类别

条款

PIC/S annex1征求意见稿2017-12-29

中文

影响

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4.1

4.1 The manufacturer should ensure that there are sufficient appropriate personnel, suitably qualified and experienced in the manufacture and testing of sterile medicines and any of the operations, to ensure compliance with Good Manufacturing Practice applicable to the manufacture of sterile medicinal products.

4.1 企业应当配备足够数量适当人员，这些人员应具有无菌药品制造测试和操作的资质和经验，以保障符合GMP有关无菌药品制造的相关规定。

无影响- 长期以来一直是基本GMP原则的内在要求（条款2.1）。本条款引用了无菌生产和测试。

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4.10

4.10 Changing and hand washing should follow a written procedure designed to minimize contamination of clean area clothing or carry-through of contaminants to the clean areas. Garments should be visually checked for cleanliness and integrity prior to entry to the clean room. For sterilized garments, particular attention should be taken to ensure that garments and eye coverings have been sterilized and that their packaging is integral before use. Reusable garments should be replaced based at a set frequency determined by qualification or if damage is identified.

4.10 应当建立更衣和洗手书面程序，以最大降低对洁净服和对洁净区的污染。进入洁净室前，应目视检查洁净服的清洁和完整程度。使用前应特别注意无菌服和护目镜已经灭菌，包装完整。应当根据验证确定无菌服使用次数，发现破损即应更换。

洗手和管理服装的改变，在灭菌检查之后，增加对服装外观清洁和完整性的要求。许多公司以粗略或非正式的方式进行清洁/完整性检查。现在，它是强制性的，将需要更详细的程序，并需要有证明文件证明已经完成

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4.11

4.11 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.

4.11 服装质量应和所从事工作和洁净室级别相适应。穿戴方式应能保护产品不受污染。

用不用采取相应的措施。

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4.12

4.12 The description of clothing required for each grade is given below: a) Grade D: Hair, beards and moustaches should be covered. A general protective suit and appropriately disinfected shoes or overshoes should be worn. Appropriate measures should be taken to avoid any contamination coming from outside the clean area. b) Grade C: Hair, beards and moustaches should be covered. A single or two-piece trouser suit gathered at the wrists and with high neck and appropriately disinfected or sterilized shoes or overshoes should be worn. They should shed virtually no fibres or particulate matter. c) Grade A/B: Sterile headgear should totally enclose hair and facial hair; it should be tucked into the neck of the sterile suit; a sterile face mask and sterile eye coverings should be worn to cover all facial skin and prevent the shedding of droplets and particles. Appropriate sterilized, non-powdered rubber or plastic gloves and sterilized 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. Garments should be packed and folded in such a way as to allow operators to change into the garments with contact to the outer surfaces of the garment reduced to a minimum. Note: This is minimum guidance and higher standards of clothing may be required dependent on the processes performed in the specific area.

4.12 各级别衣服的要求如下：
a)D级：头发，胡须应遮盖。穿普通防护服装和适当消毒过的鞋或鞋套。应采取适当措施防止外界污染物进入洁净室。
b)C级：头发，胡须应遮盖。穿腰部系紧的连体或分体洁净服和高筒适当消毒过或灭菌的鞋或鞋套。洁净衣物不应掉纤维或脱落粒子。
c)A/B级：灭菌头罩应完全遮盖头发和前额发际，披肩应塞入到无菌服颈部；无菌口罩和护目镜应能遮盖面部皮肤防止散布液滴和粒子。戴经过适当灭菌的无粉尘的橡胶或塑料手套，穿灭菌的鞋套。裤腿硬塞进鞋套，袖口应塞入手套里。洁净衣物不应掉毛或脱落粒子，并能限制体屑散出。洁净服折叠包装方式应当使操作者在穿戴时尽量少接触无菌服外表面。
注：这是最低要求，特殊区域所从事的操作可能要求更高标准洁净服。

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4.13

4.13 Outdoor clothing should not be brought into changing rooms leading to grade B and C rooms. It is recommended that facility suits, including dedicated socks be worn before entry to change rooms for grade C and B. Where clothing is reused this should be considered as part of the qualification.

4.13 不得穿着室外衣服进入B级和C级更衣室。建议更换厂服包括专用袜子后，再进入B级和C级更衣室。多次使用的洁净服要进行验证。

增加在进入C级之前穿专用袜子的建议。这不是普遍的做法，很多情况下可能需要对更衣要求进行改变。

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4.14

4.14 For every worker in a grade A/B area, clean sterilized protective garments (including eye coverings and masks) of an appropriate size should be provided at each work session. Gloves should be regularly disinfected during operations. Garments and gloves should be changed at least for every working session.

4.14 A/B级洁净室的工作人员每次进入洁净室要更换相应尺码的清洁灭菌的洁净服，包括无菌护目镜和口罩。操作中手套要经常消毒。每次进入无菌室要更换洁净服和手套。

是不是应该对规定哪些操作后必须消毒。

A/B级服装，增加需要无菌眼罩，至少每进入进行更衣，无菌眼罩过去未被强制执行，之前只有口罩和手套要求如此频繁的进行更换

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4.15

4.15 Clean area clothing should be cleaned, handled and worn 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. After washing and before sterilization, garments should be checked for integrity.

4.15 洁净服在清洗处理时，不要受到额外污染，这种污染可能脱落在无菌室里。最好设置独立的洗衣设施。不恰当的洗涤可能损伤衣物纤维，增加粒子脱落。洗涤后灭菌前应检查衣物的完整性。

洁净服的清洗和灭菌增加了在灭菌前清洗后需要检查完整性，作为强制性的GMP要求，这将需要通过外包洗衣或者在内部进行程序化

是不是洗衣服的水至少是纯化水要求。不要受额外的污染，这种污染指是什么？

是不是需要单独设置洗衣设施，检测衣服设施，净化衣服设施，晾晒衣服设施等。

洗衣服需要标准操作规程吗？

微小变化

4.16

4.16 Activities in clean areas, especially when aseptic operations are in progress, should be kept to a minimum and movement of personnel should be controlled and methodical to avoid excessive shedding of particles and organisms due to over-vigorous activity. Operators performing aseptic operations should adhere to strict aseptic technique at all times. To prevent changes in air currents that introduce lower quality air, movement adjacent to the critical area should be restricted and the obstruction of the path of the unidirectional airflow must be avoided. The ambient temperature and humidity should be set to prevent shedding due to operators becoming too cold (leading to excessive movement) or too hot.

4.16 洁净区的动作，特别在进行无菌操作时，要尽可能少，人员的走动应加以控制并且加以规范，以免过度的活动散发出过量的粒子和微生物。环境的温度湿度要适当，避免过热过冷使操作者散发更多的粒子。

增加关于潜在的对气流的改变的说明。在对操作员干扰有争议时，检查人员可以借助气流可视化研究

怎借助气流可视化说明潜在的对气流的改变说明？

SOP中是否应该对洁净室无菌操作进行控制

微小变化

4.2

4.2 Only the minimum number of personnel required should be present in cleanrooms. The maximum number of operators in critical areas should be determined based on QRM principles, documented in the contamination control strategy, and validated during activities such as initial qualification and aseptic process simulations, so as not to compromise sterility assurance. This is particularly important during aseptic processing. Inspections and controls should be conducted outside the clean areas as far as possible.

4.2 洁净室操作人员数量应尽少。根据QRM原则确定关键操作区域人员最大容许数量，并在污染控制策略中加以表述，在初始确认活动和无菌模拟灌装中加以验证，以免破坏无菌保障。
这对于无菌工艺特别重要。应当尽量在洁净区外进行进行监察和控制。

扩展引用QRM进行确定，在CCS中记录并验证。更重视无菌加工的重要性。通常已经执行，可能有一些需要加强QRM和验证

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4.3

4.3 All personnel (including those performing cleaning and maintenance) employed in such areas should receive regular training, qualification (including sampling of the operators bioburden, using methods such as contact plates, at key locations e.g. hands arms and chest) and assessment in disciplines relevant to the correct manufacture of sterile products. This training should include reference to hygiene, cleanroom practices, contamination control, aseptic techniques, and potential safety implications to the patient of a loss of product sterility and in the basic elements of microbiology.

4.3 无菌区所有人员（包括从事清洁和维修工）应定期参加培训，确认（包括对操作工关键部位，手，手臂和胸部接触碟取样测验微生物负荷）并且评估是否遵守无菌生产的正确操作。培训应当包括个人卫生，洁净室操作，污染控制，无菌操作技术，产品染菌危及患者安全潜在可能性和微生物基本知识。

需要培训所有无菌操作相关人员，增加期望目标“确认和评估”，扩展了一些角色的具体定义。对于清洁人员，维修人员和监测人员的确认和评估可能不普遍。评估的概念展开进行解释。

怎样确认和评估是否遵守无菌生产的正确操作。

培训的内容应该进行完善。

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4.4

4.4 The personnel working in a grade A/B cleanroom should be trained for aseptic gowning and aseptic practices. Compliance with aseptic gowning procedures should be assessed and confirmed and this should be periodically reassessed at least annually and should involve both visual and microbiological assessment (using additional locations such as arms and chest). Only trained personnel who have passed the gowning assessment and have participated in a successful aseptic process simulation (APS) test, during which they performed their normal duties, should be authorized to enter any grade A/B area, in which aseptic operations will be conducted, or are being conducted, whilst unsupervised. The microbial monitoring of personnel in the grade A/B area should be performed to assess their aseptic behaviour. This monitoring should take place immediately after completion of a critical intervention and upon each exit from the cleanroom. It should be noted that there should also be an ongoing continuous monitoring program for personnel including some consideration of periodic monitoring under the supervision of the quality unit.

4.4 A/B区操作工应当进行无菌更衣和无菌操作的培训。对于无菌更衣应进行评估和确定，每年至少进行一次评估和确定，评估应包括目视观察和微生物检查（利用手臂和胸部新增部位）。只有经过培训并通过更衣确认和参与成功模拟灌装，并在模拟灌装中完成其本职操作的员工才能授权在无监管情况下进入无菌操作A/B区。

对于A/B区操作工应进行微生物监测以便评估其无菌行为。监测应在关键干预操作后和每次离开洁净室立即进行。 应当指出对于操作工应当制定由质管部进行的定期和持续的监测。

中等- 大多数企业都对操作员工进行资格确认，并对每个出A级的人员进行取样检测。然而，两者均不是世界统一的操作，所以需要相当多的资源来实施和维持。

评估什么？评估无菌更衣的步骤和方式是否合理？

现有的更衣方式每年都进行验证。为啥还要评估。

关注A/B区操作工应进行微生物监测以便评估其无菌行为

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4.5

4.5 There should be systems in place for disqualification of personnel from entry into cleanrooms, based on aspects including ongoing assessment and/or the identification of an adverse trend from the personnel monitoring program. Once disqualified, retraining and requalification is required before permitting the operator to have any further involvement in aseptic practices. This should include consideration of participation in a successful Aseptic Process Simulation (APS).

4.5 应当根据持续评估和/或人员监测系统确认的不良发展趋势，建立洁净室人员退出机制。人员一旦被取消资格，必须重新培训和重新确认，否则不能参与任何无菌操作。其中应包括重新参加成功的模拟灌装。

中等- 大多数企业可能有取消权限的规定，但可能与本条款不完全一致。

是否应该增加相关SOP的内容

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4.6

4.6 Manufacturers should establish written procedures outlining the process by which outside staff who have not received such training (e.g. building or maintenance contractors) need to be brought into grade A/B areas. Access by these persons should only be given in exceptional circumstances, evaluated and recorded in accordance with the PQS.

4.6 生产商应建立书面程序，规定未经过这些培训的外来人员（例如外委的维修人员）进入A/B区的程序。只有在特殊情况，经过PQS评估，并进行记录才可允许这些人员进入。

轻微- 大多数企业可能都有这样的程序，少部分可能没有

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4.9

4.9 Wristwatches, make-up and jewellery and other personal items such as mobile phones should not be allowed in clean areas.

4.9 不允许将手表，化妆品，首饰和其它个人物品包括手机带入洁净区。（洁净区的含义应包括D级包括D级以上级别）

之前的清单增加了“其他私人物品例如手机”。对于是否应该全面禁止使用移动电话，或者是否允许将公司电话作为低级别清洁区域（例如D级）的通信设备进行控制，尚不清楚

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5.3

5.3 For the manufacture of sterile medicinal products 4 grades of clean room can be distinguished. 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 localised air flow protection, such as laminar air flow work stations or isolators. Unidirectional air flow systems should provide a homogeneous air speed in a range of 0.36 – 0.54 m/s (guidance value), the point at which the air speed measurement is taken should be clearly justified in the protocol. During initial qualification and requalification air speeds may be measured either close to the terminal air filter face or at the working height, Where ever the measurement is taken it is important to note that the key objective is to ensure that air visualization studies should correlate with the airspeed measurement to demonstrate air movement that supports protection of the product and open components with unidirectional air at the working height, where high risk operations and product and components are exposed. The maintenance of unidirectional airflow should be demonstrated and validated across the whole of the grade A area. Entry into the grade A area by operators should be minimized by facility, process and procedural design. Grade B: For aseptic preparation and filling, this is the background environment for the grade A zone. In general, only grade C cleanrooms should interface with the grade B aseptic processing area. Lower grades can be considered where isolator technology is used (refer to clause 5.19-5.20). Grade C and D: Clean areas for carrying out less critical stages in the manufacture of sterile products.

5.3 制造无菌医药产品的洁净室分为4级。A级：进行高风险操作的区域，例如灌装，胶塞斗，敞口的安瓿和玻璃瓶，无菌连接。通常由局部的空气流加以保护，例如层流台或隔离器。单向流系统在其工作区域必须均匀送风，风速为0.36-0.54m/s（指导值），应当在方案中清晰说明风速测量点的位置。在初始确认和再确认时，风速可以在接近高效出风面或工作高度测量。无论哪种测量方法，关键目的是要确保和流型视频检查相关，从而证实在工作面的产品和组件处于单向流保护之下，高风险操作和敞口的产品和组件处于单向流保护之下。要显示和验证所有的A级区可以维持单向流。要从厂房，工艺和操作步骤的设计上做到进入A级区的人员达到最少。B级区：无菌配制和灌装等高风险操作A级区所处的背景区域。隔离器可以考虑低级的背景区（参见5.19和5.20条款）。C级和D级区：生产无菌产品过程中重要程度较次的洁净操作区。

单向流做静态还是动态的，是所有的操作都需要做单向流?

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5.9

5.9 Airlocks should be designed and used to provide physical separation and to minimize microbial and particulate contamination of the different areas, and should be present for material and personnel moving from different grades, typically airlocks used for personnel movement are separate to those used for material movement. They should be flushed effectively with filtered air. The final stage of the airlock 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 generally desirable.  a) Personnel airlocks. A cascade concept should be followed for personnel (e.g. from grade D to grade C to grade B). In general hand washing facilities should be provided only in the first stage of the changing rooms.  b) Material airlocks (used for materials and equipment).  i. Pass through hatches without active filtered air supply should be avoided. If necessary, provisions and procedures should be in place to avoid any risk of contamination (e.g. by the incoming material or by entering air).  ii. For airlocks leading to grade A and B areas, only materials and equipment that have been included as part of the qualification list should be allowed to be transferred into the grade A/B area via the air lock or pass through; the continuity of grade A should be maintained in the aseptic core when the materials have to be transferred from grade B to grade A areas, consideration should be given to listing these items on an authorized list. Any unapproved items that require transfer should be an exception. Appropriate risk evaluation and mitigation strategies should be applied and recorded as per the manufacturers contamination control strategy and should include a specific sanitisation and monitoring regime approved by quality assurance. iii. The movement of material from clean not classified (CNC) to grade C should be based on QRM principles, with cleaning and disinfection commensurate with the risk.

5.9 应当设计安装气闸室，提供实体隔离来降低不同区域的微生物和粒子污染，不同级别洁净区之间的物流和人流应设置气闸室，通常人员和物料通道应分开。气闸间应配置过滤空气进行有效冲刷。更衣室后段的静态级别应与其相应洁净区的级别相同。人员进出通道分开更为理想。

a)人员缓冲间。房间洁净度逐级提高（例如D级到C级到B级）,洗手台通常设置在通道入口的第一间。

b）物流缓冲间（用于物料和设备）i.避免使用无高效过滤空气的双开门传递窗。如果必须使用，一旦发生进入物料或外界空气进入造成污染，应当有预案规定处理的步骤。通往A级和B级区的气闸，只有列入确认清单的物料和仪器才允许传入；B到A级核心无菌区的传递窗须保持A级，传递的物品应当列入授权清单。不在清单之列的物品需要传递进去都属于例外情况。对此应进行适当的风险评估和迁移策略，按照企业污染控制策略进行记录，包括QA批准的特殊消毒监察方法。iii.从洁净非控制区到C级区物流应当符合QRM原则，清洁和消毒方式应与风险相适应

不能给AB级转仪器，除非能够耐受过氧化氢灭菌

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8.13

8.13 Unless subsequently sterilized by steam-in-place or conducted with validated intrinsic sterile connection devices, aseptic connections should be performed in a grade A environment with a grade B background (or in an isolator with a suitable background), in a way that minimizes the potential contamination from the immediate environment, e.g. from operators or boundaries with lower grades. Aseptic connections, including those performed to replace equipment, should be appropriately assessed and their effectiveness verified as acceptable by process simulation tests. (For requirements regarding intrinsic sterile connection devices (refer clause 8.115).

8.13 无菌连接应在B级背景下的A级环境下（或在适当环境下的隔离器）进行，除非连接后进行SIP或已经过验证的固有无菌的连接装置，连接方式应使来自相邻环境的（操作者或相邻低级别洁净区）潜在污染可能性最低。无菌连接，包括仪器更换的行动，应进行适当评估，其影响应在模拟灌装中加以确认。（详细要求参见8.115条款）。

　翻译和原文不清楚。

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8.16

8.16 The duration for each aspect of the aseptic manufacturing process should be limited to a defined and validated maximum, including: a) Time between equipment, component, and container cleaning, drying and sterilization. b) Holding time for sterilized equipment, components, and containers prior to and during filling/assembly. c) The time between the start of the preparation of a solution and its sterilization or filtration through a micro-organism-retaining filter. There should be a set maximum permissible time for each product that takes into account its composition and the prescribed method of storage. d) Aseptic assembly. e) Holding sterile product prior to filling. f) Filling.  g) Maximum exposure time of sterilized containers and closures in the critical processing zone (including filling) prior to closure.

8.16 无菌工艺每个事件的最大时程都要加以规定和验证，包括：a）仪器、组件、容器清洁、干燥和灭菌的间隔时间。b）灭菌的仪器、组件和容器灌/组装最大保持时限和灌/组装过程的最大时限。c）配液开始到灭菌或除菌过滤的时程。每种产品的组分都要设定最大允许时程和储存的方法。d) 无菌组装。 e) 无菌产品灌装前保持时间 f) 灌装。 g) 灭菌容器和胶塞在关键工序（包括灌装）在封口前最大暴露时间。

需要考虑都有哪些时间需要进行验证。每一个步骤

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8.2

8.2 Filling of products for terminal sterilization should be carried out in at least a grade C environment.

8.2 最终灭菌产品的灌装最低也要在C级环境进行。

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8.25

8.25 RABS and isolators may be beneficial in assuring the required conditions and minimising direct human interventions into the capping operation.

8.25 在RABS和隔离器可能有利于保障达到规范要求的条件，同时可以在轧盖操作过程中降低人员直接干预。

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8.29

8.29 Results of the inspection should be recorded and defect types and levels trended. Reject rates for the various defect types should also be trended. Investigations should be performed as appropriate to address adverse trends or discovery of new defect types. Impact to product on the market should be assessed as part of this investigation.

8.29 检查结果应加以记录，注意偏差类型和程度的趋势。要注意各种偏差的不合格品剔除率发展趋势，以便发现重大的不良趋势和新型偏差。调查应包括受影响产品对市场的影响。

　是不是所有偏差均应考虑不合格品剔除率问题？

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8.42

8.42 Transfer of materials, equipment, and components into an aseptic processing area should be via a unidirectional process (e.g. through a double-door autoclave, a depyrogenation oven, effective transfer disinfection, or, for gaseous or liquid materials, a bacteria-retentive filter).

8.42 物料、仪器和组件应通过单向传递窗进入无菌操作区（双开门灭菌柜，除热原热风烘箱，有效的传递消毒，气体或液体物料通过除菌过滤）。

　传递窗单向传递

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8.6

8.6 Aseptic processing is the handling of sterile product, containers and/or devices in a controlled environment, in which the air supply, materials and personnel are regulated to prevent microbial contamination. Additional requirements apply to Restricted Access Barrier Systems (RABS) and isolators (refer clauses 5.15-5.22).

8.6 无菌工艺是在受控环境里处置无菌产品、容器和/或器械，该环境的空气、物料和人员要遵守规则防止微生物污染。对于限制进入隔离系统（RABS）和隔离器的规定详见（5.15-5.22条款）。

对于受控环境的空气、物料、人员的管理控制

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8.7

8.7 The aseptic process should be clearly defined. The risks associated with the aseptic process, and any associated requirements, should be identified, assessed and appropriately controlled. The site’s contamination control strategy should clearly define the acceptance criteria for these controls, requirements for monitoring and the review of their effectiveness. Methods and procedures to control these risks should be described and implemented. Residual risks should be justified.

8.7 无菌工艺应清晰规定。无菌操作的风险和相关的要求都应一一列明，评估和适当的控制。现场污染控制策略应明确规定这些控制的接受限，监察要求和执行的效果的审查。控制这些风险的方法步骤应加以说明并贯彻执行。对剩余风险应有合理判断。

无菌操作步骤进行识别，风险识别及控制。

需不需要采取额外的措施。

在风险评估前对这些控制明确规定可接受限，监督要求和控制的有效性。

控制风险的方法步骤需详细说明，并在文件中进行规定。

剩余风险有合理判断。

在风险识别前，对工艺操作细而又细分解。

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9.31

9.31 Recommended action limits for microbial contamination are shown in Table 6 Table 6: Recommended maximum limits for microbial contamination (a) Individual settle plates may be exposed for less than 4 hours. Where settle plates are exposed for less than 4 hours the limits in the table should still be used. Settle plates should be exposed for the duration of critical operations and changed as required after 4 hours. (b) It should be noted that for grade A the expected result should be 0 cfu recovered; any recovery of 1 cfu or greater should result in an investigation.

9.31 表6列举了各种活动微生物污染最大限值。(a) 单个沉降碟放置时间可以不足4小时。即使不足4小时，表6的限值仍然有效。在关键操作整个阶段，每4小时换碟一次。(b) 值得指出A级区沉降碟的结果应是0 cfu，对任何大于等于1 cfu的值都要展开调查。

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9.32

9.32 Monitoring procedures should define the approach to trending. Trends can include but are not limited to: a) Increasing numbers of action or alert limit breaches. b) Consecutive breaches or alert limits. c) Regular but isolated breaches of limits that may have a common cause, for example single excursions that always follow planned preventative maintenance. d) Changes in flora type and numbers.

9.32 监测程序应当规定判别趋势的方法。趋势包括但不限于：a)突破警戒限或行动限的次数增加。b)接连突破警戒限。c)有规律的突破警戒限提示存在共同的原因，例如，计划内的预防性维修后发生参数偏移。d)菌群类型和数量改变。

菌群类型和数量改变是不是菌群监测不应只在AB级区进行。

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9.35

9.35 The process simulation test should imitate as closely as possible the routine aseptic manufacturing process and include all the critical manufacturing steps. Specifically: a) Process simulation tests should assess all aseptic operations performed subsequent to the sterilisation of materials utilised in the process. b) For non-filterable formulations any additional aseptic steps should be assessed. c) Aseptic manufacturing performed in a strict anaerobic environment should be evaluated with an anaerobic media in addition to aerobic evaluation. d) Processes requiring the addition of sterile powders should employ an acceptable surrogate material in containers identical to those utilised in the process being evaluated. e) Processes involving blending, milling and subdivision of a sterile powder require similar attention. f) The process simulation test for lyophilized products should include the entire aseptic processing chain, including filling, transport, loading, chamber dwell, unloading and sealing. The process simulation should duplicate the lyophilization process, with the exception of freezing and sublimation, including partial vacuum and cycle duration and parameters as appropriate for the media. Boiling over or actual freezing of the solution should be avoided.

9.35 模拟灌装测试应当尽量与正常无菌生产过程相近似，包括所有的关键生产步骤。特别是：a)模拟灌装应评估生产使用的物料在灭菌后涉及的所有无菌操作。b)对于非过滤的配方，任何附加的无菌操作都要进行评估。c) 在严格厌氧环境进行的无菌生产除了进行有氧模拟还要进行厌氧培养基模拟。 d)需要加入无菌粉末的生产工艺需要使用适当的替代物质，使用与正常生产同样的容器进行评估。e) 工艺涉及混粉、磨粉和无菌粉再细分过程需要类似关注。f) 冻干产品的模拟灌装应包括完整的无菌操作环节，包括：灌装、传送、装箱、在冻干箱放置、出箱和封口。要模拟冻干过程，冻结和升华除外，包括部分抽真空和时程以及采取适合培养基的冻干参数。应当避免培养基冻结或沸腾。

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9.36

9.36 The process simulation testing should take into account various aseptic manipulations and interventions known to occur during normal production as well as worst-case situations, including: a) Inherent interventions at the maximum accepted frequency per number of filled units. b) Corrective interventions in representative number and with the highest degree of intrusion acceptable.

9.36 模拟灌装测试应考虑到生产过程中，正常的和最差条件下发生的各种操作和干预，包括：a) 每一灌装单元可接受固有干预的最大频率。b) 纠正性干预代表性次数和可接受的最大干扰程度

按照灌装数量计，固有干预的最大可接受频率？

纠正性干预代表性次数和可接受的最大干扰程度。