美化版-在线监测系统法规 Best practice for particlemonitoring in pharmaceutical f

THE PHARMACEUTICAL AND HEALTHCARE SCIENCES SOCIETY BEST PRACTICE FOR PARTICLE MONITORING IN PHARMACEUTICAL FACILITIES Technical Monograph No. 16 CONTENTS PAGE目录 1 Foreword 1、前言 2 Acknowledgments 6 2、确认 3 Introduction 73、介绍 4 Air particle monitoring to EU GMP Annex 1:2008 84、欧盟 GMP中关于空气粒子监测的附件 5 System design 145、系统设计 6 Operations 256、操作 7 Maintenance and Cleaning 307、保养和清洁 8 Disaster 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 快递公司问题件快递公司问题件货款处理关于圆的周长面积重点题型关于解方程组的题及答案关于南海问题 论文 政研论文下载论文大学下载论文大学下载关于长拳的论文浙大论文封面下载 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：  exchanging dialogue between suppliers and users 推动供应商和客户之间信息的交换  discussing and shaping how and where the industry is moving 讨论企业的未来之路  discussing practical issues and guidance 讨论标准规范  networking and discussions 互相交流和讨论  producing 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 定性数据统计分析pdf销售业绩分析模板建筑结构震害分析销售进度分析表京东商城竞争战略分析 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。 3 INTRODUCTION 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。 4 AIR 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 工程第三方检测合同工程防雷检测合同植筋拉拔检测方案传感器技术课后答案检测机构通用要求培训 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。 5 SYSTEM 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.