欧盟新无菌附录中洁净室确认和分级的解读（二）

自欧盟新版附录1征求意见稿发布以来，引起了行业的广泛热议，我们有幸邀请了常州千红生化制药股份有限公司的周翔先生，谈一谈对欧盟新无菌附录中洁净室确认(Cleanroom qualification)和分级(Cleanroom classification)的解读，该解读分为3篇文章，今天发布第2篇（系列的第一篇：欧盟新无菌附录中洁净室确认和分级的解读（一））

周翔

副总经理/质量受权人
江苏省药学会医药产业发展专委会委员、常州市药学会理事、常州市中青年专业技术拔尖人才。资深无菌生产管理专家，具有丰富的国际GMP检查主持经验，2016年受邀参与起草国家2010版GMP生化药附录。


洁净室确认相关条文
4.28 Cleanroom classification is part of a 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 non-viable airborne particulate concentration. Reference for the classification of the cleanrooms and clean air equipment can be found in the ISO 14644 series of standards.
解读

条款4.28定义了洁净室分级的概念，是洁净室确认的一部分，是通过检测空气的洁净程度，即非活性粒子浓度来定义的。这个也是洁净室定义的本源，所谓A级（传统意义上的百级），其0.5 μm粒子浓度3520/m3，也就是100个每立方英尺（即百级是英制概念）。在半导体工业的洁净室应用中，同样遵循的ISO14644的规范，关注的也主要是粒子水平。微生物水平则只是医药行业的特殊要求，所以是洁净室确认的内容。

洁净室确认相关条文
4.29 For cleanroom classification, the airborne particulates equal to or greater than 0.5 and 5 µm should be measured. For Grade A zone and Grade B at rest, classification should include measurement of particles equal to or greater than 0.5 µm; however, measurement using a second, larger particle size, e.g. 1 µm in accordance with ISO 14644 may be considered. This measurement should be performed both at rest and in operation. The maximum permitted airborne particulate concentration for each grade is given in Table 1.
Table 2: Limits for microbial contamination during qualification
Grade
Maximum limits for particulates 
≥ 0.5 μm/m3
Maximum limits for particulates
≥ 5 μm/m3
at rest
in operation
at rest
in operation
A
3520
3520
N/A
N/A
B
3520
352000
N/A
2900
C
352000
3520000
2900
29000
D
3520000
Not defined (a)
29000
Not defined (a)
(a).For Grade D, in operation limits are not defined. The company should establish in operation limits based on a risk assessment and historical data where applicable.
解读

在4.29及其附表1中，定义了各个洁净室的粒子浓度限值，对照现行版附录，0.5 μm粒子未有变化，5 μm粒子取消了对于A级动/静态和B级静态的要求。但是也提到除测定0.5 μm粒子外也应测定更大的粒子，如1 μm粒子。对照ISO14644-1中ISO5级的标准，0.5 μm：3520，1 μm：832（ISO3/4级均监测），5 μm：29（ISO4级不监测），这也应该是新版附录取消5 μm粒子强制性标准的原因，因为ISO14644-1中明确提到粒子测量过程中存在不确定性，而且实际的粒子在线检测过程中，不是按立方米而是按28.3L/min的速率来采样的，测得的数据是每分钟28.3L空气中的粒子含量，按原标准29/m3（或20）换算，每28.3L允许报告值低于1，实际就应该是不得检出，但是累计到1个立方米后，完全可能出现某时间点测得大于1的数据，但是总的累计值低于29/m3（或20）的情况。基于上文对于微生物数<1cfu/4小时不合理的原因分析，同理5 μm粒子的限值也存在不合理之处，故此处作了修改。虽然条款中1 μm粒子只是指导值，但是查阅ISO14644-1中只有0.1 μm/0.2 μm/0.3 μm/0.5 μm/1 μm/5 μm的限值规定，选择1 μm粒子代替5 μm粒子作为监测指标应该是唯一的选择。1 μm粒子每立方米限制折算28.3L/min为23，生产中制定设备报告值1 μm 不超过20个较5 μm不超过1个具备更高的实际可行性。

洁净室确认相关条文
4.30 For classification of the cleanroom, the minimum number of sampling locations and their positioning can be found in ISO 14644 Part 1. In addition, for the aseptic processing room and the background environment (Grade A zone and Grade B area, respectively), sample locations should also consider all critical processing zones such as the point of fill and stopper bowls. Critical processing locations should be based on a documented risk assessment and knowledge of the process and operations to be performed in the area.
解读

条款4.30是针对粒子采样点位的规定，明确应按ISO14644-1执行。对无菌生产区A/B级，规定采样点位应考虑所有的核心区如灌装点位和胶塞斗等。这些都应该基于对工艺和操作的知识，在风险评估中书面化的描述。

洁净室确认相关条文
4.31 Clean room classification should be carried out in the “at rest” and “in operation” states.
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 and standing by for operation, without personnel in the room.
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. In operation classification may be performed during simulated operations or during aseptic process simulations (where worst case simulation is required).
iii) The particulate limits given in Table 1 above for the “at rest” state should be achieved after a “clean up” period on completion of operations. The "clean up" period should be determined during the classification of the rooms (guidance value of 15 to 20 minutes).
解读

对照现行版附录，条款4.31是对静态和动态定义的细化。其中静态强调在完成所有操作后，经过一个净化周期就达到，这个净化周期根据洁净室的级别一般指导值在15-20分钟，较原先无明确规定，往往充分自净很久再监测，对洁净室的自净要求更为严格；动态在现行版附录指的是设备在规定的操作模式下运转且有规定数量的人员在工作，而新版附录改为最大数量的人员或模拟日常的操作，这个是明显提升性的要求，即动态指的是在最差条件，并建议在模拟操作或培养基验证时进行。

       文章来源：TDV制药咨询

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