洁净区自净时间测试的法规要求和分析.docx

1、洁净区自净时间测试的法规要求和分析洁净室自净时间测试的法规规定和建议一我们先来看看 2010GMP的原型欧盟GMP Annex 1 Manufacture of Sterile medicinal Products(2008).2二再看看我们中国 2010GMP附录 1 第八条、第九节选、十条节选 3三那我们来看看ISO14644-3 和等同采用此标准的国标GB25915.3-2010 中对自净时间的规定。.4四再看看洁净室测试的另一重要标准NEBB(national environmental balancing bureau): Proceduralstandards for certif

2、ied testing of cleanrooms 2009-THIRD EDITION 9五GB50591-2010 洁净室施工及验收规范P127 的规定 10六FDA无菌工艺指南限度标准表和GMP实施指南：厂房与设施HVAC部分.11七结论.13一我们先来看看 2010GMP 的原型欧盟 GMP Annex 1 Manufacture of Sterile medicinal Products (2008)3.Clean areas for the manufacture of sterile products are classified according to the require

3、d 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” condi

4、tions 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 operati

5、on” 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 gra

6、des 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。，（静态和动态的定义。）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：4.Clean rooms and clean air devices should be classfied in accordance with EN ISO 14644-1. Classification should be clearly differentiated from op

7、erational process environmental monitoring. The maximum permitted airborne particle concentration for each grade is given in the following table.上述级别的环境的空气中尘埃粒子标准如下：Grade空气级别maximum permitted number of particles/m3 equal to or above等于或大于允许最大尘埃粒子数/m3at rest 静态in operation 动态0.5m5m0.5m5mA352020352020B

8、3520293520002900C3520002900352000029000D352000029000未规定未规定洁净区和洁净空气设施的级别应该按照EN ISO14644-1划分级别。应将级别的划分与操作工艺环境的监测明确区分开来。在下表中给出了各级别最大允许的空气尘埃粒子浓度。5.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 th

9、e largest considered particle size and the method of evaluation of the data collected.EN/ISO 14644-1规定了划分级别的方法，它根据所考虑的最大粒径相应的级别，规定了最少取样点的位置及样本的大小，并规定了对所获得数据的评估方法。9.it is accepted that it may not always be possible to demonstrate low levels of 5.0um particles at the point of fill when filling is in p

10、rogess, due to the generation of particles or droplets from the product itself.14.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.表中的“静态”下的微粒

11、情况，应在操作完成后，人员撤离条件下，经大约15-20分钟“自净”（指导值）后达到。15.The monitoring of Grade C and D areas in operation should be performed in accordance with principles of quality risk management. The requirements and alert/action limits will depend on the nature of the operationscarried out, but the recommended “clean up

12、 period” should be attained.应按照质量风险管理原则，对 C 和D 级区进行动态监测。应根据所从事操作的性质来确定监控要求已经警戒/纠偏限度，但应能达到建议的“自净期限”（未在 D 级后面加上“必要时”3 个字，未对 C 级和 D级加以区别。）二再看看我们中国 2010GMP 附录 1 第八条、第九节选、十条节选第八条洁净区的设计必须符合相应的洁净度要求，包括达到“静态”和“动态”标准。注：未对静态和动态做定义说明。第九条节选：以上各级空气的悬浮粒子标准规定如下表:洁净度级别悬浮粒子浓度最大允许数/立方米静态动态0.5um5.0um0.5um5.0umA 级35202

13、0352020B 级3520293520002900C 级3520002900352000029000D 级352000029000不做规定不做规定第十条节选：（二）灌装或分装时，由于产品本身产生的粒子或液滴，允许灌装点5.0um 的悬浮粒子出现不符合标准的情况。（七）生产操作全部结束、操作人员撤出生产现场并经 15-20 分钟（指导值）自净后，洁净区的悬浮粒子应当达到表中的“静态”标准。（八）应当按照质量风险管理原则对 C 级洁净区和 D 级洁净区（必要时）（此三个字说明，我国标准制）进行动态监测。监控要求以及警戒限度和纠偏限度可根据操作的性质决定GMP 实施指南 厂房设施与设备 P261部

14、气体是活塞流形式运动，所以产生的尘埃在 A 级区停留的时间理论上为产生点位置到层流最低点的距离同层流风速的比值，只有数秒钟而已，很短，故 1:1。B 级区静态浓度限度值同 ISO5 级（层流）限度值相同，但它是乱流而不是层流，所以气体不是活塞流运动，是靠稀释来带走尘埃，从而达到净化的目的。当人在 B 级区进行正常操作时，人是洁净区最大的污染源，其所带来的污染尘埃数量很容易超过 B级的10 倍标准(根据上表估算，小心走动-好的洁净服，所产生的 0.5um 粒子约 1000 个/秒=60,000 个/分钟，如果加上操作过程中所使用的工具及房间本身浓度呢？)，所以 B 级的动静比是 100:1。C 级是乱流，动静比=10:1，无需说明。D 级只有静态没有动态规定。原因分析：1. D 级静态标准值已经很大，对于医药洁净室来说，已经是最低容忍限度了（本人曾测试过室外一般灰尘不多的室外环境，尘埃浓度也就在 2 千万左右）。如法规规定最终灭菌可采用 C+A 或 D+A，此时 C 和 D 的区别仅