态对环境有相应的洁净级别的要求，以降低对物料或产品造成微粒或微生物的污染的风险。In order to meet “in operation” conditions these areas should be designed to reach certain specified air-cleanliness levels in the “at rest” occupancy state. The “at-rest” state is the condition where the installation is installed and operating, complete with production equipment but with no operating personnel present. The “in operation” state is the condition where the installation is functioning in the defined operating mode with the specified number of personnel working.为达到“动态”的条件，这些区域在设计上要达到特定的“静态”的空气洁净度洁净标准。“静态”指设备已经安装并运行，生产设备就位但是没有操作人员在场。“动态”是指在设备正常运转状态下和有规定的工作人员在场的情况下。The “in operation” and “at rest” states should be defined for each clean room or suite of cleanrooms.每个或每套房间都要分别进行“静态”和“动态”的确定。For the manufacture of sterile medicinal products 4 grades can be distinguished.无菌产品的生产有4个环境级别：Grade A: The local zone for high risk operations, e.g. filling zone, stopper bowls, open ampoules and vials, making aseptic connections. Normally such conditions are provided by a laminar air flow work station. Laminar air flow systems should provide a homogeneous air speed in a range of 0.36 0.54 m/s (guidance value) at the working position in open clean room applications. The maintenance of laminarity should be demonstrated and validated.A uni-directional air flow and lower velocities may be used in closed isolators and glove boxes.A级：用于高风险的生产操作，如灌装区、加盖区、容器开口区、和进行无菌连接的地方。通常这种情况是带有层流罩的工作站。在开放的洁净区内的工作站上，层流罩应该能产生风速为0.36 0.54米/秒的均匀气流。层流罩的维护，必须有充分的证明和经过验证。密封隔离器和手套箱内，可采用单向低速气流。Grade B: For aseptic preparation and filling, this is the background environment for the grade A zone.B级：对于无菌制备和灌装，B级区域是A级区域的背景环境。Grade C and D: Clean areas for carrying out less critical stages in the manufacture of sterile products.C级和D级：无菌产品非关键生产步骤的洁净区。Clean room and clean air device classification 洁净室及空气洁净装置分级4. Clean rooms and clean air devices should be classified in accordance with EN ISO 14644-1. Classification should be clearly differentiated from operational process environmental monitoring. The maximum permitted airborne particle concentration for each grade is given in the following table.洁净室及空气洁净装置分级与EN ISO14644-1要求一致。应按照操作过程的环境监控数据明确区分级区。下表列出了各个级别所允许的最大数量空气尘埃粒子数目。Grade空气级别Maximum permitted number of particles/m3 equal to or greater than the tabulated size允许最大尘埃粒子数/m3 等于或大于表中粒子粒径at rest静态in operation 动态0.5m(d)5m0.5m(d)5mA3 520203 52020B3 52029352 0002 900C352 0002 9003 520 00029 000D3 520 00029 000未规定未规定5. For classification purposes in Grade A zones, a minimum sample volume of 1m3 should be taken per sample location. For Grade A the airborne particle classification is ISO 4.8 dictated by the limit for particles 5.0 m. For Grade B (at rest) the airborne particle classification ISO 5 for both considered particle sizes. . For Grade C (at rest & in operation) the airborne particle classification is ISO 7 and ISO 8 respectively. For Grade D (at rest) the airborne particle classification is ISO 8. For classification purposes EN/ISO 14644-1 methodology defines both the minimum number of sample locations and the sample size based on the class limit of the largest considered particle size and the method of evaluation of the data collected.为达到洁净区划分标准，A级区每次取样点的最少取样量应不少于1 m3。A级区空气粒子数按照ISO 4.8中5.0 m的规定来划分。B级区（静态）的两种粒径粒子数按照ISO标准中5级来划分。C级区（动态及静态）分别按照ISO标准中7级和8级标准来划分。D级区（静态）按照ISO标准中8级来划分。EN/ISO 14644-1根据最大可能粒子粒径的级区限度规定及对已收集数据的评估方法，对取样点及取样量的都进行了最低规定。6. Portable particle counters with a short length of sample tubing should be used for classification purposes because of the relatively higher rate of precipitation of particles 5.0m in remote sampling systems with long lengths of tubing. Isokinetic sample heads shall be used in unidirectional airflow systems.应采用带有短取样管的便携式粒子计数器用于级区划分，因为带有长取样管的遥控取样系统对于5.0m的粒子会有相对较高比率的沉淀粒子。单向层流系统中可 采用正向等速抽样。7. “In operation” classification may be demonstrated during normal operations, simulated operations or during media fills as worst-case simulation is required for this. EN ISO 14644-2 provides information on testing to demonstrate continued compliance with the assigned cleanliness classifications.“动态”状态中的数据应在正常生产状态，模拟生产及培养基灌装的过程中测得，以模拟最差情况。EN ISO 14644-2中提供了相关测试信息，以保证能 持续符合制定的洁净度划分。Clean room and clean air device monitoring 洁净室及空气洁净装置监控8. Clean rooms and clean air devices should be routinely monitored in operation and the monitoring locations based on a formal risk analysis study and the results obtained during the classification of rooms and/or clean air devices.洁净室及空气洁净装置在生产过程中应进行常规监控。监控点根据正式的风险分析调研及洁净室和洁净装置级区划分的结果来确定。9. For Grade A zones, particle monitoring should be undertaken for the full duration of critical processing, including equipment assembly, except where justified by contaminants in the process that would damage the particle counter or present a hazard, e.g. live organisms and radiological hazards. In such cases monitoring during routine equipment set up operations should be undertaken prior to exposure to the risk. Monitoring during simulated operations should also be performed. The Grade A zone should be monitored at such a frequency and with suitable sample size that all interventions, transient events and any system deterioration would be captured and alarms triggered if alert limits are exceeded. It is accepted that it may not always be possible to demonstrate low levels of 5.0 m particles at the point of fill when filling is in progress, due to the generation of particles or droplets from the product itself.A级区进行的所有关键操作的全过程都必须进行实时的粒子监控，这些操作包括设备的调试与安装活动，除非由于操作过程中所产生的污染物本身的原因，例如污染物会破坏粒子计数器或者造成危害，这种情况下可以不进行粒子的监控，如活性生物体和放射性危害。此种情况下，常规设备安装操作时的环境监控应在设备暴露并造成危害前进行。模拟生产操作时也应进行环境监控。A级区必须进行适当监控频率及控制适当的取样量，所有的非正常干涉，短暂事故，系统变化应当被实时监测，当超过警戒限度时触发警报。灌装时，在灌装点由于产品本身产生的微粒和液滴，有时达不到5.0 m微粒的控制标准是可以接受的。10. It is recommended that a similar system be used for Grade B zones although the sample frequency may be decreased. The importance of the particle monitoring system should be determined by the effectiveness of the segregation between the adjacent Grade A and B zones. The Grade B zone should be monitored at such a frequency and with suitable sample size that changes in levels of contamination and any system deterioration would be captured and alarms triggered if alert limits are exceeded.推荐在B级区使用相类似的系统，虽然取样频率可以降低。B级区粒子监控系统的重要性取决于相邻的A级区与B级区的隔离效果。根据污染水平和任何系统退化都因该被察觉到，而且如果超过警界先会触发报警，选用B级区需要的取样规格和频率进行监控。11. Airborne particle monitoring systems may consist of independent particle counters; a network of sequentially accessed sampling points connected by manifold to a single particle counter; or a combination of the two. The system selected must be appropriate for the particle size considered. Where remote sampling systems are used, the length of tubing and the radii of any bends in the tubing must be considered in the context of particle losses in the tubing. The selection of the monitoring system should take account of any risk presented by the materials used in the manufacturing operation, for example those involving live organisms or radiopharmaceuticals.空气粒子监控系统可以有独立的粒子计数器；或由一系列取样点组成的网络连接到单一粒子计数器；或者两者的结合。系统的选择必须适合粒子的规格。如果使用远距离取样，一定要考率管道的长度和管道转弯处的半径对粒子遗失的影响。选择监控系统时应该考虑对于现有生产操作中使用的材料的风险，例如对于那些含有活有机体或放射性药品。12. The sample sizes taken for monitoring purposes using automated systems will usually be a function of the sampling rate of the system used. It is not necessary for the sample volume to be the same as that used for formal classification of clean rooms and clean air devices.使用自动监控系统用于监控目的的取样一般可以使用系统自身设计的方式取样。并不一定要使用于级区分类和空气洁净装置正式分类的取样方式。13. In Grade A and B zones, the monitoring of the 5.0 m particle concentration count takes on a particular significance as it is an important diagnostic tool for early detection of failure. The occasional indication of 5.0 m particle counts may be false counts due to electronic noise, stray light, coincidence, etc. However consecutive or regular counting of low levels is an indicator of a possible contamination event and should be investigated. Such events may indicate early failure of the HVAC system, filling equipment failure or may also be diagnostic of poor practices during machine set-up and routine operation.在A级区和B级区里，监控大于5.0 m的粒子浓度有重要的意义，可以做为早期发现问题的重要诊断工具。大于5.0 m粒子的偶然出现可能是由于电子噪声、光路的问题导致的错误计数。然而连续或规律性低水平计数可能暗示了潜在的污染事件，应该给予调查。这种情况可能是由于HVAC系统故障、灌装仪器故障，或者在设备安装和常规操作的不良习惯引起的。14. The particle limits given in the table for the “at rest” state should be achieved after a short “clean up” period of 15-20 minutes (guidance value) in an unmanned state after completion of operations.上表中的“静态”下的微粒情况，必须在操作完成后的无人条件下，“清洁”运行15-20分钟（指导值）后达到。15. The monitoring of Grade C and D areas in operation should be performed in accordance with the principles of quality risk management. The requirements and alert/action limits will depend on the nature of the operations carried out, but the recommended “clean up period” should be attained.对C级区、D级区的动态监测应该符合质量风险管理的原则。虽然监测的要求和警界限度/措施限度的设定取决于生产操作的性质，但应该达到推荐的清洁周期。16. Other characteristics such as temperature and relative humidity depend on the product and nature of the operations carried out. These parameters should not interfere with the defined cleanliness standard.其他特征参数，如温度和相对湿度，必须根据操作的性质和相应的产品而定。这些参数必须不影响规定的洁净度。17. Examples of operations to be carried out in the various grades are given in the table below(see also paragraphs 28 to 35):下表列出各种洁净级别所适应的生产操作：Grade级别Examples of operations for terminally sterilised products. (see par. 11)最终灭菌产品的操作举例（见11节）AFilling of products, when unusually at risk产品灌装、高风险的情况CPreparation of solutions, when unusually at risk. Filling of products.高风险情况下的配液。产品灌装DPreparation of solutions and components for subsequent filling灌装前溶液及各组分准备级别Examples of operations for aseptic preparations. (see par. 12)无菌制备型操作举例（见12节）AAseptic preparation and filling.无菌制备和灌装CPreparation of solutions to be filtered.过滤前溶液配制DHandling of components after washing.清洗后材料处理18. Where aseptic operations are performed monitoring should be frequent using methods such as settle plates, volumetric air and surface sampling (e.g. swabs and contact plates).Sampling methods used in operation should not interfere with zone protection. Results from monitoring should be considered when reviewing batch documentation for finished product release. Surfaces and personnel should be monitored after critical operations. Additional microbiological monitoring is also required outside production operations, e.g. after validation of systems, cleaning and sanitization.对无菌操作区，必须经常使用沉降皿、空气定量法和表面取样（棉签或接触皿）等方法进行监控。生产过程中所用的取样方法，必须不影响洁净区的保护，当审核最终产品放行的批记录时，也要考虑环境监控的结果。在关键操作后，要对人员和设施的表面进行监控。在非生产状态下，要进行微生物的监控，包括在系统的验证、清洁或消毒后。19. Recommended limits for microbiological monitoring of clean areas during operation:生产过程中微生物的监控标准推荐如下：Recommended limits for microbial contamination (a)建议的微生物污染限度Grade级别air sample空气取样CFU/m3settle plates沉降皿diam. 90mmcfu/4 hours(b)contact plates接触皿diam. 55mmcfu/plateglove print手套5 fingers5个手指cfu/gloveA 1 1 1 1B10555C1005025-D20010050-Notes注意(a) These are average values.此为平均值(b) Individual settle plates may be exposed for less than 4 hours.单个沉降皿放置的时间可以少于4小时20. Appropriate alert and action limits should be set for the results of particulate and microbiological monitoring. If these limits are exceeded operating procedures should prescribe corrective action.对尘埃粒子和微生物的监控结果，要设置适当的警戒限度和措施限度。当超出这些限度时，操作规程应说明需要采取的措施。Isolator technology隔离技术21. The utilisation of isolator technology to minimize human interventions in processing areas may result in a significant decrease in the risk of microbiological contamination of aseptically manufactured products from the environment. There are many possible designs of isolators and transfer devices. The isolator and the background environment should be designed so that the required air quality for the respective zones can be realised. Isolators are constructed of various materials more or less prone to puncture and leakage. Transfer devices may vary from a single door to double door designs to fully sealed systems incorporating sterilization mechanisms.在生产区采用人员方面的隔离技术，在无菌产品的生产中，会显著降低周围环境微生物污染的风险。有很多隔离和传递设施可供选择。隔离和背景环境的设计，必须保证各区域相应的空气质量要求可以实现。隔离设施的建造材料，多少有些易于穿孔和泄漏。传递设施可以是单门、双门或结合无菌机制的全封闭系统。22. The transfer of materials into and out of the unit is one of the greatest potential sources of contamination. In general the area inside the isolator is the local zone for high risk manipulations, although it is recognised that laminar air flow may not exist in the working zone of all such devices.原材料的进出是污染的最大来源之一。通常隔离区内仍是操作的高风险区域，即使我们认识到层流不可能存在于所有隔离设施的工作区内。23. The air classification required for the background environment depends on the design of the isolator and its application. It should be controlled and for aseptic processing it should be at least grade D.背景环境的洁净级别，视隔离区的设计和应用而定。要控制无菌生产的背景环境，并且最低为D级24. Isolators should be introduced only after appropriate validation. Validation should take into account all critical factors of isolator technology, for example the quality of the air inside and outside (background) the isolator, sanitisation of the isolator, the transfer process and isolator integrity.在经过适当的验证之后，隔离室才能使用。验证必须将隔离技术的所有关键因素考虑在内，如：隔离室的内外部空气质量、隔离室的消毒，传递过程和隔离室的完整性。25. Monitoring should be carried out routinely and should include frequent leak testing of the isolator and glove/sleeve system.必须进行常规监控，包括隔离室和手套/袖系统的泄漏检查。Blow/fill/seal technology 吹/灌/封技术26. Blow/fill/seal units are purpose built machines in which, in one continuous operation,containers are formed from a thermoplastic granulate, filled and then sealed, all by the one automatic machine. Blow/fill/seal equipment used for aseptic production which is fitted with an effective grade A air shower may be installed in at least a grade C environment, provided that grade A/B clothing is used. The environment should comply with the viable and non viable limits at rest and the viable limit only when in operation. Blow/fill/seal equipment used for the production of products which are terminally sterilised should be installed in at least a grade D environment.吹/灌/封单元都安装在一台专用的设备上，连续运转完成从热塑材料吹成容器、然后灌装、密封一次自动完成。吹/灌/封设备用于配备了有效的A级空气流的无菌生产时，假如使用A/B级的工作服，设备最少要安装在最低C级的环境里。静态时环境必须符合可行限度和非可行限度，动态时要求符合可行限度。用于生产终端灭菌产品时，吹/灌/封设备必须安置在最低D级环境中。27. Because of this special technology particular attention should be paid to, at least the following:对此特别的技术，最少要特别注意如下几点： Equipment design and qualification Validation and reproducibility of cleaning-in-place and sterilization-in-place Background clean room environment in which the equipment is located Operator training and clothing Interventions in the critical zone of the equipment including any aseptic assembly prior to the commencement of filling.设备设计和验证现场清洁和现场灭菌的验证和可重复性设备安装环境人员的培训和服装包括在灌装前的任何无菌装置对设备关键区域的影响Terminally sterilised products 最终灭菌产品28. Preparation of components and most products should be done in at least a grade D environment in order to give low risk of microbial and particulate contamination, suitable for filtration and sterilisation. Where the product is at a high or unusual risk of microbial contamination (for example, because the product actively supports microbial growth or must be held for a long period before sterilisation or is necessarily processed not mainly in closed vessels), then preparation should be carried out in a grade C environmen