Cleanroom and clean air equipment qualification
洁净室和洁净空气设备确认
4.23 Cleanrooms and clean air equipment such as unidirectional airflow units (UDAFs), RABS and isolators, used for the manufacture of sterile products, should be qualified according to the required characteristics of the environment. Each manufacturing operation requires an appropriate environmental cleanliness level in the operational state in order to minimize the risk of contamination of the product or materials being handled. Appropriate cleanliness levels in the “at rest” and “operational” states should be maintained.
用于制造无菌产品的洁净室和洁净空气设备，如单向气流单元（UDF）、RABS和隔离器，应按照所需的环境特性进行确认。每个生产操作都需要在动态条件下具有适当的环境洁净度水平，以最大限度地降低所处理的产品或物料受到污染的风险。应保持在“静态”和“动态”状态的适当洁净度水平。
4.24 Cleanrooms and clean air equipment should be qualified using methodology in accordance with the requirements of Annex 15. Cleanroom qualification (including classification) should be clearly differentiated from operational environmental monitoring.
洁净室和洁净空气设备应使用符合附录15要求的方法进行确认。洁净室确认（包括分级）应与生产环境监测明确区分开来。
4.25 Cleanroom and clean air equipment qualification is the overall process of assessing the level of compliance of a classified cleanroom or clean air equipment with its intended use. As part of the qualification requirements of Annex 15, the qualification of cleanrooms and clean air equipment should include (where relevant to the design/operation of the installation):
洁净室和洁净空气设备确认是评估已分级洁净室或洁净空气设备适合其预期用途的总体过程。作为附录15确认要求的一部分，洁净室和洁净空气设备的确认应包括（在设计/运行有关）：
i. Installed filter system leakage and integrity testing.
已安装过滤系统泄漏和完整性测试。
ii. Airflow tests - volume and velocity.
气流测试-风量和风速
iii. Air pressure difference test.
压差测试
iv. Airflow direction test and visualisation.
气流方向测试和可视化
v. Microbial airborne and surface contamination.
空气微生物和表面微生物
vi. Temperature measurement test.
温度测试
vii. Relative humidity test.
相对湿度测试
viii. Recovery test.
恢复测试
ix. Containment leak test.
隔离泄漏测试
Reference for the qualification of the cleanrooms and clean air equipment can be found in the ISO 14644 series of standards.
有关洁净室和洁净空气设备确认的参考，请参见 ISO 14644 系列标准。
4.26 Cleanroom classification is part of the cleanroom qualification and is a method of assessing the level of air cleanliness against a specification for a cleanroom or clean air equipment by measuring the total particle concentration. Classification activities should be scheduled and performed in order to avoid any impact on process or product quality. For example, initial classification should be performed during simulated operations and reclassification performed during simulated operations or during aseptic process simulation (APS).
洁净室级别确认是洁净室确认的一部分，是通过测量总粒子浓度来根据洁净室或洁净空气设备的规范评估空气洁净度水平的方法。应安排和执行级别确认活动，以避免对工艺或产品质量产生任何影响。例如，初始级别确认应在模拟操作期间执行，级别再确认可在模拟操作或无菌工艺模拟（APS）期间进行。
4.27 For cleanroom classification, the total of particles equal to or greater than 0.5 and 5 µm should be measured. This measurement should be performed both at rest and in simulated operations in accordance with the limits specified in Table 1.
对于洁净室级别确认，应测量等于或大于0.5和5μm的粒子总数。该测量应根据表1中规定的限值在静态和模拟动态中进行。
Table 1: Maximum permitted total particle concentration for classification
表1:用于分级的最大允许总粒子浓度
| Grade 级别 | Maximum limits for total particle 总粒子最大限度 | Maximum limits for total particle 总粒子最大限度 | ||
| ≥ 0.5 µm/m3 | ≥ 5 µm/m3 | |||
| at rest 静态 | in operation 动态 | at rest 静态 | in operation 动态 | |
| A | 3 520 | 3 520 | Not specified (a) 不作规定 | Not specified (a) 不作规定 |
| B | 3 520 | 352 000 | Not specified (a) 不作规定 | 2 930 |
| C | 352 000 | 3 520 000 | 2 930 | 29 300 |
| D | 3 520 000 | Not predetermined (b) 未设定 | 29 300 | Not predetermined (b) 未设定 |
a) Classification including 5µm particles may be considered where indicated by the CCS or historical trends.
根据CCS或历史趋势，可考虑5 μ m粒子的级别。
b) For grade D, in operation limits are not predetermined. The manufacturer should establish in operation limits based on a risk assessment and routine data where applicable.
对于D级，（本文件）未预先确定动态标准。制造商应根据风险评估和日常数据(如适用)建立动态标准。
4.28 For classification of the cleanroom, the minimum number of sampling locations and their positioning can be found in ISO 14644 Part 1. For the aseptic processing area and the background environment (the grade A and grade B areas, respectively), additional sample locations should be considered and all critical processing areas such as the point of fill and container closure feeder bowls should be evaluated. Critical processing locations should be determined by documented risk assessment and knowledge of the process and operations to be performed in the area.
对于洁净室的级别确认，可以在ISO 14644第1部分中找到采样点的最小数量及其位置。对于无菌加工区域和背景环境（分别为A级和B级区域），应考虑额外的取样位置，并应评估所有关键处理区域，例如灌装点和容器密封部件给料斗。关键处理位置应通过书面的风险评估和对该区域所执行的工艺和操作的了解来确定。
4.29 Cleanroom classification should be carried out in the “at rest” and “in operation” states.
4.29 洁净室级别确认应在“静态”和“动态”状态下进行。
i. The definition of “at rest” state is the condition whereby the installation of all the utilities is complete including any functioning HVAC, with the main manufacturing equipment installed as specified but not operating and without personnel present in the room.
“静态”状态的定义是所有公用设施的安装已完成，包括任何正常运行的HVAC，主要生产设备按既定安装但不运行并且没有人员在房间内的条件。
ii. The definition of “in operation” state is the condition where the installation of the cleanroom is complete, the HVAC system fully operational, equipment installed and functioning in the manufacturer’s defined operating mode with the maximum number of personnel present performing or simulating routine operational work.
“动态”状态的定义是洁净室的安装完成，HVAC系统完全运行，设备在制造商定义的操作模式下安装和运行，并且具有执行或模拟日常操作工作的最大人员数量的条件。
iii. The total particle limits given in Table 1 above for the “at rest” state should be achieved after a “clean up” period on completion of operations and line clearance/cleaning activities. The "clean up" period (guidance value of less than 20 minutes) should be determined during the qualification of the rooms, documented and adhered to in procedures to reinstate a qualified state of cleanliness if disrupted during operation.
上文表1中给出的“静态”条件的总粒子限度应在完成操作和生产线清除/清场活动后的“自净”期后达到。“自净”期（指导值小于20分钟）应在房间的确认期间确定，并在操作期间中断时记录并遵守程序，以恢复已确认的洁净状态。
4.30 The speed of air supplied by unidirectional airflow systems should be clearly justified in the qualification protocol including the location for air speed measurement. Air speed should be designed, measured and maintained to ensure that appropriate unidirectional air movement provides protection of the product and open components at the working position (e.g. where high-risk operations occur and where product and/or components are exposed). Unidirectional airflow systems should provide a homogeneous air speed in a range of 0.36 – 0.54 m/s (guidance value) at the working position, unless otherwise scientifically justified in the CCS. Airflow visualization studies should correlate with the air speed measurement.
单向流系统提供的气流速度应在确认方案中明确证明，包括风速测量的位置。应设计、测量和维护气流速度，以确在工作位置（例如，发生高风险操作以及产品和/或组件暴露的位置）有足够的单向气流为产品和暴露的组件提供保护。单向流系统应在工作位置提供 0.36 – 0.54 m/s（指导值）范围内的均匀气流速度，除非 CCS 中另有科学论证。气流可视化研究应与风速相关联。
4.31 The microbial contamination level of the cleanrooms should be determined as part of the cleanroom qualification. The number of sampling locations should be based on a documented risk assessment and the results obtained from room classification, air visualization studies and knowledge of the process and operations to be performed in the area. The maximum limits for microbial contamination during qualification for each grade are given in Table 2. Qualification should include both “at rest” and “in operation” states.
洁净室的微生物污染水平应作为洁净室确认的一部分来确定。采样点的数量应基于书面的风险评估和从房间级别确认，气流可视化研究以及有关在该区域执行的工艺和操作的知识中获得的结果。每个级别的确认过程中微生物污染的最大限值见表2。确认应包括“静态”和“动态”状态。
Table 2: Maximum permitted microbial contamination level during qualification
表2：确认期间最大允许微生物污染水平
| Grade 级别 | Air sample CFU/m3 浮游菌 CFU/立方 | Settle plates (diameter 90 mm) CFU/4 hours (a) 沉降菌（直径90mm） CFU/4小时 | Contact plates (diameter 55 mm) CFU/plate 接触皿（直径55mm） CFU/皿 |
| A | No growth 无生长 | ||
| B | 10 | 5 | 5 |
| C | 100 | 50 | 25 |
| D | 200 | 100 | 50 |
a) Settle plates should be exposed for the duration of operations and changed as required after a maximum of 4 hours. Exposure time should be based on recovery studies and should not allow desiccation of the media used.
沉降皿应在操作期间进行暴露，并在最多4小时后根据需要更换。暴露时间应基于回收率研究，并且不应使所用的培养基干燥。
Note 1: All methods indicated for a specific grade in the table should be used for qualifying the area of that specific grade. If one of the methods tabulated is not used, or alternative methods are used, the approach taken should be appropriately justified.
注1：表中为各洁净级别所指定的所有方法应应用于确认该级别的领域。如未使用表中的任一方法，或者使用了替代方法，则应适当证明所采用的方法的合理性。
Note 2: Limits are applied using CFU throughout the document. If different or new technologies are used that present results in a manner different from CFU, the manufacturer should scientifically justify the limits applied and where possible correlate them to CFU.
注 2：在整个文件中使用了单位为CFU 的限度。如果使用其他的或新的技术，以不同于CFU的方式呈现结果，制造商应科学证明所使用的限度的合理性，并在可能的情况下将其与CFU相关联。
Note 3: For the qualification of personnel gowning, the limits given for contact plates and glove prints in Table 6 should apply.
注3：对于人员更衣的确认，应使用表6中给出的接触皿和手套的限度。
Note 4: Sampling methods should not pose a risk of contamination to the manufacturing operations.
注4：取样方法不应对生产操作造成污染风险。
4.32 The requalification of cleanrooms and clean air equipment should be carried out periodically following defined procedures. The requalification should include at a minimum the following:
洁净室和洁净空气设备应按照规定的程序定期进行再确认。再确认至少应包括以下内容：
l Cleanroom classification (total particle concentration).
l 洁净室级别确认（总粒子浓度）
l Integrity test of final filters.
l 终端过滤器完整性测试
l Airflow volume measurement.
l 风量测试
l Verification of air pressure difference between rooms.
l 不同房间之间的压差确认
l Air velocity test (Note: For grade B, C and D the air velocity test should be performed according to a risk assessment documented as part of the CCS. However, it is required for filling zones supplied with unidirectional airflow (e.g. when filling terminally sterilised products or background to grade A and RABS). For grades with non-unidirectional airflow, a measurement of recovery testing should replace velocity testing).
l 风速测试（注：对于B级，C级和D级，应根据CCS中记录的风险评估进行风速测试。但是，对于提供单向流的灌装区域（例如，最终灭菌产品的灌装或A级和RABS背景）是必须的。对于非单向流的洁净区域，可用恢复测试取代风速测试）。
The maximum time interval for requalification of grade A & B areas, is 6 months.
A级和B级区域再确认的最大时间间隔为6个月。
The maximum time interval for requalification of grade C & D areas, is 12 months.
C&D级区域再确认的最大时间间隔为12个月。
Appropriate requalification consisting of at least the above tests should also be carried out following completion of remedial action implemented to rectify an out of compliance equipment or facility condition or after changes to equipment, facility or processes as appropriate. The significance of a change should be determined through the change management process. Examples of changes to be considered include but are not limited to the following:
在为纠正设备或设施不合规状况而采取的补救措施完成后，或在适当的设备、设施或工艺变更之后，也应进行适当的再确认，至少包括上述测试。变更的重要性应通过变更管理流程来确定。需要考虑的变更示例包括但不限于以下：
l Interruption of air movement which affects the operation of the installation.
l 影响设备操作的空气流动中断。
l Change in the design of the cleanroom or of the operational setting parameters of the HVAC system.
l 改变洁净室的设计或HVAC系统的运行设置参数。
l Special maintenance which affects the operation of the installation (e.g. change of final filters).
l 影响设备操作的特殊维护（例如更换终端过滤器）。
Disinfection
消毒
4.33 The disinfection of cleanrooms is particularly important. They should be cleaned and disinfected thoroughly in accordance with a written programme. For disinfection to be effective, prior cleaning to remove surface contamination should be performed. Cleaning programmes should effectively remove disinfectant residues. More than one type of disinfecting agent should be employed to ensure that where they have different modes of action, their combined usage is effective against bacteria and fungi. Disinfection should include the periodic use of a sporicidal agent. Monitoring should be undertaken regularly in order to assess the effectiveness of the disinfection programme and to detect changes in types of microbial flora (e.g. organisms resistant to the disinfection regime currently in use).
洁净室的消毒尤为重要。应按照书面程序彻底清洁和消毒。为了使消毒有效，应在此之前进行清洁以去除表面污染。清洁程序应有效去除消毒剂残留。应使用一种以上的消毒剂，以确保在它们具有不同作用机理且它们的组合使用对细菌和真菌有效。消毒应包括定期使用杀孢子剂。应定期进行监测以评估消毒程序的有效性，并监测微生物菌群类型的变化（例如，对当前使用的消毒模式耐受的生物体）。
4.34 The disinfection process should be validated. Validation studies should demonstrate the suitability and effectiveness of disinfectants in the specific manner in which they are used and on the type of surface material, or representative material if justified, and should support the in-use expiry periods of prepared solutions.
应验证消毒过程。验证研究应以具体使用方式和表面材料类型或代表性材料（如经论证）证明消毒剂的适用性和有效性，并应支持所制备溶液的使用有效期。
4.35 Disinfectants and detergents used in grade A and grade B areas should be sterile prior to use. Disinfectants used in grade C and D may also be required to be sterile where determined in the CCS. Where the disinfectants and detergents are diluted / prepared by the sterile product manufacturer, this should be done in a manner to prevent contamination and they should be monitored for microbial contamination. Dilutions should be kept in previously cleaned containers (and sterilized where applicable) and should only be stored for the defined period. If the disinfectants and detergents are supplied “ready-made” then results from certificates of analysis or conformance can be accepted subject to successful completion of the appropriate vendor qualification.
在A级和B级区域使用的消毒剂和清洁剂在使用前应无菌。在C级和D级中使用的消毒剂也可能在CCS中要求是无菌的。如消毒剂和清洁剂由无菌产品制造商稀释/制备，则应以防止污染的方式进行，并应监测微生物污染。（消毒液）稀释液应保存在预先清洁的容器中（并在适当时进行灭菌），并且只应储存在规定的期限内。如使用“市售现成”消毒剂和清洁剂，那么在成功完成适当的供应商确认后，分析或合格证书的结果可以接受。
4.36 Where fumigation or vapour disinfection (e.g. Vapour-phase Hydrogen Peroxide) of cleanrooms and associated surfaces are used, the effectiveness of any fumigation agent and dispersion system should be understood and validated.
在对洁净室和相关表面进行熏蒸或蒸汽消毒(例如，汽化过氧化氢)时，应了解和验证任何熏蒸剂和分散系统的有效性。
5 Equipment
设备
5.1 A written, detailed description of the equipment design should be available (including process and instrumentation diagrams as appropriate). This should form part of the initial qualification package and be kept up to date.
应提供设备设计的书面详细描述（包括适当的过程和仪表图）。这应作为初始确认的一部分，并保持最新状态。
5.2 Equipment monitoring requirements should be defined in “user requirements specifications” during early stages of development, and confirmed during qualification. Process and equipment alarm events should be acknowledged and evaluated for trends. The frequency at which alarms are assessed should be based on their criticality (with critical alarms reviewed immediately).
设备监测需求应在开发的早期阶段在“用户需求规范”中定义，并在验证期间确认。应确认过程和设备报警事件并评估其趋势。评估警报的频率应基于其严重性（严重警报立即审查）。
5.3 As far as practicable, equipment, fittings and services should be designed and installed so that operations, maintenance, and repairs can be performed outside the cleanroom. If maintenance has to be performed in the cleanroom, and the required standards of cleanliness and/or asepsis cannot be maintained, then precautions such as restricting access to the work area to specified personnel, generation of clearly defined work protocols and maintenance procedures should be considered. Additional cleaning, disinfection and environmental monitoring should also be considered. If sterilisation of equipment is required, it should be carried out, wherever possible, after complete reassembly.
如可行，设备，配件和服务应设计和安装以在洁净室外进行操作，维护和维修。如果必须在洁净室内进行维护，并且无法保持所需的洁净度和/或无菌标准，则应考虑采取预防措施，例如限制特定人员进入工作区域，制定明确定义的工作规程和维护程序。还应考虑额外的清洁、消毒和环境监测。如果需要对设备进行灭菌，则应在完全重新组装后尽可能进行灭菌。
5.4 The cleaning process should be validated to be able to:
清洁过程应验证能够：
i. Remove any residue or debris that would detrimentally impact the effectiveness of the disinfecting agent used.
清除任何会对所用消毒剂的有效性产生不利影响的残留或杂物。
ii. Minimize chemical, microbial and particulate contamination of the product during the process and prior to disinfection.
在清洁过程中和消毒之前，最大限度地减少产品的化学、微生物和颗粒污染。
5.5 For aseptic processes, direct and indirect product contact parts should be sterilised. Direct product contact parts are those that the product passes through, such as filling needles or pumps. Indirect product contact parts are equipment parts that do not contact the product, but may come into contact with other sterilised surfaces, the sterility of which is critical to the overall product sterility (e.g. sterilised items such as stopper bowls and guides, and sterilised components).
对于无菌工艺，应对产品直接和间接接触的部件进行灭菌。直接接触产品的部件是产品通过的部件，例如灌装针头或泵。间接产品接触部件是指不接触产品但可能与其他灭菌表面接触的设备部件，其无菌性对产品的整体无菌至关重要（例如，灭菌物品，如胶塞斗和导轨，以及已灭菌组件）。
5.6 All equipment such as sterilisers, air handling systems (including air filtration) and water systems should be subject to qualification, monitoring and planned maintenance. Upon completion of maintenance, their return to use should be approved.
所有设备，如灭菌器、空气处理系统（包括空气过滤）和水系统，都应进行确认、监测和计划性维护。维护完成后，其恢复使用应经批准。
5.7 Where unplanned maintenance of equipment critical to the sterility of the product is to be carried out, an assessment of the potential impact to the sterility of the product should be performed and recorded.
如果要对产品无菌性至关重要的设备进行计划外维护，则应评估对产品无菌性的潜在影响。
5.8 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).
传送带不应穿过 A 级或 B 级区域与空气洁净度较低的加工区域之间的隔板，除非传送带本身连续灭菌（例如在灭菌隧道中）。
5.9 Particle counters, including sampling tubing, should be qualified. The manufacturer’s recommended specifications should be considered for tube diameter and bend radii. Tube length should typically be no longer than 1m unless justified and the number of bends should be minimized. Portable particle counters with a short length of sample tubing should be used for classification purposes. Isokinetic sampling heads should be used in unidirectional airflow systems. They should be oriented appropriately and positioned as close as possible to the critical location to ensure that samples are representative.
粒子计数器，包括采样管，应经确认。应考虑制造商对管径和弯曲半径的建议标准。采样长度通常不应超过1m（否则应进行论证）且应最大限度减少弯曲次数。应使用采样管长度较短的便携式粒子计数器进行级别确认。应使用等动力采样头应用于单向流系统。它们应有适当的方向并尽可能靠近关键位置，以确保样品具有代表性。
402
被折叠的 条评论
为什么被折叠?
到【灌水乐园】发言
