MANUFACTURE OF STERILE MEDICINAL PRODUCTS
无菌医药产品的生产
Principle 原则
The manufacture of sterile products is subject to special requirements in order to minimise 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。这很大程度上要依赖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 一般要求
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、设备或原料，必须通过气闸室。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.
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.
The “in operation” and “at rest” states should be defined for each clean room or suite of clean rooms. For the manufacture of sterile medicinal products 4 grades can be distinguished.
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，在操作状态，对环境有相应的洁净级别的要求，以防止对所处理的材料或产品造成粉尘或微生物的污染。
为达到“动态”的条件，这些区域在设计上要达到“静态”的洁净标准。“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。每个或每套房间都要分别进行“静态”和“动态”的确定。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点。在开放的洁净区内的工作点上，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。
密封隔离箱和手套箱内，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。
 Notes注:
a)        Particle measurement based on the use of a discrete airborne particle counter to measure the concentration of particles at designated sizes equal to or greater than the threshold stated. A continuous measurement system should be used for monitoring the concentration of particles in the grade A zone, and is recommended for the surrounding grade B areas. For routine testing the total sample volume should not be less than 1 m3 for grade A and B areas and preferably also in grade C areas.
尘埃粒子检查是用不连续尘埃粒子记数器测量一定量空气中等于或大于一定粒子大小的尘埃粒子的浓度。在A区必须有持续监控的装置，来检测该区域内尘埃粒子的浓度，建议在A区周围的B区也安装这样的装置。在A级和B级区常规的检查取样量，应不少于1 m3，在C级区的取样量最好也达到该要求。
b)        The particulate conditions 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. The particulate conditions for grade A “in operation” given in the table should be maintained in the zone immediately surrounding the product whenever the product or open container is exposed to the environment. It is accepted that it may not always be possible to demonstrate conformity with particulate standards at the point of fill when filling is in progress, due to the generation of particles or droplets from the product itself.
上表中的“静态”下的微粒情况，必须在操作完成后，“自净”运行15-20分钟后达到。当产品和开口容器接触环境时，在紧接产品的的周围区域，尘埃情况必须保持在A级“动态”标准。灌装时，在灌装点由于产品本身产生的微粒和液滴，有时达不到微粒标准是可以接受的。
c)        In order to reach the B, C and D air grades, the number of air changes should be related to the size of the room and the equipment and personnel present in the room. The air system should be provided with appropriate terminal filters such as HEPA for grades A, B and C.
为达到B、C、D级洁净，要结合房间的大小、设备和相关人员的情况确定换气次数。在A、B、C级洁净区，必须在空气系统中使用合适的终端过滤器，如HEPA。
d)        The guidance given for the maximum permitted number of particles in the "at rest" and “in operation” conditions correspond approximately to the cleanliness classes in the EN/ISO 14644-1 at a particle size of 0.5 µm.
对粒径为0.5μm的粒子，规范规定的“静态”和“动态”下允许的最多尘埃粒子数，与EN/ISO14644-1中洁净区的规定相当。
e)        These areas are expected to be completely free from particles of size greater than or equal to 5 µm. As it is impossible to demonstrate the absence of particles with any statistical significance the limits are set to 1 particle / m3. During the clean room qualification it should be shown that the areas can be maintained within the defined limits.
这些区域不允许有大于或等于5μm的粒子，由于不可能用任何统计学意义证明没有尘埃粒子，这里将限度定为1个/m3。在洁净房间的验证中，必须表明在规定的限度内。
f)        The requirements and limits will depend on the nature of the operations carried out.
要求和限度，将根据操作的性质而定。
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。
4. The areas should be monitored during operation, in order to control the particulate cleanliness of the various grades.
这些区域内必须有运行过程中的监控，以控制各个级别下的尘埃粒子洁净度。
5. 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.
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。
Additional microbiological monitoring is also required outside production operations, e.g. after validation of systems, cleaning and sanitisation.
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。
6. 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。

10. 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.
Because of this special technology particular attention should be paid to, at least the following: equipment design and qualification, validation and reproducibility of cleaning-in-place and sterilisation-in-place, background cleanroom environment in which the equipment is located, operator training and clothing, and interventions in the critical zone of the equipment including any aseptic assembly prior to the commencement of filling.
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，设备可以安装在最低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，动态时只要求符合可行限度。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。
对此设备，要特别注意如下几点：
设备设计和验证，现场清洁消毒的验证和可重复性，设备安装环境，人员的培训和服装，
设备关键区域的设备连接，包括灌装前的无菌装置。
Terminally sterilised products 最终灭菌产品
11. 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 environment.
Filling of products for terminal sterilisation should be carried out in at least a grade C environment.
Where the product is at unusual risk of contamination from the environment, for example because the filling operation is slow or the containers are wide-necked or are necessarily exposed for more than a few seconds before sealing, the filling should be done in a grade A zone with at least a grade C background. Preparation and filling of ointments, creams, suspensions and emulsions should generally be carried out in a grade C environment before terminal sterilisation.
为了降低微生物和微粒污染的风险，原材料和大部分产品的处理，应在最低D级的环境里进行，适用于过滤和灭菌。如果产品的微生物污染的风险很高（如产品易生菌、或灭菌前要长时间存放，生产过程要在开口容器中进行），生产应在C级环境进行。最终灭菌产品的灌装最低要在C级环境进行。
如果产品受到环境污染的风险高，例如：灌装速度慢，使用大口容器，或密封前要暴露几秒钟，灌装要在C级环境中的A级区域进行，背景环境最低为C级。在灭菌前，软膏、霜剂、混悬剂、栓剂的制备和灌装应在C级环境进行。

Aseptic preparation 无菌制备
12. Components after washing should be handled in at least a grade D environment. Handling of sterile starting materials and components, unless subjected to sterilisation or filtration through a micro-organism-retaining filter later in the process, should be done in a grade A environment with grade B background. Preparation of solutions which are to be sterile filtered during the process should be done in a grade C environment; if not filtered, the preparation of materials and products should be done ina grade A environment with a grade B background.
Handling and filling of aseptically prepared products should be done in a grade A environment with a grade B background.
Prior to the completion of stoppering, transfer of partially closed containers, as used in freeze drying should be done either in a grade A environment with grade B background or in sealed transfer trays in a grade B environment.
Preparation and filling of sterile ointments, creams, suspensions and emulsions should be done in a grade A environment, with a grade B background, when the product is exposed and is not subsequently filtered.
清洗后的材料要在最低D级环境下处理。无菌产品的原料和辅料，除非将在生产过程中进行灭菌或采用微生物滞留过滤器过滤除菌，要在B级环境下的A级区处理。采用过滤除菌的溶液的制备，要在C级环境下进行，如果不过滤，要在B级环境下的A级区处理。
通过无菌方法生产的产品，要在B级环境下的A级区处理和灌装。
在完成加盖前，半密封容器的传递，如在冻干中使用的， 要在B级环境下的A级区进行，或在B级环境中的密封的转移盘中进行。
如果产品有暴露和不再进行灭菌，软膏、霜剂、混悬剂、栓剂和乳剂的制备和灌装，要在B级环境下的A级区处理。
Personnel 人员
13. Only the minimum number of personnel required should be present in clean areas; this is particularly important during aseptic processing. Inspections and controls should be conducted outside the clean areas as far as possible.
只有工作需要的最低人数可以进入洁净区，这对无菌生产过程特别重要。检查和控制都要尽可能在洁净区外面进行。
14. All personnel (including those concerned with cleaning and maintenance) employed in such areas should receive regular training in disciplines relevant to the correct manufacture of sterile products. This training should include reference to hygiene and to the basic elements of microbiology. When outside staff who have not received such training (e.g. building or maintenance contractors) need to be brought in, particular care should be taken over their instruction and supervision.
所有在这些区域工作的人员（包括清洁和维护人员）都要定期进行与无菌药品生产有关的纪律培训。这些培训要包括卫生和微生物学的基本知识。当外来的没有接受培训的人员（如建造或维修人员）需要进入时，要特别注意给予指导和监督。
15. Staff who have been engaged in the processing of animal tissue materials or of cultures of micro-organisms other than those used in the current manufacturing process should not enter sterile-product areas unless rigorous and clearly defined entry procedures have been followed.
从事动物组织加工处理或微生物培养的人员，不包括生产在用的材料，除非遵照严格明确的进入程序，不可进入洁净区。
16. High standards of personal hygiene and cleanliness are essential. Personnel involved in the manufacture of sterile preparations should be instructed to report any condition which may cause the shedding of abnormal numbers or types of contaminants; periodic health checks for such conditions are desirable. Actions to be taken about personnel who could be introducing undue microbiological hazard should be decided by a designated competent person.
高标准的人员卫生和清洁是非常关键的。要指导涉及生产的人员，及时报告可能产生异常污染的任何情况；要对人员定期进行健康检查。对可能带来微生物污染的人的处理措施，要由 指定的合格的人员作出决定。
17. Changing and washing should follow a written procedure designed to minimise contamination of clean area clothing or carry-through of contaminants to the clean areas.
要按照书面的更换和清洗程序，尽可能降低对洁净区工作服的污染或将污染物带进洁净区。
18. Wristwatches, make-up and jewellery should not be worn in clean areas.
在洁净区内不准戴手表、首饰和化装。
19. The clothing and its quality should be appropriate for the process and the grade of the working area. It should be worn in such a way as to protect the product from contamination.
The description of clothing required for each grade is given below:
工作服及其材质必须适应所从事的工作和工作场所的洁净级别。要正确穿戴，防止对产品产生污染。下面对各个级别洁净区的工作服的要求进行说明：
Grade D: Hair and, where relevant, beard should be covered. A general protective suit and appropriate shoes or overshoes should be worn. Appropriate measures should be taken to avoid any contamination coming from outside the clean area.
D级：头发和胡须要覆盖，要穿戴一般工作服和合适的工作鞋或鞋套。要采取适当措施防止污染物从外界进入洁净区。
Grade C: Hair and where relevant beard and moustache should be covered. A single or two-piece trouser suit, gathered at the wrists and with high neck and appropriate shoes or overshoes should be worn. They should shed virtually no fibres or particulate matter.
C级要覆盖头发和所有胡须，要穿戴一件或两件套裤式、袖口收拢、高领的工作服，穿合适的工作鞋或鞋套。这些工作服都不得脱落纤维或颗粒。
Grade A/B: Headgear should totally enclose hair and, where relevant, beard and moustache; it should be tucked into the neck of the suit; a face mask should be worn to prevent the shedding of droplets. Appropriate sterilised, non-powdered rubber or plastic gloves and sterilised or disinfected footwear should be worn. Trouser-legs should be tucked inside the footwear and garment sleeves into the gloves. The protective clothing should shed virtually no fibres or particulate matter and retain particles shed by the body.
A/B级：头套要覆盖所有的头发和胡须并要收紧在工作服领子内；要带口罩以防止液体飞沫的喷射。要穿戴正确消毒后的、不脱落粉尘的橡胶或塑料手套、灭菌或消毒的鞋子。袖口要塞进手套内，裤腿要塞进鞋子里。保护工作服要不脱落任何纤维或颗粒，并阻隔身体产生的颗粒。
20. Outdoor clothing should not be brought into changing rooms leading to grade B and C rooms. For every worker in a grade A/B area, clean sterile (sterilised or adequately sanitised) protective garments should be provided at each work session. Gloves should be regularly disinfected during operations. Masks and gloves should be changed at least for every working session.
外界的衣服不得带进通向B级和C级的更衣室。在A/B级区域工作的各个岗位工作的人员，要穿戴洁净服（灭菌的或充分消毒的）。在生产操作中要对手套定期消毒。每班都要更换口罩和手套。
21. Clean area clothing should be cleaned and handled in such a way that it does not gather additional contaminants which can later be shed. These operations should follow written procedures. Separate laundry facilities for such clothing are desirable. Inappropriate treatment of clothing will damage fibres and may increase the risk of shedding of particles.
洁净区工作服的清洁和处理的方法，要保证不吸附或携带随后又会脱落的污染物。这些操作要按照书面规程。这些工作服最好分开洗涤。对工作服不适当的处理方法会损害纤维、增加颗粒脱落的风险。

22. In clean areas, all exposed surfaces should be smooth, impervious and unbroken in order to minimise the shedding or accumulation of particles or micro-organisms and to permit the repeated application of cleaning agents, and disinfectants where used.
在洁净区，所有暴露的表面都要光滑、不透水的和不破裂，以减少粉尘和微生物的脱落和累积，允许重复使用清洁剂和消毒剂。
23. To reduce accumulation of dust and to facilitate cleaning there should be no uncleanable recesses and a minimum of projecting ledges, shelves, cupboards and equipment. Doors should be designed to avoid those uncleanable recesses; sliding doors may be undesirable for this reason.
为减少粉尘的累积并且易于清洁，不能有清洁不到的角落，保持最少量的突出物、支架、厨柜和设备。门的设计要避免难清洁角落。该区域内不宜用拉门。
24. False ceilings should be sealed to prevent contamination from the space above them.
吊顶要密封，防止来自上面空间的污染。
25. Pipes and ducts and other utilities should be installed so that they do not create recesses, unsealed openings and surfaces which are difficult to clean.
管道和其他设施的安装不得产生死角、空隙或表面不易清洁。
26. Sinks and drains should be prohibited in grade A/B areas used for aseptic manufacture. In other areas air breaks should be fitted between the machine or sink and the drains. Floor drains in lower grade clean rooms should be fitted with traps or water seals to prevent back-flow.
用于无菌生产的A/B区不得设水池和地漏。其他区域的设备或水槽与排水系统间的空气要断路。低洁净级别区域的房间的地漏要有水弯或水封防止倒流。
27. Changing rooms should be designed as airlocks and used to provide physical separation of the different stages of changing and so minimise microbial and particulate contamination of protective clothing. They should be flushed effectively with filtered air. The final stage of the changing room should, in the at-rest state, be the same grade as the area into which it leads.
The use of separate changing rooms for entering and leaving clean areas is sometimes desirable. In general hand washing facilities should be provided only in the first stage of the changing rooms.
更衣室要设计成气闸室，以提供不同阶段更衣的实际隔离，减少对工作服的微生物和尘埃粒子的污染。更衣室要经过过滤空气有效的冲洗。更衣室的最后阶段要与所进入的区域的洁净级别（静态）相一致。最好在进入洁净区和离开洁净区时使用不同的更衣室。一般洗手要在更衣的第一阶段。
28. Both airlock doors should not be opened simultaneously. An interlocking system or a visual and/or audible warning system should be operated to prevent the opening of more than one door at a time.
气闸室的两个门不可以同时打开。要有联锁装置，或视觉或听觉的报警装置，防止超过一个的门同时打开。
29. A filtered air supply should maintain a positive pressure and an air flow relative to surrounding areas of a lower grade under all operational conditions and should flush the area effectively. Adjacent rooms of different grades should have a pressure differential of 10 - 15 pascals (guidance values). Particular attention should be paid to the protection of the zone of greatest risk, that is, the immediate environment to which a product and cleaned components which contact the product are exposed. The various recommendations regarding air supplies and pressure differentials may need to be modified where it becomes necessary to contain some materials, e.g. pathogenic, highly toxic, radioactive or live viral or bacterial materials or products. Decontamination of facilities and treatment of air leaving a clean area may be necessary for some operations.
过滤空气要对周围低级别区域保持相对的正气压和气流，并有效地冲洗整个区域。相邻的不同级别的房间要保持10-15Pa的压差(指导值)。对高风险区域，即产品和与产品直接接触的洁净部件的暴露环境，要特别注意保护。对供气和压差方面的各种建议，在含有病原体、高毒性、放射性和有活病毒或活菌的原材料或产品的地方，可能需要修改。在一些操作中，对设备污染的清除和洁净区排风的处理是必要的。
30. It should be demonstrated that air-flow patterns do not present a contamination risk, e.g. care should be taken to ensure that air flows do not distribute particles from a particle-generating person, operation or machine to a zone of higher product risk.
要证明空气流动的方式不会带来污染的风险，例如：要注意保证气流不会将一个人员、操作或机器产生的尘埃扩散到高风险产品区。
31. A warning system should be provided to indicate failure in the air supply. Indicators of pressure differences should be fitted between areas where these differences are important. These pressure differences should be recorded regularly or otherwise documented.
要安装供气失效的警报系统，在压差重要的区域之间，要安装压差计。这些压差要定期进行记录或用文件记录。

32. A conveyor belt should not pass through a partition between a grade A or B area and a processing area of lower air cleanliness, unless the belt itself is continually sterilised (e.g. in a sterilising tunnel).
传送带不可以穿过A/B级区和其他低洁净度处理区域的间隔，除非传送带被持续的灭菌（如在灭菌隧道中）。
33. As far as practicable equipment, fittings and services should be designed and installed so that operations, maintenance and repairs can be carried out outside the clean area. If sterilisation is required, it should be carried out, wherever possible, after complete reassembly.
设备、配件和设施要以能够在洁净区外面进行操作、维护和修理的方式进行设计和安装。重新安装后，如果需要消毒，在可能的地方要进行消毒
34. When equipment maintenance has been carried out within the clean area, the area should be cleaned, disinfected and/or sterilised where appropriate, before processing recommences if the required standards of cleanliness and/or asepsis have not been maintained during the work.
在洁净区内进行设备维护工作后，如果维修工作不能保持要求的清洁和无菌标准，要对该区域适当的地方进行清洁、消毒或灭菌。
35. Water treatment plants and distribution systems should be designed, constructed and maintained so as to ensure a reliable source of water of an appropriate quality. They should not be operated beyond their designed capacity. Water for injections should be produced, stored and distributed in a manner which prevents microbial growth, for example by constant circulation at a temperature above 70°C.
水处理和分配系统的设计、安装和维护要保证可靠的供水质量。系统的运行不可以超过设计的性能。注射用水的制备、储存和输送，要防止微生物的生长，例如在70°C以上持续循环。
36. All equipment such as sterilisers, air handling and filtration systems, air vent and gas filters, water treatment, generation, storage and distribution systems should be subject to validation and planned maintenance; their return to use should be approved.
所有设备如灭菌柜、空气处理和过滤系统、排风和气体过滤、水处理、制备、储存和输送系统都要进行验证和有计划地维护，重新使用要经过批准。
Sanitation 清洁卫生
37. The sanitation of clean areas is particularly important. They should be cleaned thoroughly in accordance with a written programme. Where disinfectants are used, more than one type should be employed. Monitoring should be undertaken regularly in order to detect the development of resistant strains.
洁净区的卫生特别重要。要按照书面程序进行彻底清洁。在进行消毒的地方，要用一种以上的消毒剂。要定期进行监控，以检查抗性菌的生长。
38. Disinfectants and detergents should be monitored for microbial contamination; dilutions should be kept in previously cleaned containers and should only be stored for defined periods unless sterilised. Disinfectants and detergents used in Grades A and B areas should be sterile prior to use.
要对清洁剂和消毒剂进行微生物监控；稀释溶液要装在预先清洁的容器内，除非进行灭菌，只能保存规定的期限。A/B区使用的清洁剂和消毒剂在使用前应该是无菌的。
39. Fumigation of clean areas may be useful for reducing microbiological contamination in inaccessible places.
对洁净区内难以进入的角落进行熏蒸是减少微生物污染的有用的方法。

40. Precautions to minimise contamination should be taken during all processing stages including the stages before sterilisation.
在所有生产阶段，包括灭菌前各阶段，要注意采取措施预防和减少污染。
41. Preparations of microbiological origin should not be made or filled in areas used for the processing of other medicinal products; however, vaccines of dead organisms or of bacterial extracts may be filled, after inactivation, in the same premises as other sterile medicinal products.
微生物制品不能在其他药品生产使用的区域进行处理或灌装，但是死的微生物或细菌提取物的疫苗在灭活后可以在其他无菌产品生产的设施中进行灌装。
42. Validation of aseptic processing should include a process simulation test using a nutrient medium (media fill). Selection of the nutrient medium should be made based on dosage form of the product and selectivity, clarity, concentration and suitability for sterilisation of the nutrient medium. The process simulation test should imitate as closely as possible the routine aseptic manufacturing process and include all the critical subsequent manufacturing steps. It should also take into account various interventions known to occur during normal production as well as worst case situations. Process simulation tests should be performed as initial validation with three consecutive satisfactory simulation tests per shift and repeated at defined intervals and after any significant modification to the HVAC-system, equipment, process and number of shifts. Normally process simulation tests should be repeated twice a year per shift and process. The number of containers used for media fills should be sufficient to enable a valid evaluation. For small batches, the number of containers for media fills should at least equal the size of the product batch. The target should be zero growth but a contamination rate of less than 0.1% with 95% confidence limit is acceptable. The manufacturer should establish alert and action limits. Any contamination should be investigated.
无菌生产过程的验证，要包括利用营养培养基进行的模拟试验。要根据产品的剂型和培养基的选择性、澄明度、浓度和灭菌的适应性来选择使用培养基。过程模拟试验要尽可能地接近正常的无菌生产程序，包括随后的各个关键生产步骤。同时要考虑在正常生产过程中的各种干预和挑战性状况。过程模拟试验在验证的开始阶段，要每个班次连续做三次满意的试验，在规定的时间间隔或空气处理系统、设备、生产方法和班次的任何重要改变后，重复进行。通常每班和每个工艺每年重复两次过程模拟试验。试验中用于培养基灌装的容器的数量要足够进行有效的评估。对一个小批量，用于培养基灌装的容器数量至少等于产品的批量。目标是零生长，但在污染率低于0.1%，可信度在95%时是可以接受的。生产商要设置警戒限度和措施限度。所有的污染都要进行调查。
43. Care should be taken that any validation does not compromise the processes.
要注意任何验证都不会影响生产。
44. Water sources, water treatment equipment and treated water should be monitored regularly for chemical and biological contamination and, as appropriate, for endotoxins. Records should be maintained of the results of the monitoring and of any action taken.
水源、水处理设备和处理过的水，要定期在化学和微生物污染方面、可能的情况下包括内毒素进行监控。对监控结果和采取的任何措施都要进行记录。
44. Water sources, water treatment equipment and treated water should be monitored regularly for chemical and biological contamination and, as appropriate, for endotoxins. Records should be maintained of the results of the monitoring and of any action taken.
在洁净区内，特别是当无菌生产在进行中，活动要尽可能少，人员的活动要受到控制并按照方法，避免由于过多活动带来尘埃颗粒和微生物的扩散。周围环境的温度和湿度不能高到不舒服，因为工作服是相当密封的。
46. Microbiological contamination of starting materials should be minimal. Specifications should include requirements for microbiological quality when the need for this has been indicated by monitoring.
原料的微生物污染必须低。当指明该项目需要控制时，标准里要包括微生物方面的质量要求。
47. Containers and materials liable to generate fibres should be minimised in clean areas.
容易产生纤维的容器和原料要尽量少进入洁净区。
48. Where appropriate, measures should be taken to minimise the particulate contamination of the end product.
适当的条件下，要采取措施，减少对终产品的尘埃粒子的污染。
49. Components, containers and equipment should be handled after the final cleaning process in such a way that they are not recontaminated.
原辅料、容器和设备在进行清洁后，在处理过程中要避免再次污染。
50. The interval between the washing and drying and the sterilisation of components, containers and equipment as well as between their sterilisation and use should be minimised and subject to a time-limit appropriate to the storage conditions.
原辅料、容器、和设备的清洗和干燥以及灭菌之间的间隔时间，灭菌和使用之间的间隔时间，在规定的储存条件下要尽可能缩短，并控制在时间限度内。
51. The time between the start of the preparation of a solution and its sterilisation or filtration through a micro-organism-retaining filter should be minimised. There should be a set maximum permissible time for each product that takes into account its composition and the prescribed method of storage.
溶液的开始配制到灭菌或微孔过滤处理的时间间隔要尽可能短。应该根据产品的组分和规定的储存方法，设定最长允许时间。
52. The bioburden should be monitored before sterilisation. There should be working limits on contamination immediately before sterilisation which are related to the efficiency of the method to be used. Where appropriate the absence of pyrogens should be monitored. All solutions, in particular large volume infusion fluids, should be passed through a micro-organism-retaining filter, if possible sited immediately before filling.
在灭菌前要对微生物的含量进行监控。对于同灭菌方法的效果相关的灭菌前的步骤的污染，要有工作限度。适当的情况下，要对无热源进行监控。所有溶液，特别是大剂量注射液，要通过微生物过滤器，如果可能，过滤步骤紧接着灌装。
53. Components, containers, equipment and any other article required in a clean area where aseptic work takes place should be sterilised and passed into the area through double-ended sterilisers sealed into the wall, or by a procedure which achieves the same objective of not introducing contamination. Non-combustible gases should be passed through micro-organism retentive filters.
原辅料、容器、和设备以及其他无菌操作的洁净区内需要的物品，应该灭菌并且通过穿墙安装的两端开门的灭菌柜，或通过能够达到同样目的，不带进污染的程序。非易燃气体要通过微生物过滤器。
54. The efficacy of any new procedure should be validated, and the validation verified at scheduled intervals based on performance history or when any significant change is made in the process or equipment.
任何一个新程序的效果都要进行验证，要根据运行历史定期地，或当生产工艺或设备有重大改变时，对验证的结果进行再确认。

55. All sterilisation processes should be validated. Particular attention should be given when the adopted sterilisation method is not described in the current edition of the European Pharmacopoeia, or when it is used for a product which is not a simple aqueous or oily solution. Where possible, heat sterilisation is the method of choice. In any case, the sterilisation process must be in accordance with the marketing and manufacturing authorisations.
所有灭菌过程都要进行验证，特别要注意现行欧洲药典没有采用的灭菌方法，或当所灭菌的产品不是简单的水溶液或油溶液时。可能的情况下，加热灭菌是一种可以选择的方法。任何情况下，灭菌方法必须与生产批文规定的方法一致。
56. Before any sterilisation process is adopted its suitability for the product and its efficacy in achieving the desired sterilising conditions in all parts of each type of load to be processed should be demonstrated by physical measurements and by biological indicators where appropriate. The validity of the process should be verified at scheduled intervals, at least annually, and whenever significant modifications have been made to the equipment. Records should be kept of the results.
在采用任何一种灭菌方法前，其对产品的适应性，和在灭菌产品的各种装载情况的每一个部分达到期望的灭菌状态的有效性，要在适当情况下，用实际的测量或生物指示剂的方法进行证明。要定期验证过程的有效性，至少每年一次，并且在设备进行重大改变时要验证确认。对验证结果进行记录。
57. For effective sterilisation the whole of the material must be subjected to the required treatment and the process should be designed to ensure that this is achieved.
为保持灭菌的有效性，所有的原料要按照要求进行处理，生产工艺的设计要保证这是能够实现的。
58. Validated loading patterns should be established for all sterilisation processes .
要为所有的灭菌工艺建立验证的装载方式。
59. Biological indicators should be considered as an additional method for monitoring the sterilisation. They should be stored and used according to the manufacturers instructions, and their quality checked by positive controls. If biological indicators are used, strict precautions should be taken to avoid transferring microbial contamination from them.
要将生物指示作为灭菌监控的辅助手段。要按照操作指南进行储存和使用，并利用阳性控制检查其质量。如果采用了生物指示，要采取严格的措施，防止由此所带来的微生物污染。
60. There should be a clear means of differentiating products which have not been sterilised from those which have. Each basket, tray or other carrier of products or components should be clearly labelled with the material name, its batch number and an indication of whether or not it has been sterilised. Indicators such as autoclave tape may be used, where appropriate, to indicate whether or not a batch (or sub-batch) has passed through a sterilisation process, but they do not give a reliable indication that the lot is, in fact, sterile
要有清楚的方法区分灭菌的和没有经过灭菌的产品。每一篮子、盘子或其他容器装的产品或原辅料要用物料名称、批号以及是否灭菌的指示清楚的标记。在适当的地方，可能使用灭菌指示带等指示来表明一批（或亚批）产品是否经过灭菌处理，但是，在实际上，它们不能可靠的指示该批产品无菌。
61. Sterilisation records should be available for each sterilisation run. They should be approved as part of the batch release procedure.
每一次灭菌都要有灭菌记录，并作为批产品放行程序的一部分进行批准。
Sterilisation by heat 加热灭菌
62. Each heat sterilisation cycle should be recorded on a time/temperature chart with a sufficiently large scale or by other appropriate equipment with suitable accuracy and precision. The position of the temperature probes used for controlling and/or recording should have been determined during the validation, and where applicable also checked against a second independent temperature probe located at the same position.
每一个加热灭菌循环都要在有足够大范围的时间/温度表上，或在其它有适当精确度的设备上记录。用于控制和/或记录的温度探针的位置要在验证时予以确定，如果可能，要用另一个温度探针放在同一个位置进行核对。
63. Chemical or biological indicators may also be used, but should not take the place of physical measurements.
化学或微生物指示剂可以使用，但不能代替物理检测。
64. Sufficient time must be allowed for the whole of the load to reach the required temperature before measurement of the sterilising time-period is commenced. This time must be determined for each type of load to be processed.
在开始测定灭菌时间前，要有足够的时间让所有装载的产品达到规定的温度。对每种装载要确定这个时间。
65. After the high temperature phase of a heat sterilisation cycle, precautions should be taken against contamination of a sterilised load during cooling. Any cooling fluid or gas in contact with the product should be sterilised unless it can be shown that any leaking container would not be approved for use.
在加热灭菌的高温阶段后，在冷却阶段要采取措施防止污染。任何与产品接触的冷却剂或气体都要进行灭菌，除非证明不使用任何有泄露的容器。
Moist heat 湿热灭菌
66. Both temperature and pressure should be used to monitor the process. Control instrumentation should normally be independent of monitoring instrumentation and recording charts. Where automated control and monitoring systems are used for these applications they should be validated to ensure that critical process requirements are met. System and cycle faults should be registered by the system and observed by the operator. The reading of the independent temperature indicator should be routinely checked against the chart recorder during the sterilisation period. For sterilisers fitted with a drain at the bottom of the chamber, it may also be necessary to record the temperature at this position, throughout the sterilisation period. There should be frequent leak tests on the chamber when a vacuum phase is part of the cycle.
使用温度和压力来监控灭菌过程。控制仪器与监控仪器和记录表是各自独立的。如果采用自动化的控制和监控系统，要进行验证，保证达到关键生产工艺要求。系统的和周期性的故障要通过系统进行记录和由操作者进行观察。要对照灭菌过程中的记录图纸，对独立的温度指示器的读取进行定期检查。在底部有排水装置的灭菌柜，在整个灭菌过程中也要记录这个位置的温度。如果灭菌循环中有真空阶段，要经常进行泄露检查。.
67. The items to be sterilised, other than products in sealed containers, should be wrapped in a material which allows removal of air and penetration of steam but which prevents recontamination after sterilisation. All parts of the load should be in contact with the sterilizing agent at the required temperature for the required time.
如果灭菌的产品不是在密封的容器里，要用能够排除空气并让蒸汽渗入，但能够防止灭菌后再污染的材料进行包装。所有的装载的产品，都要与灭菌剂在规定的温度下接触达到规定的时间。
68. Care should be taken to ensure that steam used for sterilisation is of suitable quality and does not contain additives at a level which could cause contamination of product or equipment.
要注意保证灭菌所用的蒸汽的质量，保证其包含物不会污染产品或设备。
Filtration of medicinal products which cannot be sterilised in their final container 不能在最终容器内进行灭菌的产品的过滤
82. Filtration alone is not considered sufficient when sterilisation in the final container is possible. With regard to methods currently available, steam sterilisation is to be preferred. If the product cannot be sterilised in the final container, solutions or liquids can be filtered through a sterile filter of nominal pore size of 0.22 micron (or less), or with at least equivalent micro-organism retaining properties, into a previously sterilised container. Such filters can remove most bacteria and moulds, but not all viruses or mycoplasmas. Consideration should be given to complementing the filtration process with some degree of heat treatment.
当灭菌能在最终容器内进行的时候，只进行过滤是不充分的。就目前可用的方法，蒸汽灭菌是较好的。如果产品不能在最终容器中进行灭菌，溶液或液体可以用孔径为0.22微米（或更小）的无菌过滤器，或有相当的微生物滞留能力的过滤器，过滤到预先灭菌的容器中。这样的过滤器可以除去大部分的细菌和霉菌，但对病毒和支原体不能全部除去。应该考虑采取带有一定程度热处理的过滤方法。
83. Due to the potential additional risks of the filtration method as compared with other sterilization processes, a second filtration via a further sterilised micro-organism retaining filter, immediately prior to filling, may be advisable. The final sterile filtration should be carried out as close as possible to the filling point.
由于过滤方法与其他灭菌方法相比较，有潜在的额外风险，建议在灌装前用另一个无菌的微生物滞留过滤器进行第二次除菌过滤。终端无菌过滤要尽可能靠近灌装处。
84. Fibre shedding characteristics of filters should be minimal.
过滤器要尽可能不脱落纤维。
85. The integrity of the sterilised filter should be verified before use and should be confirmed immediately after use by an appropriate method such as a bubble point, diffusive flow or pressure hold test. The time taken to filter a known volume of bulk solution and the pressure difference to be used across the filter should be determined during validation and any significant differences from this during routine manufacturing, should be noted and investigated. Results of these checks should be included in the batch record. The integrity of critical gas and air vent filters should be confirmed after use. The integrity of other filters should be confirmed at appropriate intervals.
除菌过滤器的完整性应该在使用前进行检查，并且在使用后要立即用适当的方法，如气泡点、气散流、或压力保持试验等方法进行测试。过滤一定量溶液所用的时间和过滤器两侧的压差要在验证时确定，在正常生产时任何明显的偏差都要记录和进行调查。这些检查的结果要包括在批记录内。关键气体和空气过滤器的完整性要在使用后进行检查，其他的过滤器要在适当的时间间隔内进行检查。
86. The same filter should not be used for more than one working day unless such use has been validated.
同一个过滤器使用不能超过一个工作日，除非有验证支持。
87. The filter should not affect the product by removal of ingredients from it or by release of substances into it.
过滤器不应因为除去产品中成分或向产品中释放某些物质而影响产品质量。
Finishing of sterile products 无菌产品的完成
88 Containers should be closed by appropriately validated methods. Containers closed by fusion, e.g. glass or plastic ampoules should be subject to 100% integrity testing. Samples of other containers should be checked for integrity according to appropriate procedures.
容器要用经过验证的方法密封。用熔融方法密封的容器，如玻璃或塑料安瓶要100%做完整性检查。其他容器要根据适当的程序取样检查其完整性。
89. Containers sealed under vacuum should be tested for maintenance of that vacuum after an appropriate, pre-determined period.
在真空条件下密封的容器，应该在适当的预先确定的日期后检查真空保持度。
90. Filled containers of parenteral products should be inspected individually for extraneous contamination or other defects. When inspection is done visually, it should be done under suitable and controlled conditions of illumination and background. Operators doing the inspection should pass regular eye-sight checks, with spectacles if worn, and be allowed frequent breaks from inspection. Where other methods of inspection are used, the process should be validated and the performance of the equipment checked at intervals. Results should be recorded.
灌装了的注射剂的容器，要逐个检查有无异物污染或其它缺陷。如果用目视检查，要在有散射光为背景的合适的受控条件下进行。进行目视检查的操作人员要定期进行视力检查，可以戴眼镜，并允许经常间断检查。采用其他检查方式时，要进行方法验证，并对设备的性能进行定期检查，记录检查结果。
Quality control 质量控制
91. The sterility test applied to the finished product should only be regarded as the last in a series of control measures by which sterility is assured. The test should be validated for the product(s) concerned.
对最终产品的无菌检查仅是一系列无菌保证控制措施的最后一步。对产品有关的检查方法要进行验证。
92. In those cases where parametric release has been authorised, special attention should be paid to the validation and the monitoring of the entire manufacturing process.
当产品在进行参数放行时，要特别注意对整个生产过程的验证和监控。
93. Samples taken for sterility testing should be representative of the whole of the batch, but should in particular include samples taken from parts of the batch considered to be most at risk of contamination, e.g.:
a. for products which have been filled aseptically, samples should include containers filled at the beginning and end of the batch and after any significant intervention,
b. or products which have been heat sterilised in their final containers, consideration should be given to taking samples from the potentially coolest part of the load.
灭菌检验所取的样品，要代表整个批的产品，但是特别应该包括特殊情况下从一批产品的污染风险最大的部分中所取的样品，例如：
a.        对无菌灌装的产品，样品应包括批的开始、结束以及中间任何重要调整之后的样品。
b.        或对在最终容器中进行加热灭菌的产品，应该考虑从装载的最低温度的地方取样。