日志
PHSS-在线监测系统法规中英对照版
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THE PHARMACEUTICAL AND HEALTHCARE SCIENCES SOCIETY
BEST PRACTICE FOR PARTICLE MONITORING IN
PHARMACEUTICAL FACILITIES
Technical Monograph No. 16
CONTENTS PAGE 目录
1Foreword 1、前言
2Acknowledgments 6 2、确认
3Introduction 73、介绍
4Air particle monitoring to EU GMP Annex 1:2008 84、欧盟 GMP 中关于空气粒子监测的附件
5System design 145、系统设计 6 Operations 256、操作
7Maintenance and Cleaning 307、保养和清洁
8Disaster Recovery and Data Back-up 328、容灾恢复和数据备份 9 Training 339、培训
10 Appendix A - Worked example of monitoring system layout . . . 3410、附件 A：监控系统布局的成功案例 11 Appendix B - Manifold and remote particle monitoring
systems 3611、附件 B：集成和远程粒子监控系统的案例
12 Appendix C - Examples of particle loss in transport tubing 3912、附件 C：管道输送中粒子损失的案例 13 Appendix D - Isokinetic probes 4213、附件 D：等动力采样头
14 Appendix E - Validation and risk assessment standards and guidelines 4314、附件 E：验证和风险评估的标准 与指导方针
1 FOREWORD
前言
The Pharmaceutical and Healthcare Sciences Society (PHSS) exists as a science based forum for individuals active in the fields of Pharmaceutical and Healthcare Sciences. The society evolved from the former Parenteral Society, which was primarily focused on sterile injectable and implantable drugs and devices, to meet the needs of a wider community and broaden its horizons and membership, with the change of name effective from 1 March 2006.
制药科学和保健学会（PHSS）是研究制药和保健学科，由活跃在制药和保健行业的专家组成的以科学为依
据的社会团体。学会前身为注射剂协会，关注无菌注射剂和植入式药品和器械。为适应更多团体的需求， 拓展会员并拓宽研究范围，学会从 2006 年 3 月 1 日起改名为制药科学和保健学会（PHSS）
The PHSS objectives are: PHSS 的宗旨和目标是：
1.To foster and advance, in the interest of public health, pharmaceutical and healthcare science and practice.
促进和提高制药科学和保健领域的发展；
2.To provide and disseminate to its members information concerning all aspects of pharmaceutical technology and administration of medicines.
向会员提供和传播各种制药以及给药技术信息
3.To identify specific areas where there is a need for new information or the collecting together of existing information and to satisfy this need by organising meetings or by publishing monographs or articles in the European Journal of Parenteral and Pharmaceutical Sciences. 通过组织研讨会或在欧洲注射剂和制药协会杂志发表专题论文或文章，识别行业内有需要技术突破的 专项领域
4.To foster and encourage a spirit of friendly co-operation among the members of the society and to promote favourable relations between its members and the medical, pharmaceutical, hospital and related health professions. 促进会员间的的友好合作，促进行业内会员间不同领域之间的友好互助，包括如制药，医院，医疗等 健康相关领域。
5.To cultivate and maintain co-operative relations with governmental departments and agencies, medical, pharmaceutical and related health organisations, the academic community and compendial bodies and other branches of the pharmaceutical and other life science industries; and to originate and participate in co-operative enterprises and undertakings with them. 培养和维持政府部门，政府各级代理机构，医疗组织团体，制药以及健康相关组织，学术组织，一些 制药行业的分支机构和其他生命科学的企业的合作关系，并创造和参与以及协助相关合作事宜。
6.To encourage the education and training of personnel in the fields of pharmaceutical technology and administration of medicines.
鼓励药事管理和给药技术的培训和教育
7.To promote high standards in the production, quality assurance and administration of pharmaceutical and other life science products.
促进生产，质量保证和制药以及相关生命科学产品标准的发展。
The PHSS actively encourages it's members to form and contribute to Special Interest Groups (SIG) with the aims of:
PHSS 鼓励它的成员积极投身于 SIG(特别兴趣小组)中，目的在于：
lexchanging dialogue between suppliers and users
推动供应商和客户之间信息的交换
ldiscussing and shaping how and where the industry is moving
讨论企业的未来之路
ldiscussing practical issues and guidance
讨论标准规范
lnetworking and discussions
互相交流和讨论
lproducing technical monographs on specialist and relevants subjects
针对某一专题创作技术专论
2 ACKNOWLEDGMENTS 2 致谢
The SIC formed to create this document consists of the following members:
该著作编写小组由以下人员组成：
Tony Harrison 小组主持人 制药和保健科学学会（PHSS） 大客户经理，生命科学 哈希超纯分析
Ian Johnson 设备与验证经理 阿斯利康研发部 Simon Veysey 生产部经理 生物制品实验室 Padraig Mullarkey 工艺技术员 勃林格殷格翰 Annette Ellison QA 和微生物学经理 博姿集团 Gillian Oldham 质量受权人 卡地纳健康
Andy Durber 工艺技术员 葛兰素史克
Penny Morris QA 主管 伊普森生物制药有限公司
Janice Wallace 项目工程师 工程项目组（PMT） Kevin Leggett 团队主管，无菌产品 英国惠氏研发部 Richard Kettlewell 全球验证总监 葛兰素史克
John Neiger 顾问
Johnwrite
Further comments and input has been received from the following people:
收到以下人员对该著作提出宝贵意见：
John Clarke | 高级检察官 | 英国药监局 |
Andrew Hopkins | 高级检察官 | 英国药监局 |
The following companies have very kindly provided material and diagrams:
以下公司热情地提供材料和图表：
Particle Measuring Systems Inc.离子测量系统公司
Facility Monitoring Systems Limited 设备监控系统有限公司
Lighthouse Worldwide Solutions 莱特浩斯仪器有限公司
The contents of this monograph are designed to provide guidance. However,no reponsibility can be accepted for the use of any information therein. The contents of this monograph represent the views of the members of the PHSS Special Interest Group should not be taken as endorsed by any organisation to which they are affiliated. 本专著内容的编写是为了对业内提供指导，大家可以免费共享本书内任何信息。本专著内容代表了 PHSS 成员的个人观点，编写小组不应被视为得到任何组织的支持，他们是所属公司的成员，但是观点不代表公 司立场。
3INTRODUCTION
介绍
a)Aims of this document
本文件目的
This monograph takes a practical, pragmatic approach to particle monitoring, following the aims of good quality assurance practice, whilst addressing the aims of GMP. It has been created by the PHSS Special Interest Group made up from members representing major global pharmaceutical manufacturing companies, and sub-contract manufactures. Input and comment has also been received from Medicines and Healthcare prouducts Regulatory Agency(MHRA).
本专题论述紧跟良好质量保证实践的目的，同时服务于 GMP 目标，提供一种实用的粒子监测方法。它已
经由 PHSS 专门兴趣组织通过主要全球制药公司和合同生产商的代表建立完毕。已经获得药品和保健产品 监督局（MHRA）的输入和建议。
b)Scope
范围
This monograph is specific to advice on non-viable particle monitoring systems used in pharmaceutical facilities governed by EU GMP Annex 1, 2008. Non-viable particale counting systems should be part of suite of environmental monitoring meausures, including microbiological monitoring (viable particales), termperature monitoring and differential pressure monitoring.
本专题论述对受控于欧盟 GMP annex 1, 2008 的非活性粒子监测系统提供针对性建议。非活性粒子计数系
统应包含整套环境监测手段中，包括微生物监测（活性粒子），温度监测和压差监测。
4AIR PARTICLE MONITORING TO EU GMP ANNEX 1: 2008
EU GMP 附录 1（2008）对空气尘埃粒子的监测的描述
a)EU GMP requirements (taken directly from EU GMP Annex 1) EU GMP 的要求（直接引自 EU GMP 附录 1）
9.For Grade A zones, particle monitoring should be undertaken for the full duration of critical processing, including equipment assembly, except where justified by contaminants in the process that would damage the particle counter or present a hazard, e.g. live organisms and radiological hazards. In such cases monitoring during routine equipment set up operations should be undertaken prior to exposure to the risk. Monitoring during simulated operations should also be performed. The Grade A zone should be monitored at such a frequency and with suitable sample size that all interventions, transient events and any system deterioration would be captured and alarms triggered if alert limits are exceeded. It is accepted that it may not always be possible to demonstrate low levels of particles at the point of fill when filling is in progress, due to the generation of particles or droplets from the product itself.
9.对于 A 级区, 在关键操作的全过程中，包括设备组装操作，应当对 A 级洁净区进行尘埃粒子监测。生产
过程中的污染（如活生物、放射危害）可能损坏尘埃粒子计数器时，应当在设备调试操作和模拟操作期间 进行测试。A 级洁净区监测的频率及取样量，应能及时发现所有人为干预、偶发事件及任何系统的损坏。 灌装或分装时，由于产品本身产生粒子或液滴，允许灌装点≥5.0μm 的尘埃粒子出现不符合标准的情况。
10.It is recommended that a similar system be used for Grade B zones although the sample frequency may be decreased. The importance of the particle monitoring system should be determined by the effectiveness of the segregation between the adjacent Grade A and B zones. The Grade B zone should be monitored at such a frequency and with suitable sample size that changes in levels of contamination and any system deterioration would be captured and alarms triggered if alert limits are exceeded.
10.建议在 B 级区采用相似的监测系统,尽管采样平率可以降低。尘埃粒子监测系统的重要性取决于 A 级区
和相邻 B 级区之间隔离的有效性。B 级区监测的频率及取样量，应能及时发现所有人为干预、偶发事件 及任何系统的损坏且能在尘粒浓度超过警戒限时报警。
11.Airborne particle monitoring systems may consist of independent particle counters; a network of sequentially accessed sampling points connected by manifold to a single particle counter; or a combination of the two. The system selected must be appropriate for the particle size considered. Where remote sampling systems are used, the length of tubing and the radii of any bends in the tubing must be considered in the context of particle losses in the tubing. The selection of the monitoring system should take account of any risk presented by the materials used in the manufacturing operation, for example those involving live organisms or radiopharmaceuticals. 11.尘埃粒子监测系统可以由独立的尘埃粒子计数器组成；用一个粒子计数器和汇流排相接，构成多点有程 采样网；或用两台设备连接成一个网络。所选的系统必需适合于需测试尘粒的粒径。若应用遥控采样系统， 应考虑到采样管的长度和管路中任何弯管的半径与尘粒丢失的关系。监测系统的选择还应考虑到生产操作 所用物料带来的任何风险，例如物料中有活的有机体或放射性物质等。
12.The sample sizes taken for monitoring purposes using automated systems will usually be a function of the sampling rate of the system used. It is not necessary for the sample volume to be the same as that used for formal classification of clean rooms and clean air devices. 12.自动化监测系统的采样量通常是所用系统采样速率的函数。监控的采样量没有必要与洁净区和洁净区设 施级别正式确认时的空气采样量相同。
13.In Grade A and B zones, the monitoring of the particle concentration count takes on a particular significance as it is an important diagnostic tool for early detection of failure. The occasional indication of particle counts may be false counts due to electronic noise, stray light, coincidence, etc. However consecutive or regular counting of low levels is an indicator of a possible contamination event and should be investigated. Such events may indicate early failure of the HVAC systems, filling equipment failure or may also be diagnostic or poor practices during machine set-up and routine operation.
13.在 A 级区和 B 级区，由于尘埃粒子的浓度计数是早期诊断系统失灵的重要手段，因此尘埃粒子的监测
十分重要。电子噪声、光散射及偶发因素等的影响，可能会偶尔导致尘粒的虚假计数。连续或有规律地出 现少量≥5.0 μm 的尘埃粒子时，应当进行调查。这类事件可早期指示 HVAC 系统的故障、灌装设备的问题， 也可以判断设备安装调试不当和常规操作的不良习惯。
14.The particle limits 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. 14.表中“静态”的尘粒限度，应在操作完成，人员撤离条件下，经大约 15-20 分钟（指导值）“自净”后达到。
15.The monitoring of grade C and D areas in operation should be performed in accordance with the principles of quality risk management. The requirements and alert/action limits will depend on the nature of the operations carried out, but the recommended "clean up period" should be attained.
15.应当按照质量风险管理的原则对 C 级洁净区和 D 级洁净区（必要时）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确定，但自净时间应当达到规定要求。
b)Relationship between EU GMP Annex 1: 2008 and ISO 14644 EU GMP 附录 1 和 ISO1464 的关系
i.EU GMP Annex 1 defines limits for airborne particle concentrations at ≥0.5μm and ≥5μ for different activities in pharmaceutical facilities, using classification grades that have near equivalents in ISO 14644-1:1999: Clean rooms and associated controlled environments – Part 1: Classification of air cleanliness.
EU GMP 附录 1 使用了与 ISO14644-1:1999(洁净室和相关受控环境-第一部分:空气洁净度分级)相似的分
类等级对制药厂的不同活动定义了和空气尘埃粒子浓度的极限值.
Note: EU GMP refers to ISO Classes 7 and 8 at ≥5μbut gives maximum particle counts of 2900 and 29000 in its classification table. The actual ISO classification has maximum particle counts of 2930 and 29300 at
≥5μfor these Classes respectively.
备注:欧盟 GMP 附录 1 引用了 ISO7 级和 8 级,但对此 2 级(≥5μ)给定最大粒子浓度分别是 2900 和 29000(见 表 1).而实际上 ISO 对于这 2 个级别(≥5μ)给定的最大粒子浓度分别是 2930 和 29300.
Table 1: Comparison of EU GMP Annex 1 and ISO 14644-1
表 1:欧盟 GMP 附录 1 和 ISO14644-1 的比较
EU GMP Grade EU GMP 级别 | ISO 14644-1 Class ISO14644-1 分级 | |||
At Rest 静态 | In operation 动态 | |||
0.5μm | 5μm | 0.5μm | 5μm | |
A | 5 | 4.8 | 5 | 4.8 |
B | 5 | 5 | 7 | 7 |
C | 7 | 7 | 8 | 8 |
D | 8 | 8 | 未定义 | 未定义 |
ii.EU GMP Annex 1 refers to ISO 14644-1 for the methodology for classification and to ISO 14644-2:2000: Cleanrooms and associated controlled environments - Part 2: Specification for testing and monitoring to prove continued compliance with ISO 14644-1, for information on testing to demonstrate continued compliance.
欧盟 GMP 附录 1 引用了 ISO14644-1 用于分类的方法来分类和 ISO14644-2:2000 洁净室和相关受控环境
-第 2 部分:证明持续符合 ISO14644-1 的检测与监测技术条件,有关测试的信息以证明持续符合.
iii.ISO 146441-1 and ISO 14644-2 specify procedures for classifying, testing and monitoring clean rooms and clean air facilities.
ISO14644-1 和 ISO14644-2 规定了洁净室和洁净设施的分级、测试和监测程序.
c)Relationship between FDA cGMP, IS014644-1 and EU GMP Annex 1 FDA cGMP,ISO14644-1 和 EG GMP 附录 1 之间的关系
Both FDA cGMP and EU GMP Annex 1 follow the classification of airborne particulate classes of ISO 14644-1:1999 with the following differences:
虽然 FDA cGMP 和 EU GMP 附录 1 对尘埃粒子的分类都遵循了 ISO16444-1:1999,但它们之间有如下不同之
处：
i.FDA cGMP only defines particulate levels in operation, whereas EU GMP Annex 1 defines target cleanliness levels both at rest and in operation.
FDA cGMP 仅定义了动态的尘埃粒子水平,而 EU GMP 附录 1 定义了静态和动态.
ii.FDA cGMP only refers to particles of ≥0.5μm and does not refer at all to≥5μm particles.
FDA cGMP 仅引用了 ISO 中≥0.5μm 的尘埃粒子数据而没有引用≥5μm (所有级别)的尘埃粒子数据.(译注：也就是说,cGMP 中只对≥0.5μm 的尘埃粒子数据作出了规定,而对≥0.5μm 的尘埃粒子没有要求)
iii.The highest grade in FDA cGMP is ISO 5 in operation at ≥0.5μm. The highest grade in EU GMP, Grade A, is ISO 5 at rest and in operation at ≥0.5μm and ISO 4.8 at rest and in operation at ≥5μm. A facility operating to EU GMP Annex 1 Grade A is therefore operating at a slightly higher level of particulate air cleanliness than the highest level in FDA cGMP.
在 FDA cGMP 中最高级别是 ISO5 级(≥0.5μm)的动态.在 EU GMP 中最高级别的 A 级,也就是 ISO5 级的
静态和动态(≥0.5μm)和 ISO4.8 级的静态和动态(≥5μm).因此,对于正在运行的设施而言,在空气洁净度方 面 EU GMP 附录 1 的 A 级略高于 FDA cGMP 的最高水平.
Table 2: Comparison of FDA cGMP, IS0146441-1 and EU GMP Annex 1 in operation
表 2:FDA cGMP,ISO14644-1 和 EU GMP 附录 1 动态的比较
Clean Area Classification （0.5μm particles/ft3） 洁净区分级(粒/ft3) | ISO Designation ISO 名称 | ≥0.5μm particles/m3 ≥0.5μm 粒/m3 | EU GMP Grade EU GMP 级别 |
100 | 5 | 3,520 | A |
1,000 | 6 | 35,200 | |
10,000 | 7 | 352,000 | B |
100,000 | 8 | 3,520,000 | C |
d)5μm particles 5μm 的尘埃粒子
i.Particles counts at ≥0.5μm include all particles ≥0.5μm irrespective of size. The presence of particles over 5μm in size is an indication of a potential microbial contamination of the Grade A or B environment. It is important to monitor for particles of a size ≥5μm.
≥0.5μm 粒子数包括所有粒径≥0.5μm 的粒子.对于 A 级和 B 级环境,粒径超过 5μm 的粒子出现是微生物污
染的潜在标识.所以,监测粒径≥5μm 的粒子是非常重要的.
ii.Measurement at ≥0.5μm will give a much quicker indication of something going wrong than measurement at 5μm, due to the much smaller sample size and therefore shorter sampling time required to give a statistically meaningful result.
≥0.5μm 的粒子的测量结果对”故障”的指示比 5μm 粒子快得多,由于其取样体积更小并给出统计学结果,
因此需要更短的取样时间. ≥0.5μm 的尘粒测量结果对“故障”能给出更快（相比于 5μm 尘粒）的指示。
iii.EU GMP Annex 1 states that monitoring at ≥5μm 'takes on particular significance as it is an important diagnostic tool for early detection of failure'. At the same time it acknowledges that there may be occasional false counts, due to 'electronic noise, stray light, coincidence, etc'. False counts can also be due to particles previously trapped in the sample pipe or the counter itself shaking free. (This is a very real possibility as particles counters are challenged with large numbers of ≥5μm particles during calibrations and some may get trapped in the counter, only to shake free later). It is correct to assume that 'consecutive or regular counting of low levels of ≥5μm particles is an indicator of a possible contamination event and should be investigated' but out of specification ≥0.5μm readings will give a much earlier indication as explained in ii. It is accepted however that readings at ≥0.5μm and at ≥5μm are both important.
EU GMP 附录 1 说明,监测≥5μm 的粒子具有特别的意义,因为它是早期发现故障的重要诊断工具.同时也 存在由“电子噪声，杂散光，巧合等”引起的偶然计数错误。错误的计数也可能是由于取样管内部之前附 着的粒子或者计数器本省的晃动所致.(这是非常有可能的，因为在尘埃粒子计数器校准的时候使用了大 量的粒子挑战，其中一些粒子可能被尘埃粒子计数器捕获，后来晃动时落下造成干扰)。连续或有规律 地出现少量≥5μm 的尘埃粒子时，应当进行调查，因为这是可能发生污染的一种迹象。但是超出≥0.5μm 规定限度会对可能的污染给出更早的迹象，参见 ii. 因此，监测≥0.5μm 的粒子和≥5μm 的粒子都是重要 的。
iv.If there is an increase in ≥0.5μm and ≥0.5μm particles at the same time, this is likely to be indicative of an air quality problem due to HEPA filter failure, differential pressure failure or an open door or inspection hatch to an adjacent lower grade area. If there is an increase in ≥0.5μm particles only, then this may be indicative of mechanical failure, e.g. conveyor bearing failure or poor cleaning practice.
如果≥0.5μm 和≥0.5μm 的尘粒同时出现增加的趋势，有可能是由于高效过滤器故障、压差故障、门被打
开或与被测区域与相邻低级别区域有开口引起的空气质量问题。如果只是≥0.5μm 的尘粒有增加的趋势， 有可能表明是机械故障，例如，传送轴承故障或清洁不彻底。
e)Frequency of monitoring
监测频率
EU GMP Annex 1: 2008 does not use the term 'continuous' but specifies that ‘the Grade A zone should be monitored at such a frequency and with suitable sample size that all interventions, transient events and any system deterioration would be captured and ,alarms triggered if alert limits are exceeded’. In practice, this can
only be achieved by continuous monitoring, using particle counters that are dedicated to individual sampling points and that run continuously, with the exception of cleaning or gaseous sanitization activities or periods of declassification that would potentially cause damage to the particle monitoring units. Such activities should be clearly documented and justified.
虽然 EU GMP 附录 1(2008)不使用术语“连续监测”，但其监测的频率，应能及时发现所有人为干预、偶发
事件及任何系统的损坏且能在尘粒浓度超过警戒限时报警。在实践中，只能通过使用针对单点采样的尘埃 粒子计数器连续监测（清洁或气体消毒可能对尘埃粒子计数器造成损坏的情况除外，对于这样的活动应详 细记录并说明理由）来实现。
For Grade B zones, EU GMP Annex 1 states that 'the sampling frequency may be decreased' which implies that continuous monitoring is not obligatory.
对于 B 级区，EU GMP 附录 1 说明“采样频率可以降低”这表明连续监测不是强制的。
For Grades C and D zones, the monitoring, and therefore the frequency, 'is in accordance with the principles of risk management'.
对于 C、D 级区，其监测及监测频率应依据风险评估来确定。
f)Definition of occupancy states
状态的定义
EU GMP Annex 1 states:-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.
EU GMP 附录 1 规定：为了达到“动态”的要求，其空气洁净度水平的设计应达到“静态”要求。“静态”指所
有生产设备均已安装就绪（设备空转），但没有生产活动且无操作人员在场的状态。“动态”指生产设备按预 定的工艺模式运行并有规定数量的操作人员在现场操作的状态。
The "in operation" and at rest" states should be defined for each clean room or suite of clean rooms.
对每个或者每套洁净室都应定义出“动态”和“静态”。
The definition of the 'at rest' state should include a list of the equipment that is present in the room or facility and a statement of what equipment is running so that the 'at rest' state is always measured under the same conditions. “静态”的定义应包括目前在室内的设备或设施清单（并记录哪些设备处于运行状态）这样以便于以后“静态” 始终在相同的状态下测定。
5SYSTEM DESIGN
系统设计
This section sets out the main points to consider when designing a particle monitoring system for Grade A, B, C and D areas in facilities covered by EU GMP Annex 1: Manufacture of Sterile Medicinal Products: 2008. 这一部分介绍了设计时要考虑的一个要点，A 级，B 级粒子监测系统，C、D 区由欧盟 GMP 附件 1：无菌 药品的生产产品：2008。
The system may be a combination of:
可能有下列系统：
•A series of dedicated particle counters that will each provide a continuous reading
一系列专用的粒子计数器，可以单独提供持续的监测
•A network of sequentially accessed sampling points connected by tubing and a manifold to a single central particle counter.
网络访问顺序采样点连接通过采样管和集成到一个单一的中央粒子计数器。
•A portable particle counter that can be moved between specified positions.
可移动的便携式粒子计数器
Recommended best practice is:
推荐的最佳粒子系统：
i.Grade A areas should be monitored continuously using dedicated particle counters per sampling point for the full duration of critical processes.
A 级区，应该使用专用的连续粒子计数器监测系统监测，并生产全程采样点连续监测。
ii.Grade B areas, where they are the background for a Grade A area, the preference is for dedicated particle counters. However a manifold system or portable counters may be used provided that the sampling interval is carefully considered and is in the order of 10 minutes (guidance value). The sample size must be sufficient to be of statistical significance, particularly when considering >5μm particle counts in the at rest state.
B 级区，作为 A 级的背景区，应该使用专用的粒子计数器。如果采用集成粒子监测系统或便携式，应
仔细考虑采样间隔时间，不少于 10 分钟（指导值）。样本量必须足够的统计学意义，尤其是静态下时考
虑 5 微米以上的粒子计数。
iii.Other Grade B areas and Grade C areas may be monitored by manifold systems to check that they are under control.
其他的 B 区和 C 级区可以用集成粒子监测系统来监测。
Note: There are no limits for the 'in operation' state in Grade D areas.
注：动态 D 级没有限制。
iv.Corridors and change areas may be checked on a routine basis using portable particle counters or monitored using manifold systems.
走廊和更衣的区域可能会定期使用便携式粒子计数器或者集成粒子监测系统。
v.Enhanced monitoring shoud be provided in certain Grade C and D areas, for example in facilities processing biological products where low grade areas can potentially contribute a significant bioburden (to the pointof
sterility failure).
某些 C 级和 D 级区域应加强监测，例如，在低级别区域可能有潜在微生物污染的生物制品设备（无菌 失败的要点）。
A risk assessment to determine critical locations should be part of the design process. Risk assessment methods are listed in Appendix E.
风险评估，确定关键位置应在设计过程时考虑。风险评估方法见附录 E
5.1Particle monitoring systems for Grade A areas A 级区粒子监测系统
a) Risk Assessment
风险评估
The design of the monitoring system should be based on a formal risk assessment carried out in accordance with one of the methods listed in Appendix E. The risk assessment is used to identify representative locations where the product is most at risk of exposure to potential contamination from airborne particulates. Sampling positions are then defined as close as is practicable to these representative locations. It is recommended that dedicated particle counters are used with isokinetic probes sited at these sampling positions so that there is continuous recording of the particle count at each sampling position for the full duration of critical processing. Monitoring at these same points can also be used to demonstrate that the location is under control at other times. 该监控系统的设计应基于一个正式的风险分析进行评估，根据附录 E 中的方法这个风险评估是用别那些产 品是在暴露于潜在的风险的采样位置，这个位置最有可能来自于空气中的颗粒物污染。然后确定这些典型 的位置是合适的位置。建议使用专用的粒子计数器，并用等动力学采样头放置在这些采样位置，在每个采 样位置连续计数并记录，对关键工艺的位置要全程监监测，这一点也可以用来显示该位置在不同生产时间 状态下的区别。
Note: Isokinetic sampling probes should always be used in undirectional airflow systems as generally provided in Grade A areas.
注：等动力学采样头应该规定在层流系统 A 级中使用。
The risk assessment should take into account:
风险评估应考虑：
•All locations where there is a possibility of operator intervention, for example access points to the Grade A environment. The process should be observed over a suitable period of time and a list of observed interventions collated to determine the most appropriate sampling positions. 所有地点有可能的人为干预，例如人员靠近 A 级区环境的活动。这个过程应该是在一个适当的时间观 察时间和一个列表的干预对照观察，确定最合适的采样位置。
•Original room classification studies, qualification studies and the rationales for previously used sampling/monitoring arrangements.
对最初的许多洁净级别定级数据分析，得到合理的分析结果
•Areas where there are normally no interventions, but sterile components/products are still potentially exposed to airborne particulate contamination due to abnormal interventions or for other reasons. 无菌区通常是没有人工干预的区域，但无菌部件/产品仍有可能暴露在空气中，粒子污染由于异常的干 预或其他原因
•The length of time that sterile components and and/or products are exposed during processing. An example might be stoppers in a feed hopper. In this instance, there is little risk of intervention. However, the stoppers may well remain exposed in the hopper for some time, so that there is a potential for buildup of particulate contamination over time. It would therefore be good practice to sample air at this location to demonstrate continued compliance of the air quality in contact with components over the processing time. 在生产过程中，长时间的无菌部件/或产品暴露。一个例子是可能胶塞在进料斗中。在这种情况下，很 少有人为干扰风险。然而，塞子可能长时间的保持暴露在空气中，所以这是一个潜在的风险点，他会随 着时间的增加而增加粒子污染的风险。因此将长时间暴露的设备组件、产品、等位置作为采样点作为风 险点事很好的选择。
The monitoring approach for isolator filling operations is slightly different from that for cleanroom filling operations. For continuous monitoring of isolators, it must be ensured that the sampling does not adversely affect the isolator airflow or pressurisation. The sampling position(s) must monitor the area of aseptic filling. However the impact of interventions and the location and operation of transfer devices must also be taken into consideration. In addition, the airflow patterns of the isolator should be considered as this will impact upon the particle monitoring strategy and the choice of sampling probe (see section c). Siting a sampling point immediately before the extract filter can also be considered as a option as this can represent the worst case location, provided the presence of process generated particulates is taken into account. 隔离器灌装生产的在线监测方法是稍微不同于无菌灌装操作。隔离器中连续的采样监测，它必须确保采样 不产生影响的隔离器的气流或加压等因素。采样位置（S）必须监控无菌灌装的区域。然而，人工的干预 和的位置和操作转移的影响设备位置还必须考虑。此外，取样探头对于隔离器的气流模式应被视为会在粒 子监测策略选择的影响（见 C 节）。采样点选择在迅速插拔过滤器的位置也可以被视为一个选项，因为这 可以代表最坏的情况下的位置，可考虑设置可能产生的微粒过程的位置。
Mapping is a useful technique in the risk assessment, to aid the identification of suitable sampling positions. Initially particle count data should be obtained by placing isokinetic probes and counters at various locations within the Grade A environment (e.g. around a filling machine or within an isolator) and recording the level of particulates recovered under 'at rest' and 'in operation' conditions. This should determine the worst case/highest risk to the process being monitored. Particular attention should be given to critical areas where the product and or components are exposed and areas that have been identified as potential 'dead spots' as a result of initial smoke pattern studies. 比对方法是在风险评估的一个有用的技术，可以帮助识别合适的采样位置。最初的粒子计数数据应放在等 动力学采样头和台面获得在一个级别环境不同的位置（例如，在一个灌装机或在一个隔离器）粒子数据， 或粒子在静态和动态条件不同的数据。以此来确定最差条件情况下的最高风险的过程监测。应特别注意的 关键区域，尤其是当产品或部件暴露的区域，在最初的定级过程中的烟雾实验研究已被确定为潜在的“死 点”是可考虑的。
Critical areas to be considered are:
关键区域被认为是：
•The point of fill
灌装点
•Component hopper
部件料斗（装胶塞用）
•Inspection hatches
观察舱
•Descrambler tables
控制台
•Stoppering and capping stations
加塞盖点（胶塞站和铝盖站）
•Loading of Freeze Dryers
冻干机的加载（冻干上料）
•Unloading of sterile components
无菌组件拆卸
•Interfaces between equipment and the Grade A area
设备与 A 级区之间的接口
•Isolator transfer devices
隔离器传送装置
•Aseptic manipulations
无菌操作
•Operator interventions
操作员的干预
Smoke studies can be used to demonstrate that the proposed or final position of the particle counting probe in a critical Grade A monitoring location does not impact the unidirectional airflow over the exposed vials/ampoules. 烟雾实验的研究可以用来证明所提出的最终的采样位置，粒子计数探头的位置不应该影响层流和暴露产品 瓶/安瓿等。
b)Written plan
书面计划
A written plan should be produced from the risk assessment, specifying sample positions including height above a specified reference level, minimum volume of air per sample, duration of measuring period (in terms of the manufacturing process being monitored), particle size or sizes to be counted (normally 0.5μm and 5μm, count acceptance criteria, alert limits and action limits. 一个书面的计划应该从风险评估的产生，样本包括指定位置上面指定的高度，空气样品体积，持续时间， 测量时间（在生产过程的条款监测），粒子的大小必须计算（通常 0.5 微米和 5.0 微米的数据，文件中还要 有计数的验收标准，警戒限和行动的限制。
c)Sampling probes and mounting
采样探头和装置
Isokinetic sampling probes should always be used in Grade A unidirectional airflow facilities. Not all isolators rely on unidirectional airflow to provide the Grade A air quality, In such cases isokinetic probes are not necessary and a simple tube is sufficient. Isokinetic sampling probes are described in Appendix D. 等动力学采样头常便捷的使用在单向流的 A 级区。并不是所有的隔离器都是单向流，（可以提供 A 级质量 的空气），在这种情况下是不需要等动力学采样头的，等动力学采样头的描述见 Appendix D
Probes should be located as close to the exposed product or aseptic process area as is practically possible. The FDA cGMP suggests probes should be located within 1 foot (305mm) of the exposed product, with the probe orientated towards the filtered air bathing the area, or, in the case of non-unidirectional airflow, in a vertical orientation (see Fig. 1).
采样头被设置在产品暴露或可能有无菌操作的无菌区。FDA cGMP 建议探头应该设置在产品暴露区周围 1
英尺范围内，这个探头正对着高效过滤器，在非单向流中，探头应该垂直于地面，见图 1。
Fig. 1 Location of isokinetic sampling probe over open containers
图 1，等动力采样头在容器开口之上
Note: The 305mm relates to a hemispherical zone
注意：305mm 范围是指的半球区域内
Fig. 2 An example of an isokinetic probe at a stoppering station
图 2，等动力采样头在胶塞站附近的例子
Fig. 3 An example of an isokinetic probe at a filling station
图 3，等动力采样头在灌装头附近的例子
However, both EU GMP and FDA cGMP recognise that it is not always possible to place the sampling probe as close as this when filling is in progress due to the generation of particles, or droplets from the product itself. 不论是 EU GMP 还是 FDA cGMP，两者都认可采样头采集到的粒子，产品本身产生的粒子是有可能的， 如小液滴，产品本身。
For this reason it is important when designing the system to consider not making the position of the sampling probe a fixed position. If possible, the probe should be mounted on a moveable bracket, allowing horizontal and vertical movement, so that it can be moved to the optimum position for a representative sample of air without interference from particles or droplets of the product. This is shown in Fig. 2. 在系统设计的时候显得尤其重要，采样头如不能考虑固定位置，如可能可设计安装在一个活动的支架上， 可水平的，上下的移动，那样可选择一个合适的位置，空气采样不会受到诸如图 2 产品和小液滴的干扰，
Fig. 4 Adjustable mounting bracket
图 4 可调整的安装支架
In circumstances where it is not possible to get close to the exposed product during manufacturing, an alternative approach for consideration is to use two sample probes, one within the 305mm suggested dustance from the open vials and one located at such adistance as not to be affected by particulates or droplets from the process (see Fig. 5). The closer probe is used to demonstrate the cleanliness of the air surrounding the exposed product for an extended period before manufacturing commences before being capped off at the start of the production run. Then the higher probe is used to take representative samples to demonstrate the quality of the air bathing the exposed product during the production run. This is shown in Fig. 3. 在采样头不便于洁净暴露产品生产区的区域，可以考虑 2 个采样头，1 个采样头在暴露容器开口半球 305mm 范围内，另 1 个设置在远一些的不受产品和液滴粒子影响的位置（见图 5），这个近一些的采样头用于证明 产品线开始生产，但在盖塞之前的空气洁净度，另一个更高一些的采样头采集的样本用于证明生产线条件 下的空气流送风的空气质量。见图 3.
The same considerations apply at interface areas with autoclaves and freeze dryers.
同样的考虑可应用在高压灭菌器和冻干机
Fig. 5 System with two sampling probes 图 5 有 2 个采样探头的系统 Notes:注意
a)The 305mm relates to a hemispherical zone 305mm 的区域包含其范围内的半球区域
b)The higher sample probe position should be as far as possible from the HE PA face
高一些的采样头位置有可能远至正对高效过滤器的位置
The position of a dedicated particle counter and isokinetic probe must take into account equipment access/interference, mounting points, operator safety/impedance to normal aseptic processing activities and maintenance/cleaning access. 一个专门的粒子计数器等动力探头的位置必须考虑到设备的开口/干扰，安装点，操作者的安全/阻抗正常 无菌处理活动和维修/清洁口
It is recommended that the length of tubing between a dedicated particle counter and its probe should be as short as possible and certainly no more than 3 metres (guidance value from FED-STD 209E, September 11th 1992 - withdrawn).
建议粒子传感器与采样头之间用专用应尽可能的短采样管连接，确认不超过 3 米（FS209E 指导值，September
11th 1992 – withdrawn）
c)Local displays and alarms
位置显示及报警
Air particle monitoring systems are put in place to monitor that acceptable levels of airborne contamination are not exceeded during the manufacturing of sterile pharmaceutical product. 空气粒子监测系统监测的数据应显示在屏幕上，空气污染水平在无菌药品的生产过程中不超过可接受的标 准.
It is essential that the cleanroom operators are aware of the air cleanliness status so that they know when it is
unsafe to manufacture sterile product. The most effective way to ensure that the cleanroom staff are aware of the risk of potential airborne contamination is to have alarm indicators in the cleanroom where they are clearly visible to the cleanroom staff, or sounders where they can be heard by the cleanroom staff. It is also good practice that a 'safe to manufacture' indication is provided, typically in the form of a green indicator clearly visible to cleanroom operators. The 'safe to manufacture' indicator should be lit only when the particle monitoring system is working correctly and the airborne contamination is at the designed levels.
操作者能及时感知空气洁净室洁净状况，使他们知道这对无菌产品的生产是危险的，这是必不可少的。为
了保证洁净室的洁净度的最有效的方法是让操作人员及时意识到潜在的空气污染的风险，必须让他们可清 晰的知道洁净室有报警，对洁净室的工作人员来说，应该使他们能听到的报警。通常设置一个绿色指示灯 的形式指示“安全生产”，这是非常好的做法，正确的操作和适当空气污染，粒子监测系统设计应该显示正 常工作，绿色指示灯应点亮。
d)Design of system to allow easy maintenance.
系统设计应考虑易于维护
Consideration should be given to the positioning of the sampling probes and counters for ease of access for maintenance and calibration. They should not interfere with the processes and procedures that they are intended to monitor. This should be taken into account during the study to determine the positioning of the units, bearing in mind also the maximum tubing length recommended. 应考虑到采样头的位置能够便于连接采样头和粒子计数器。他们不应该干扰生产过程。考虑到确定的定位， 同时考虑最大推荐的采样管的长度。
Only the isokinetic sampling head and stem should be present within critical area, with the casing housing the particle counter outside the critical zone for access during maintenance/servicing. 只有等动力学采样头在关键区域（A 级），有盒子的粒子计数器应该不在关键区域（A 级），这便于维护。
e)Monitoring airflow through sampling heads and particle counter
通过采样头和粒子计数器监测气流
The particle counter will only count particles representative of the contamination levels present in the room when the air sample is being drawn through the particle counter at its specified operational airflow rate. Therefore t is essential, as part of the design, that provision be made for the monitoring of the airflow rate through the particle counter or the vacuum level (if it can be shown that the airflow rate is directly related to the vacuum level) otherwise there is no certainty that the counter is giving correct particle count data. 粒子计数器在洁净区里抽取空气计数的颗粒代表洁净区污染水平，被吸入粒子计数器在其指定的流速。因 此时间 t 是必不可少的，作为设计的一部分，这提供了用于监测通过气流速度,粒子计数器或真空水平（如 果它可以表明，气流速度对真空度直接相关）否则不确定性，反馈给计数器正确的的数据。
f)Special requirements for isolators sanitised by vapour phase hydrogen peroxide
用于隔离消毒的过氧化氢蒸气的特殊要求
Vapour phase hydrogen peroxide is commonly used for the sanitisation of isolators. The resistance of the particle counter, probe and tubing to vapour phase hydrogen peroxide should therefore be considered as part of system design. Manufacturers should where possible select materials that are not affected by vapour phase hydrogen peroxide or use Teflon coating to protect vulnerable surfaces. Vapour phase hydrogen peroxide is however a very strong oxidiser and over time will be able to penetrate and corrode even ' the most robustly designed systems. As no product manufacturing operations are in progress during sanitisation, the isolator does not have to be monitored for particles during this time. Therefore the particle monitoring system should be protected from exposure by turning the vacuum off and capping the sample probe.
气态过氧化氢常用于消毒隔离器。颗粒计数器的阻力，探头，管与气态过氧化氢应作为系统设计的一部分。 制造商选择的材料，不应该影响 VHP 的气化，使用特氟隆涂层内壁表面管道也是不能经受 VHP 腐蚀的， 气态 VHP 是一种很强的氧化剂，将随着时间的推移，能够渗透和腐蚀甚至最强劲的设计系统。在消毒操 作进行时，不能打开粒子计数器监测隔离器中的粒子。因此，在 VHP 消毒过程中，粒子监测系统应防止 暴露，将真空关闭，并用盖子盖上采样头。
5.2Particle monitoring in Grade B areas
在 B 级区域的粒子监测
Where the Grade B area is the background to the Grade A processing area, the design of the monitoring system should be based on a similar risk assessment to that for the Grade A area and the preference is for dedicated particle counters. However manifold systems are suitable provided that the sampling interval is considered and in the order of 1 0 minutes.
在 B 级区作为 A 级区域的背景区域，该监控系统的设计应基于类似 A 级区的风险评估，最好是专用的粒
子计数器。然而气流流形应该提供，系统的采样间隔可以在 10 分钟
Criticality of Grade B process areas will be based on the degree of separation between the Grade A and Grade B areas.
B 级区的控制基于 A 级和 B 级区之间的隔断
Less frequent particle monitoring can be justified where restricted access barrier systems (RABS) or isolator technology is used compared with conventional cleanroom technology. 限制进入的屏障系统(RABS)或隔离技术的应用可以少于传统的洁净室技术的监测频率
It should be sufficient to check Grade B corridors and Grade B areas at least once during each shift using portable counters or a manifold system with full re-classification on a 12-monthly basis in accordance with ISO 14644-2 应该充分检查 B 级通道和 B 级区域，在生产中每班至少有 1 次使用便携式粒子计数器对其进行监测，B 级 的重新定级应该根据 ISO 14644-2 在 12 每月一次。
Where manifold systems are used to monitor rooms, then the sampling points are usually positioned on the walls or columns in the room at a representative working height. 有多种粒子监测系统可以使用，采样点的位置通常是在墙或柱子上，采样头的高度在典型的工作高度
When installing a manifold system, consideration should always be given to equipment access and interference, operator safety, impedence to normal processing activities and access for maintenance and cleaning. 当安装一个集成粒子监测系统粒子系统时，考虑的应该是对设备的操作和干扰，操作安全，能够正常处理 的活动和操作维护保养和清洁
5.3Particle monitoring in Grade C and D areas
在 C 级和 D 级区域的粒子监测
Portable counters or manifold systems are considered suitable for monitoring Grade C and D areas.
在 C 级和 D 区粒子监测，便携式或集成粒子监测系统被认为是适合的。
Annex 1 states: 'The monitoring of Grade C and D areas in operation should be performed in accordance with the principles of quality risk management. The requirements and alert/action limits will depend on the nature of the operation carried out, but the recommended clean-up period of 1 5 - 20 minutes should be attained'. All Grade C and D areas must be monitored at intervals to be determined by a risk assessment Grade C process areas should be monitored at more frequent intervals than less critical areas such as corridors, changing rooms and grade D areas.
Re-classification of all areas should be conducted at intervals in accordance with ISO 14644-2.
附件 1：“动态的 C 级和 D 级区的监测应与质量风险的原则进行管理。要求和警报/行动范围将取决于在操 作进行的性质，但自净时间建议 15 - 20 分钟应达到。所有的 C 级和 D 级由风险评估必须监测的时间间隔， 临界区等走廊，更衣室和 D 级区，监测频次应该多于其他区域，所有级别的重新定级分类应根据 ISO 14644-2 规定进行。
5.4Maximum tubing length for manifold systems
集成粒子监测系统采样管的最大长度
Maximum tube lengths of 30m and 125ft have been specified for manifold systems. The second example in Appendix C shows that there is a significant drop-out of 5μm particles over this length of tubing. However the particle count data might still be useful for noting trends. The drop-out of 0.5μm particles is much less significant and the particle count data is therefore likely to be more reliable. Validation of manifold monitoring systems is recommended.
集成粒子监测系统 30m 和 125 英尺最大的长度已经在附录 C 中的第二个例子说明，5 微米粒子在这个长度
中，粒子数有一个显着下降，然而粒子计数的数据可能仍然是有用的注意的损失趋势。小的的 0.5 微米颗 粒损失是不明显，因此小粒子数据在长管系统中可能更可靠。集成粒子监测系统使用时建议先验证。
6OPERATIONS
操作
a)When should the particle monitoring system be on
微粒监测系统何时运行
The particle monitoring system should be run continuously to capture trend data and events, except during sanitisation and maintenance. 除了清洁处理和维护，粒子监测系统应该连续不断地记录趋势数据和相关事件。
b)Software
软件
The particle monitoring system should allow the reconciliation of events and comments in reports so that each event can clearly be tied to the relevant comment. 粒子监测系统应该可以记录事件和批注报告，这样每个事件都可以和相关的批注保持一致。
Count data should be provided on a minute-by-minute basis by the system on a 1 cubic foot sample. Sampling is performed at 1 cubic foot per minutes (1cfm) and suppliers of the system can provide software that is configured to report the particle count data both per cubic foot and per cubic metre. The cubic metre data is calculated by reporting the cumulative result over a rolling 36 1-minute samples, i.e. 36 x 1ft3 =1m3. It is useful to have software configurable to monitor and display vacuum pressure alarm limits (e.g. –500mbar and
-700mbar) as a critical parameter. Visual/audible alarms can beactivated for the specific vacuum pump when it fails and an error message is displayed on the PC for the failed point.
计数数据通过系统应该提供在每分钟 1 立方英尺的取样。抽样是在 1 立方英尺每分钟执行(1 cfm)，系
统供应商应提供软件配置包括每立方英尺和每立方米的计数数据报告。按立方米计算的数据报告是每 36 个 1 分钟的滚动样本的结果。即 36 x 1ft3 = 1m3。作为一个关键参数，应配置监控和显示真空压力报 警范围(如-500 mbar 和-700 mbar)的软件。当特定的真空泵发生故障时在计算机上会显示错误信息，并 且有声光警报。
Software should clearly indicate the operation status of each of the particle counters, i.e. on or off.
软件应该清楚地显示每个粒子计数器的运行状态,即打开或关闭。
It may be useful to consider incorporating the facility to provide a dwell/purge time in the counter software to eliminate nuisance alarms on restarting a system following scheduled shutdown of a clean room. Alternatively consideration could be given to suspension of alert and action limits during start-up so that the data collection is maintained. 设备在存在/被触发报警后，考虑计数软件能够复位的操作，并消除这个报警，并且继续后面的洁净区 粒子计数可能是很有用的. 考虑在初始的阶段收集这些数据，并依据这些数据给出警戒限和行动限， 以至于可对以后的数据维护。
It is worth considering setting a hierarchy of commands/requests to separate out alarms specifically for certain parameters: for instance temperature only, humidity only, non viable particles only, differential pressure only, rather than having one report that includes all alarms. 值得考虑设置一个层次结构的命令/请求分离出警报专门为特定的参数:例如温度,湿度,无活性粒子,压 差。而不是让一个报告包括所有的警报。
c)Alerts and Alarms
警戒和报警
To help warn of potential out-of-specification at the cubic metre,minute-by-minute cubic foot count data can be used to show cleanroom operators that their actions are creating particle contamination. It is helpful to have software that can be configured to include Alert and Action limits at a cubic foot and cubic metre levels. On breeching the Alert or Action limit an alarm should be activated. 以立方米作单位的数据可对超标结果（OOS）提供帮助，每分钟的数据可以为操作者提供是否由于自 己的动作而产生的粒子的信息，配备含有以立方英尺或立方米为单位的警戒限和行动限和立方米标准 的软件是很有用的。在密集地超过警戒限或行动限警报情况时指示有频繁的动作操作活动。
Where manufacturing personnel do not have access to a PC within the clean room linked to the environment monitoring system and therefore no visibility of the impact of direct processing activities on the manufacturing process, visual/audible alarm panels installed locally within the clean room environment can be used to alert operators. 生产人员没有权限进入连接洁净室环境监控系统的电脑，因此对生产过程度没有可见的影响活动。声 光报警面板可以嵌入式安装在洁净室环境中，用来提醒警示操作人员。
Operators must maintain an intervention log (see Fig. 6) throughout' the filling process, recording any interventions and noting when the particle counter goes into alarm. The times recorded on the intervention log should be synchronised with the time on the particle counter. If the operators generate an alarm on the particle counter and this has been attributed to an intervention on the filling machine, they should record on the intervention log any remedial action taken; e.g. an intervention in the area of the filling zone, may result in all open containers on the star wheel being rejected. 操作者必须在整个过程中记录数据，记录任何干预措施和笔记。当粒子计数器报警应记录任何的干预 措施和提示，记录干预事件日志，时间上与粒子计数器同步。如果粒子计数器警报则被认为是对灌装 机的干预活动，在日志应记录他们应该采取补救行动的措施。如在灌装区域的干预活动，将导致在星 轮（灌装机转盘）上所有敞开容器被剔除。
Where no visibility of the environmental monitoring system is available within the clean room it is important that manufacturing personnel have a documented procedure that clearly records the alarm event, time, date and specific activity (with sufficient detail) which was being performed (intervention) and can be linked to the alarm event within the environmental monitoring system. This information can be used to support the investigation into an out of specification result and to assess the impact on the process/product manufactured.
由于环境监测系统在洁净室的不可见性，操作人员清楚地记录了一个文档的过程是很重要的报警事件,
时间,日期和具体活动(有足够的细节)环境监测系统中报警事件。这信息可以用于支持调查超标结果
（OOS）对操作过程/产品生产影响。
It is the responsibility of every facility to set and justify appropriate alert and action limits for particle counts. ISO 14644-6:2007 has the following definitions: 警戒限和行动限这些设置值都应该管理好并证明是合适的，ISO 14644 - 6:2007 有以下定义:
Alert level: level set by the user in the context of a controlled environment giving early warning of a drift from normal conditions, which, when exceeded, should result in increased attention to the process. 警戒水平：用户设定的水平的控制，超出正常条件下环境控制水平的数据预警漂移，当超过时，应引 起增加关注操作程序。
Action level: level set by the user in the context of controlled environments, which, when exceeded requires immediate intervention, including the investigation of cause, and corrective action. 行动限:用户设定的水平的控制，当超出正常条件下环境控制水平的数据预，需要立即干预,包括原因的 调查和纠正行动。
5μm particles are an important diagnostic tool in detection of failure. Occasional 5μm particles may be false counts. However consecutive, or regular, counts are an indicator of possible contamination and should be investigated.
5um 粒子是检测失败的一个重要的诊断工具。偶尔 5um 粒子可能是电子噪音错误的。然而连续或定期
统计数据的超标可能指示的污染,应该调查。
For batch monitoring, particles are reported for 0.5μm and 5.0μm particle sizes. Counts are added up in blocks of 36 minute samples equal to one cubic meter for each sampling location.
批处理监控粒子报告有 0.5μm 和 5.0μm。36 分钟的样品采样应相当于一个立方米的体积。
d)Interventions
干预措施
Each type of intervention should be defined so that operators can select from a list when thay need to report what they were doing when an alarm/alert event occurs. This helps with investigations and improvements in processes and procedures. Note that EU GMP Annex 1 now requires particle monitoring during aseptic set-up. 每种类型的干预应该定义, 当警报/警告事件发生时，操作者从列表中选择报告需要他们做什么，这是 调查和帮助改善流程的过程。欧盟 GMP 附件 1 无菌设置粒子监测。
e)Alarm management
报警管理
Non viable particle alarms can occur due to:
无活性粒子警报可能发生项:
i.Associated with known activities - non specific batch related events.
与已知的相关活动,非相关的特定批事件。
ii.Associated with unknown activities - which could be a batch related event or not.
与未知的活动——这可能是一个批处理相关事件。
iii.Activity which has been directly linked to a batch processing event and has been recorded as such by the manufacturing operator during the intervention. 直接关联批处理事件和已经记录的在生产操作过程中的干预的活动。
iv.Contamination of the cleanroom zone.
污染的洁净室区域。
v.Failure of the air handling system.
空气处理系统的失败。
Procedures should be written around alarm management which can include a list of known activities which can cause 'nuisance' alarms which have to be responded to and documented in the audit trail due to alarm activation. 程序应该包括报警的管理和一组已知的活动事件，对这些事件可以写备注原因，需要后续跟踪处理被激活 的报警事件的分析和记录。
Examples are:
例:
i.Pre cleaning before batches
批次的前清洗
ii.Post cleaning activities
清洁
iii.Calibration activities
校准
iv.Planned Preventative Maintenance
.预防性维护计划
v.Servicing
维修
vi.Scheduled cleanroom shutdown and isolation of particle monitoring system.
关闭洁净室和隔离的粒子监测系统。
The procedure should make provision for the documented reporting and investigation of alarms which have occurred outside a routine batch manufacturing operation where the issue creating the alarm is not known. This is to ensure that the cause of the alarm event is determined, impact contained and resolved before manufacturing commences. This procedure and records are non batch related and would not constitute part of the batch manufacturing records. 该程序应提供书面报告并研究发生在一个常规的警报，批量生产操作问题创建原因不明的警报。这是为了 在确定找到报警事件的原因之前，及时的记录。本程序和记录是非批处理相关将不作为批生产记录的一部 分
A procedure should also be in place to review alarms which were specifically generated during batch manufacturing operations. This procedure and records are batch related and would therefore have to be reviewed
as part of the batch manufacturing records. 应该建立一个在批量生产操作过程中的具体产生评估警报的程序，这程序和记录和批生产有关，因此就要 作为批生产记录的一部分。
Consideration should be given to isolating potentially contaminated components and/or product following an out of specification (OOS) result for non viable particles pending a full investigation to determine the action to be taken. 应该考虑孤立潜在污染，或产品检测结果超标(OOS)，这个超标结果未调查完，需要全面调查，再确定要 采取行动。
All cleaning and sanitising activities, even when no monitoring is taking place, should be logged.
所有的清洁用品和清洁活动,即使在没有监控发生时也应该被记录。
f)Data trends in the cleanroom or isolator
洁净室或隔离器的动态数据
The particle monitoring system can be used to indicate contamination trends. A trend showing a worsening of the particle contamination may be indicative of process problems, or the requirement for further training for cleanroom operators. 粒子监测系统可以用于指示污染的趋势。这一趋势显示粒子的恶化污染可能暗示的过程问题,或洁净室运营 商要求进一步培训。
g)Demonstrating that areas are in control prior to manufacturing
证明该区域在生产前受控
It is recommended that, after an area has been closed for planned preventative maintenance, the monitoring time before production commences should be sufficient to demonstrate that the area is fully under control. 我们建议，在无监测、维护等计划的区域，在生产前时间里监控，应该首先监测这些区域，并在证明在控 制之下后，再生产。
7MAINTENANCE AND CLEANING
维护和清洁
a)Recommended frequency of maintenance/calibration
建议的维护/校准频率
This should be performed every 6 months by the system supplier, and should consider the following:
通常由供货商进行，每 6 个月 1 次，并应考虑以下因素：
i.Vacuum Pump - may include vane and filter replacement due to usage.
真空泵—根据使用情况可能包含叶片和过滤器更换。
ii.Counter calibration - IS021501-4 is the standard for calibrating air particle counters used for classification and monitoring to IS014644 and the use of this standard should be considered unless a rationale is developed for alternative calibration procedures.
计数器校准——适用于 ISO14644 分类和监测的空气粒子计数器的校准标准为 IS021501-4；除非开发出
其他的可替代校准过程，计数器校准均应参考此标准进行。
iii.Particle counter and computer - functionality check.
粒子计数器和计算机——功能检查。
iv.Alarm Panels - functionality check including verification of alarm and limits.
报警面板——功能检查，应包含报警信息和限度范围确认。
v.Sample tubing - check and replace if required, as possible tubing decay may generate particles and particles may collect in tubing over time causing bursts of counts when the particles are shaken free. 采样管——检查，必要时更换；采样管老化可能产生微粒，这些微粒在采样管中长时间聚集，当管路震 动时会导致计数器监测到的微粒数暴增。
vi.Isokinetic probes and associated stainless steel tubing - check and clean.
等动力探头和相关的不锈钢管——检查和清洁。
b)Cleaning recommendations and frequency
清洁建议和频率
Due to the potential ingress of cleaning solutions into the sampling head, down the tubing and into the particle counter during cleaning activities it is recommended that individual particle counters are switched off at the PC, the vacuum pump is turned off and sampling heads are capped off prior to cleaning activities commencing. This will protect the sensitive particle counter and tubing from damage from solution contamination which can result in erroneous or erroneous particle count results as a result of damage to the particle counter or through dried cleaning solution breaking free and generating particles. 由于清洁剂有进入采样头的潜在可能性，在清洁活动中沿着管路向下并进入粒子计数器，因此建议在清洁 时将各个粒子计数器与 PC 断开连接、关闭真空泵、并在清洁活动开始前盖上采样头的盖子。这样可以保 护灵敏的粒子计数器和管路避免受到溶剂污染的破坏，这种溶剂污染可能导致粒子计数器损坏或者清洁剂 干燥后自由扩散并产生粒子，从而产生错误或者提供错误的计数结果。
IPA or similar non-residue forming solution should be used to wash out any particles that may be present in the vacuum/sampling tubing. This must be done when the tubing is disconnected to avoid damage
异丙醇或者类似的无残留溶剂可以用来冲洗真空泵和/或采样管中可能存在的粒子。
It may be useful to configure a purge time following restart of the particle counter within the software of the environmental monitoring system to eradicate 'nuisance' alarms which can occur after initial removal of caps after cleaning. 在重新启动环境监测系统软件运行粒子计数器时配置一个清洗时间是非常有用的，这样可以从根本上杜绝 清洁后移开盖子初始发生的“令人讨厌的”报警。
Procedures around switching off particle counters, capping off and reinstating of particle counters should be clearly documented within a procedure to ensure all counters are functioning prior to manufacturing operations commencing. 断开粒子计数器，去掉盖子，和复原粒子计数器的相关操作过程应在文件中有明确规定，以保证所有的计 数器在生产操作开始前处于正常的功能状态。
There is less risk of damage to the particle counter associated with a manifold system due to the remote location and length of tubing associated with these systems. 在集成粒子监测系统逐点采样系统中，由于远端位置和管路长度，对粒子计数器造成损坏的风险是比较小 的。
However contamination of the tubing can result in erroneous isolated counts being observed, potential following residual particles within the line being released over time. Again it is advised that manifold systems are protected during cleaning activities and during routine shutdowns. 无论如何，管路污染会导致观察到错误的计数，随着运行时间延长，管路中下游潜在的残留粒子会持续释 放。再次建议集成粒子监测系统应在清洁活动中和日常关机状态下进行保护。
扩展说明：
ISO21501-4 Determination of particle size distribution -- Single particle light interaction methods -- Part 4: Light scattering airborne particle counter for clean spaces
ISO21501-4 粒径分布测定——单粒子光相互作用法——第 4 部分：洁净空间用光散射式尘埃粒子计数器
This part of ISO 21501 describes a calibration and verification method for a light scattering airborne particle counter (LSAPC), which is used to measure the size and particle number concentration of particles suspended in air. The light scattering method described in this part of ISO 21501 is based on single particle measurements. The typical size range of particles measured by this method is between 0.1 μm and 10 μm in particle size. Instruments that conform to this part of ISO 21501 are used for the classification of air cleanliness in cleanrooms and associated controlled environments in accordance with ISO 14644-1, as well as the measurement of number and size distribution of particles in various environments.
ISO21501-4 部分描述了一种用于光散射式尘埃粒子计数器的校准和验证方法，这种粒子计数器是用来测量
悬浮在空气中的粒子尺寸和浓度的。ISO21501 在本部分描述的光散射方法基于单粒子测量，这种方法可测 量的典型粒径范围为 0.1um 到 10um 之间。符合 ISO21501 本部分标准的仪器用来对洁净室和相关受控环 境的空气洁净度进行分类，并且对不同环境的粒子分布情况和数量进行测试；分类依据与 ISO14644 一致
8DISASTER RECOVERY AND DATA BACK-UP
灾难恢复和数据备份
a)Disaster recovery
灾难恢复
It is recommended that the disaster recovery plan is written into an SOP, so that it can be authorised in advance
建议将灾难恢复计划写入 SOP，保证该计划可以得到事先批准。
If a fixed-in-place particle counter is not working for a critical activity then these activities should not start until a replacement is in place. This may need to be in the form of a mobile counter set up as close to the fixed system as possible which can be used until the unit can be repaired. 如果固定位置的离子计数器在重要活动时不能工作，那么只有替代设备到位时才能继续开展这些活动。这 就需要在固定设备旁边安装可移动的计数器备用，直到固定的离子计数器修好。
The replacement counter must be calibrated and tested as working satisfactorily before use
备用的计数器在使用前必须经过校验和测试，以确保功能正常。
If there is a software or network failure meaning that the entire systerfr can not be used to monitor operations then procedures should be in place to allow mobile particle counters to be used. 如果软件或者网络问题导致整个系统不能用来监控操作， 那么就要有允许移动离子计数器使用的流程。
Consideration should therefore be given to purchasing a number of mobile counters and installing a procedure to cover such events.
因此需要考虑购买并安装一定数量的移动计数器。
However it is not recommended that particle counters from a lower classified area (e.g. Grade C or D) are placed in a higher classified area (e.g. Grade A) due to potential contamination risks. 为了防止可能的污染，不建议将离子计数器从低级洁净区（例如 C 级或 D 级）移动到高级别的洁净区（例 如 A 级）。
b)Data back-up
数据备份
Back-up of particle counting data from the main computer is recommended on a daily basis.
建议离子计数数据每天备份。
As product cannot be released unless data is available to demonstrate that there was no airborne particulate risk of contamination to the product during the manufacturing process, it is prudent to have a standby computer with validated software available as part of a disaster recovery plan. As computer specifications and operating systems change regularly, it is important to obtain the standby computer at the same time as the main computer. 因为只有数据表明在生产过程中没有粉尘污染产品的风险，产品才能放行；作为灾难恢复计划的一部分， 建议有一台软件经过验证的计算机备用。因为计算机标准和运行系统经常变化，同时有一台和主机相同的 计算机备用是非常重要的。
9TRAINING
培训
It should be recognised right from the start that the implementation of a continuous particle monitoring system will most likely lead to the need to change existing SOPs, including especially the cleaning SOPs. 在线粒子监控系统的启用，将有可能导致需要对已有 SOPs 进行修订，尤其是与清洁有关的 SOPs。
The continuous particle monitoring system will probably be monitored and operated on a day-to-day basis the cleanroom production staff. This represents a shift in practice. Previously particle counting was the generally responsibility of the quality control/Microbiology team.Minute-to-minute data on the cleanliness of the cleanrooms is now available for the cleanroom production staff.They are,for probably the first time,now directly able to see the effects of their actions on the cleanliness levels within the cleanroom. Hence, training must be provided,not only on how to operate the monitoring system,but also on techniques for cleaning when particle counters are present,how to interpret the data that the monitoring system gives them and how to react when the monitoring system indicates a trend out-of-specification. 洁净室的生产人员有可能对在线粒子监控系统进行日常的操作和监控。这是实践中的一个变化。以前的粒 子计数一般是 QC 人员或微生物人员的职责，现在，洁净室的生产人员可直接获取洁净室每分钟的洁净度 数据。他们，现在能在第一时间就能直接看到他们的行为对洁净室的洁净度的影响。因此，必须要提供以 下内容的培训，如何操作监控系统，当有粒子存在时如何进行清洁，如何诠释由监控系统采集的数据，以 及当监测系统指示粒子有超标的趋势时如何采取应对措施。
Training should include the following
培训应包括以下内容：
a)all SOPs impacting on the particle monitoring system
所有对粒子监控系统有影响的 SOPs。
b)an explanation of the respective responsibilities of QC, production staff and engineering/facilities teams QC 人员、生产人员、工程人员的各自的职责说明。
c)best practices for spraying IMS, cleaning, opening doors/hatches, moving too fast, powder product, glass from broken vials, etc.
关于 IMS 喷洒，清洁，开门，快速移动，产尘，小瓶破碎玻璃等的良好规范。
d)awareness of the implications of particle count data and alarms so that production staff can see the effect of their actions on the number of particles generated (helpful when you consider that these particles are invisible to the human eye) 意思到粒子计数的数据和报警的影响，以便于生产人员能看到他们的行为对所产生的粒子数量的影响
（对人眼无法看见的粒子）。
Appendix A - Worked example of monitoring system layout
附件 A：监控系统布局的成功案例
In the example below, vials pass into the cleanroom through a sterilising tunnel, are sorted on the descrambler table then pass into the filling and stoppering machine. Finally, the vials have a crimped cap applied. All the green shaded areas are Grade A and are separated from the rest of the cleanroom which is Grade B. 在接下来的例子中，药瓶通过灭菌隧道进入洁净室，在理瓶进行排列后，进入灌装加塞机。最后，把药瓶 加上铝盖。所有的绿色阴影区都是 A 级区，洁净室的其他位置都是 B 级洁净区。
The number of monitoring probes required for the Grade A area were determined from a risk assessment. In this example, the assessment resulted in a requirement for one probe each at the descrambler table, the filling zone, the stoppering zone and at the capping station.
A 级洁净区需要的监测探头位置需要经过风险评估的确定。在这个案例中，风险评估的结果就是在理瓶，
灌装区，加塞区和加盖区都需要一个监测探头。
From this, the monitoring probe locations were selected as shown in the diagram below.
因为这个，监测探头的安装位置如下图所示。
Notice the 5th probe location which is monitoring the background Grade B zone to ensure that it remains under control.
注意：第五个监测探头是在 B 级洁净区，是为了确保其在洁净控制之中。
If it is not practically possible to monitor close to the open product during filling/production because the product itself is generating particles (this is particularly prelevent in powder-fill operations) then two sampling locations will be required at each point in the process.This can can be achieved either through separate particle counters,or by some means of re-directing a single particle counter to monitor at the two locations at different times, using for example a small manifold system (see picture below for dual sampling locations). 实际上，在灌装生产期间近距离检测产品，因为产品自身也产生粒子，尤其是灌装粉末的操作中，在这个 过程中需要两个监测点，这样可以通过分开粒子计数器或者通过调整一个单一的粒子计数器在不同的时间 检测两个位置（见下图的双采样位置）
Outfeed from tunnel
出瓶口
Inlet HEPA Filter
入口高效过滤器
Position of continuous monitoring probe
绿色:连续监测位点
Additional points required at machine set-up
红色：在机器调试阶段新加入的监测位点。
The positions for monitoring 'at rest' can demonstrate that the cleanliness of the air around the open vials is within required limits. During filling these points are capped and the positions for monitoring during filling re used to demonstrate that the quality of the air bathing the work area is within cleanliness limits. (Note: the positions for monitoring during filling should be located as close as practically possible to the work area). 静态监测的位置可以证明药瓶周围空气的洁净度在要求的限度之内，增加灌装期间监测位点是为了证明工 作区域的洁净度在要求限度之内。（注：在灌装过程中监测位置应尽可能接近实际的操作区域）
Appendix B - Manifold and remote particle monitoring systems
附件 B：集成和远程粒子监控系统的案例
a)Manifold systems
集成粒子监测系统
A manifold particle monitoring system consists of a single particle counter which is sequentially connected to multiple locations within the cleanroom. A central vacuum pump allows an air sample to be drawn remotely down special tubing from each location and passed through the particle counter. 集成粒子监测系统由单一粒子计数器连接至洁净室内多个地点。每个位置的空气样本经过中央真空泵进入 一个特殊的管子，然后通过粒子计数器。
These systems are generally lower cost to install and, as there is only a single particle counter, the hardware costs are lower too.
这个系统一般很容易安装，因为只有一个粒子计数器，硬件的也很便宜。
However, the particles generally have to travel a long way down the vacuum tubing to reach the centrally located particle counter and this can lead to particle drop out. Equally, once there has been a build-up of particles in the long vacuum tube runs, this can lead to 'burst counting' where groups of trapped particles suddenly break free and arrive at the particle counter all at once. There is also a requirement to validate that there is no significant particle drop-out in individual tubing runs and this can be very hard to demonstrate. 然而，这些例子必须经过很长的一段路径才能经过真空泵泵到指定的粒子计数器，这有可能导致粒子的丢 失。同样的，一旦粒子在真空管中掉落后聚集在一起，这就会导致“爆裂计数”，就是指很多依附于管道的 粒子突然脱落然后到达粒子计数器。这就需要有验证证明在每个管道中无明显的粒子脱落，这就非常证明。
The main issue with these systems, though, is the gap in monitoring at each location while the counter is sampling at another location.
尽管这样，这个系统最主要的问题就是监测点和粒子计数器取样点之间的空隙。
For example, if each sample location had 10m vacuum tubing, and the particle counter were to take a 1 minute
sample at each location,preceded by a 5 minute allowance at each location for the air to be drawn all the way along the tube, then the total sample time for each location would be 6 minutes. In a system with 10 sample locations,the logical conclusion is that a sample would only be drawn once every 60 minutes, leaving the air quality at each location unmonitored for one hour periods and it is this inherent problem with this design that makes them unsuitable for use in critical Grade A or Grade B areas.
比如，如果每个样品点都有 10 米的真空管，粒子计数器在每个样品点计数 1 分钟，还有计数前 5 分钟，
让空气进去管道，这样每个取样点的总技术时间为 6 分钟。在有 10 个样品点的系统中，每个点的空气质 量在 60 分钟内都没有被检测到，这是一个长期固定的问题，这个问题是由设计造成的，不符合美国关于 A 级和 B 级洁净区的要求。
However, these systems could well be used in Grade C or D areas to replace counting by moving portable particle counters from location to location.
然而，这些系统可以被用于 C 级和 D 级区域的检测，来代替利用移动的粒子监测器到处走动的监测。
It should be noted that manifold counter systems will only sample at typically 1 cubic foot per minute. Thus, if a cubic meter sample is to be taken during a manufacturing batch, then the manifold would have to run for 36 minutes at each location before moving onto the next. This suggests that the time interval between each sampling location would be impractical.
值得注意的是，多种远程粒子监测系统取样一般每分钟 11 立方英尺，这样，如果在生产线上取 1 立方米
的样品，这个集成监测系统在每个点就得运行 36 分钟，才能转移到另外一个点，这在每个点之间的时间 安排是不合实际的。
b)Remote systems
远程系统
Remote/distributed particle monitoring systems deploy individual particle counters at each sample location, so that particle monitoring is indeed continuous. These systems are best used in critical Grade A and B areas, where the product is most at risk. They can be used in Grade C and D areas, but their high capital cost usually makes either manifold counting systems or manual counting using portable counters more attractive. 远程/分布式粒子监测系统是将每个独立的粒子监测器放在每个样品位点，所以就能进行连续的粒子监测。 这些系统最好用在严格的 A 级洁净区和 B 级洁净区，这些地区是最容易污染产品的地方。也可以用于 C 级和 D 级洁净区的检测，但是这些系统的费用和高昂，一般不用来测试 C 级和 D 级。
There are two main configurations of remote/distributed counting systems. One system deploys the particle counters at each sampling location and utilises a central vacuum pump to draw an air sample through each counter continuously, as in the example below. 远程/分布式粒子监测系统有两个重要的配置，一个是分布在每个样品点的粒子计数器，用中央真空泵将空 气样本不断通过计数器，如下图所示;
The other type of remote/distributed counting system utilises particle counters with built-in vacuum pumps, much like portable particle counters (in fact some systems use portable particle counters left in situ and connected to a remote monitoring computer). See example below. 另外一种远程/分布式粒子监测系统用的是带有内置真空泵的粒子计数器，非常像便携式粒子计数器（事实 上，有些系统是用的便携式的粒子计数器连接到了远程的一个监测电脑上）
Sometimes, the cost of installing remote counters with built-in vacuum pumps can be less than using a central vacuum system and it can be argued that the system is most robust as it is not dependant on one single vacuum pump system. Also, not having to run vacuum tubes from a central pump can reduce the amount of tubing in the cleanroom, making the system less intrusive and easier to clean. However, this is generally the more costly in hardware and each installation must be evaluated to work out the best approach. 有时候，安装携带内置真空泵的远程电脑的成本比有中央真空泵系统的成本要低，也有人认为这个系统更 加稳固，因为它不是依赖于单一真空泵。而且，不用从一个中央真空泵连接出一个很长的真空管，这也减 小了洁净室里的管线数量，使得这个系统更稳定和更容易清洗。然而，这也在硬件上更加昂贵，而且每次 安装都得调试最好的途径。
Appendix C - Examples of particle loss in transport tubing
附录 C：管道输送中粒子损失的案例
When a sample is taken using a remote sampling system, the sampling point is in a remote location from the particle counter optics. The sample is drawn through the tubing to the particle counter. When the sample is to be transported any significant distance in the tube; from the point of sampling to the point of measurement, then some particle losses will occur in the transport tubing, the losses are dependent on tubing type, velocity, diameter and distance. Large particles are lost by a combination of gravitational settling to the bottom of the duct and inertia deposition on the walls of the tubing when directional changes occur. Small particles are lost to the duct walls by Brownian motion and diffusion effects. 当一个样品空气被运到远程的样品系统中时，样品点是在距离粒子计数器很远的地方，样本经过管路到达 计数器，当样品在管路中运输了很长一段距离后，会有一些粒子损失，管路的类型，运行的速度，管路的 直径和距离决定了粒子损失的程度，当流动方向发生改变时，大粒子由于重力的原因相互结合落在管路的 底部，或是因为惯性散落在管路的壁上，小粒子由于布朗运动和分散效应而落在管壁上。
Figure 1 Particle loss in manifold sampling tubing (1/2" tubing at 100 litres/minute flow rate)
在管道中取样管粒子损失图 1（1 / 2 英寸的管道， 100 升/分钟的流量）
Figure 1 illustrates the percentage penetration of different sized particles sampled through a manifold system over distances up to 125 feet. Particles ＜1.0μm in diameter show no significant losses, and the differences are essentially experimental error, but larger particles show a significant level of loss over very short distances.
图 1，展示的是不同大小的粒子样品在经过集成系统时，发生损失的比例图，小于 1.0μm 的粒子损失的不
是很明显，但是大粒子在很短的距离中就表现出了明显的粒子损失。
Loss in tubing to portable particle counters
便携式粒子计数器管路中的粒子损失
Figure 2 Particle loss in a portable counter (3/8" tubing at 28.3 litres/minute flow rate)
图 2 便携式粒子计数器中的粒子损失（3/8 英寸的管道，28.3L/min 的流量）
When portable particle counters are used, the flow rate in the tubing is significantly reduced; therefore the maximum permissible distance is also reduced. Figure 2 shows a similar pattern to that for the manifold sampling, but over much shorter distances. 当使用便携式粒子计数器时，流量在管路中明显的减少，因此最大允许的管道长度也应当相应的减少。图 2 展示了一个多路取样的类似模式，但在距离要短得多。
Effect of tubing material on particle loss
管道材料对粒子损失的影响
Elastometric forces also account for a proportion of the losses in a sample; therefore to reduce the effect of these additional forces various types of material were tested to establish a suitable standard. The order is based on a combination of particle loss rate, electrical conductivity, and potential for oxide or sulfide formation when the tubing is exposed to urban air. 橡胶的管道也有一部分粒子损失，因此，如果想要去减少管路损失的影响，各种类型的管道都要进行测试 并出台适当的标准。这个标准主要是基于粒子损失速率，电导率和当暴露在城市空气中出现氧化物或者硫 化物的可能性。
1 | Stainless steel 不锈钢 |
2 | Bev-a-line 贝弗- 1 型油管（美国 BEV-A-Line XX 管，高纯度的耐 温耐油惰性 HYTREL 共聚物内层管，提供耐磨性及化 学品兼容性，采样中不会吸附颗粒物到内层管壁上） |
3 | Polyester (as polyurethane) 聚酯 |
4 | Polyester lined vinyl 聚酯衬里乙烯基聚合物 |
5 | Copper 铜 |
6 | High density polyethylene 高密度聚乙烯 |
7 | Glass 玻璃 |
8 | Teflon 特氟龙(聚四氟乙烯等 DUPONT 材料) |
The diameter of the tubing should be selected to ensure the Reynolds number is between 5000 and 25000 as required in FS209E. The Reynolds number range is one for which no significant deposition occurs for particles smaller than 5-10μm, a residence time in the tubing should be no more than 10-20 seconds ensuring transmission of particles larger than 0,1 p before any significant losses occur.
管道的直径也需要好好选择保证雷诺数在 5000~25000 之间，这是 FS209E 所规定的。雷诺兹数的范围是评
估粒子在管道中损失的一个常数：一个小于 5 ~ 10 微米微粒在没有明显沉积发生，且让大于 0.1μm 的粒子 停留的时间不超过 10~20 秒，这样可以让粒子不损失地通过。
Appendix D - Isokinetic probes 附件 D：等动力采样头 Isokinetic Probes 等动力采样头
EU GMP Annex 1 states Isokinetic sample heads shall he used in unidirectional airflow systems.
欧盟 GMP 规定等动力采样头应该用于单向气流系统。
In unidirectional airflow systems it is important to use isokinetic sampling. This is where the unidirectional airflow velocity in the supply air is the same as the air velocity in the sampling tube inlet of the particle counter. If the velocities differ, then either a positive or negative sample collection error occurs. The error increases with particle size, and isokinetic probes are required when particles <5< span="">μm are to be measured. Another point is that where isokinetic probes are not used in unidirectional airflow systems, the unidirectional airflow is more likely to be disturbed or disrupted. 在单向气流系统使用等动力采样头是非常重要的。在供给的空气中单向气流的速度流量和粒子计数器的进 气管道中空气速度流量是一样的，如果速度流量不一致，就会出现错误。错误发生与粒子大小有关，粒子 小于等于 5μm 的时候才可以使用等动力采样头，另外一点是，如果在单向气流系统没有用等动力采样头的 话，会导致气流的紊乱。
It is important to use the correct diameter of tubing as this will affect the flow rate and thus the accuracy of the particle count. 由于管道的直径会影响气流的速度和粒子数目的准确性，所以使用正确的管道直径很重要。
Size of Isokinetic Head
等动力采样头的尺寸
This will vary depending on the flow rate of the pump. The size of isokinetic heads used for continous monitoring systems will be different from those used on manifold systems as the tubing diameter and the flow rate are different. 这主要取决于泵的气流速率，用于不断检测系统的等动力采样头会和用于集成系统的等动力采样头不一样， 由于管道直径和气流速度不一致。
Appendix E - Validation and risk assessment standards and guidelinesl
附件 E-验证和风险评估标准、一般指导方针
Genera
EU GMP Annex 15: Qualification and validation
欧盟 GMP 附件 15：确认和验证
ICH 9 Quality Risk Management. London: EMEA, 2006 人用药品注册技术规范国际协调会 9 质量风险管理 http://www.emea.europa.eu/lnpections/docs/ICHQ9Step4QRM.pdf
ISPE Baseline® Pharmaceutical Engineering Guides for New and Renovated Facilities: Volume 5: Commissioning and Qualification 国际制药协会制药工程基准指南对于新的或更新的设备：第五册，试车和确认 http://www.ispe.org/cs/baseline guides
Risk Management GMP Paperback Volume 1 GMP Publishing GMP 风险管理平装本第一册 GMP 出版
http://www.gmp-publishing.com/produkte
ISPE GAMP® Guide for Validation of Automated Systems: GAMP 4:
良好自动化生产实践指南对于自动系统验证：良好自动化生产实践指南 4
Good Automated Manufacturing Practice 良好自动化生产实践 http://www.ispe.org/cs/gamp publ cations
lSEP GAMP® 5: A Risk-Based Approach to Compliant GxP Computerised Systems
良好自动化生产实践指南第五版 中文版)：
http://www.ispe.org/page. ww?name=WelcQme+to+the+ISPE+G AMP +COP§ion-GAMP+COP
PHSS PS Technical Monograph No. 14 (2005): Risk Management of Contamination (RMC) During Manufacturing Operations in Cleanrooms
环境监控颗粒系统技术专注 14（2005）：洁净区药品生产操作过程中产生污染物的风险管理
http://www.phss.co.uk
ASTM International Technical Committee E55 on Manufacture of Pharmaceutical Products.
美国材料与试验协会国际技术协会 E55 有关制药产品的生产 This committee meets twice each year 这个协会每年开会两次。
HACCP (Hazard Analysis Critical Control Point)
危害分析和关键控制点
Pierson, M.D. and Cortlett, D.A. Jr.: HACCP principles and applications.
New York: van Nostrand Rheinhold, 19921
FMEA (Failure Mode Effects Analysis)
失效模式及效应分析
IEC 60812: 2006, Analysis techniques for system reliability Procedure for failure mode and effects analysis (FMEA). Geneva, Switzerland: Commission Electrotechnique Internationale /International Electrotechnical Commission
瑞典：国际电子协会
Scope: This International Standard describes Failure Mode and Effects Analysis (FMEA) and Failure Mode, Effects and Criticality Analysis (FMECA), and gives guidance as to how they may be applied to achieve various objectives by: providing the procedural steps necessary to perform analysis; identifying appropriate terms; defining basic principles; providing examples of the necessary worksheets or other tabular forms. V 范围：这个国际标准描述失效模式及效应分析，给出指导他们如何应用可能达到不同的目标，提供必要的 程序步骤来执行分析；识别合适的关系；定义基本原则；提供必要学习表和 V 型扁平表的例子。
Palady P.: FMEA, failure modes and effect analysis. West Palm Beach, Florida: PT Publications Inc., 19952.
FTA (Fault Tree Analysis)
故障树分析
IEC 61025:1990, Fault tree analysis (FTA). Geneva, Switzerland: Commission Electrotechnique Internationale/International Electrotechnical Commission3
国际电工协会 61025 号文件，1990 年，故障树分析，瑞典日内瓦，国际电子技术协会委员会
Scope: Describes fault tree analysis and provides guidance on its application to perform an analysis, identifies appropriate assumptions, events and failure modes, and provides identification rules and symbols. 范围;描述故障树分析和提供指导应用到执行分析，识别合适的设想，项目和失效模式，提供识别规则和标 志
HAZOP 危险与可操作分析
CEI IEC 61882 2001 Hazard and Operability Studies (HAZOP) Application Guide
Kletz, T.A. (2006) HAZOP and HAZAN: Identifying and Assessing Process Industry Hazards, 4th Edition, IChemE,
HAZOP - Guide to best practice. 2000, European Process Safety Centre (EPSC)
Other
其他
Particle Measuring Systems 'An analysis of acceptable particle losses in tubing'
1ISO 14644-5:2004 - Cleanrooms and associated controlled environments - Part 5 Operations (A.2.1)
国际标准 14644-5，2004 版，洁净区和有关控制环境
2ISO 14644-5:2004 - Cleanrooms and associated controlled environments - Part 5 Operations {A.2.1)
3ISO 14644-5:2004 - Cleanrooms and associated controlled environments - Part 5 Operations (A.2.1)
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