PIC 对无菌药品生产重大变化的解释（中英文对照）

PHARMACEUTICAL INSPECTION CONVENTION 药品检查公约 PHARMACEUTICAL INSPECTION CO-OPERATION SCHEME 药品检查合作组织 PI 032-2 8 January 2010 2011 年 1 月 8 日 RECOMMENDATION 对 2008 修订版 GMP 附录 1， 无菌药品产品生产重大变化的解释 PIC/S January 2011 禁止以商业目的传播 如果声明来源，内部流通则被允许 GMP ANNEX 1 REVISION 2008, INTERPRETATION OF MOST IMPORTANT CHANGES FOR THE MANUFACTURE OF STERILE MEDICINAL PRODUCTS . PIC/S January 2011 Reproduction prohibited for commercial purposes. Reproduction for internal use is authorised, provided that the source is acknowledged. 1 Index 索引 0． Document history ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥2 文件历史 1. Purpose and scope ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥2 目的和范围 2. Basics‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥2 基础知识 2.1 Legal requirements (binding)‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥3 法律规定（约束） 2.2 Regulatory guidance (to be justified if not applied) ‥‥‥‥‥‥‥‥‥‥‥‥‥‥3 监管指南（如果不适用要合理） 2.3 Relevant international norms (to be justified if not applied) ‥‥‥‥‥‥‥‥‥‥‥3 有关的国际准则(如果不适用要合理) 3. Definitions and abbreviations ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥4 定义和缩写 4. New texts and their interpretation ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥4 新文本及其解释 4.1 Clean room / clean air device classification ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥4 洁净室/洁净空气设备分类 4.2 Clean room / clean air device monitoring ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥8 洁净室/洁净空气设备检测 4.3 Microbiological monitoring ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥11 微生物检测 4.4 Media simulations ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥11 模拟介质 4.5 Pre-sterilisation bioburden monitoring ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥12 灭菌前微生物负荷检测 4.6 Provisions for environmental conditions for the handling of aseptically filled vials after leaving the aseptic processing area up until final sealing ‥‥‥‥‥‥14 无菌灌装瓶离开无菌操作区后处理提供的环境条件，直到最终密封。 5. Revision history ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥18 修订历史 2 0． Document history 文件历史 The present technical interpretation of Annex 1 to the PIC/S GMP Guide (PE 009) on the manufacture of sterile medicinal products (hereinafter referred to as GMP Annex 1) was initially drafted by Switzerland / Swissmedic and then commented by PIC/S Participating Authorities. It was agreed that the technical interpretation of GMP Annex 1 should be the same between the EU and PIC/S. PIC / S 的 GMP 指南附件 1（以下简称为 GMP 附件 1）目前对无菌药品的制造的技术解释 （PE009），最初由瑞士起草，然后提交 PIC/S 参与的机关。与会者一致认为，GMP 附件 1 的技术解释应该是欧盟与 PIC / S 的附件 1 相同。 Adoption by Committee of PI 032-1 3 November 2009 Entry into force of PI 032-1 1 December 2009 Entry into force of PI 032-2 1 January 2010 委员会通过 PI 032-1 2009 年 11 月 3 日 PI 032-1 版本生效 2009 年 12 月 1 日 PI 032-2 版本生效 2010 年 1 月 1 日 1. Purpose and scope 目的与范围 In order to assure a harmonised conduct of inspections, with respect to the 2008 revision of GMP Annex 1, this document summarises the interpretations which an inspector of the competent regulatory authority should adopt when performing an inspection of a manufacturer of sterile medicinal products. 由于 2008 年修订的 GMP 附件 1，为了保证统一的检查行为，本文件汇总了检查员诠释，以 便对无菌产品的制造商执行时检查时主管监管机构采用。 This document reflects the most important changes and also addresses the feedback from industry concerning the GMP Annex 1 Revision. It is not meant to address all changes within the Revision. 本文件反映了最重要的变化，也解决了从行业反馈的有关 GMP 附件 1 的修订。这并不意味 着解决所有修订的变化。 2. Basics 基础知识 3 2.1 Legal requirements (binding) 法律规定（约束）  Refer to national legislation 参照国家立法 2.2 Regulatory guidance (to be justified if not applied) 监管指南（如果不适用要合理）  For EEA countries: Eudralex Volume 4 GMP, GMP Annex 1, revision of November 25th, 2008 对于欧洲经济区国家：Eudralex 第 4 卷的 GMP，GMP 附录 1，2008 年 11 月 25 日修订。  For non-EEA countries: PIC/S GMP Guide (PE 009), Annex 1 or equivalent 对于非欧洲经济区国家：PIC / S 的 GMP 指南（PE009），附件 1 或相同。 2.3 Relevant international norms (to be justified if not applied) 有关的国际准则（如果不适用要合理）  EN ISO 14644-1  EN ISO 14644-2  EN ISO 14644-3  EN ISO 14644-4  EN ISO 14644-5  EN ISO 14644-6 The relevant international norms used in the context of this paper were applicable at the time this document was drafted. Future revisions of these norms do not automatically apply to this document. 在本文中使用的有关国际准则，适用于这份文件起草的时间。这些的未来版本不自动适 用于本文件。 The GMP Annex 1 Revision came into effect on March 1, 2009; the provisions for crimp capping for all vials will come into effect in March 1, 2010. However, especially for new installations with respect to crimp capping, conformance with the revised GMP Annex 1 is to be encouraged already today. GMP 附件 1 的修订，2009 年 3 月 1 日起生效; 所有小瓶卷曲封盖规定将在 2010 年 3 月 1 日起生 效。然而，尤其是卷曲封顶方面的新装置，与修订后的 GMP 附件 1 地一致性，在今天已经得 4 到鼓励。 3. Definitions and abbreviations 定义和缩写 Room Classification Room classification is part of the initial qualification of a facility and is also normally performed during routine re-qualification. Both, classification activities and the final / to be achieved classification status for clean rooms / clean air devices are meant. This Annex directly links to clean room / clean air device classification according to ISO 14644. For qualification and validation and re-qualification see also PIC/S GMP Guide Annex 15. 房间分级 房间分级是设施预确认的一部分，通常也和常规的再确认同时进行。 这两种分级活动，都意味着最终将实现对洁净室/空气洁净设备的分 级。本附件与按照 ISO 14644 进行的洁净室/空气洁净设备分级直接 相关。对于确认和验证，以及再确认参见 PIC / SGMP 指南的附件 15。 RABS Restricted Access Barrier Systems 限制进出隔离系统 4. New texts and their interpretation 新文本及其解释 4.1. Clean room / clean air device classification 洁净室与空气洁净设备 General interpretation: The GMP Annex 1 Revision distinguishes very clearly between clean room / clean air device classification which is described in sections 4 to 7, and clean room monitoring, which is described in sections 8 to 20. 通则释义： GMP 附件一修订版第 4 至 7 条所述中非常清楚的区分了洁净室与空气洁净设备 的分级，和洁净室的监测，在第 8 至 20 条有描述。 Section 3 defines at rest and in operation states, which is not new. However, it should be noted that the company needs SOPs to define at rest and in operation states, which might be specifically required per production room. These SOPs should include a definition of equipment to be installed and running, number of operators to be present. 第 3 条界定的“静态”和“动态”，这不是新的。但是，应该指出的是，公司需要 SOP 去明 确的界定每一个生产车间的“静态”和“动态”。这些 SOP 应包括界定设备的安装和运行状 5 态以及现场操作人员的数量。 In general, clean room / clean air device classification is required to be performed according to EN ISO 14644-1 with the applicable limits for particle counts defined in the table in section 4 of GMP Annex 1. Probe-locations should be chosen in order to demonstrate the homogeneity across the room. A classification report should be prepared according to section 4.4 of ISO 14644-1 and section B.1.4 of ISO 14644-3. 一般来说，洁净室/空气洁净设备的分级须遵循 EN / ISO14644-1 以及 GMP 附件 1 第 4 条的 中规定的粒子数限度。探针的位置的选择必须能显示整个房间的均匀性。应根据 ISO14644-1 中 4.4 节及 ISO 14644-3 中 B.1.4 节之规定出具 A 级区定级。 Monitoring, on the other hand, does not need to be performed according to EN ISO 14644-1. It can be performed for a reduced number of sampling points and sampling volumes. A formal risk analysis study based on experiments and analysis of the monitoring data (over at least 6 month operation) should provide a basis for the determination of frequencies and limits. Frequencies and limits should be processbased and the results of the initial qualification and on going monitoring should be taken into account when setting operational alert and action limits. These limits and sample locations should be periodically reviewed for on-going validity of the risks initially considered. 从另一方面来说，监测并不需要依照 EN/ISO14644-1 执行。它可以在实际操作时减少采样点， 采样量的数量。采样频率和限度的设定应以正式的风险分析研究为基础，而正式的风险分析 研究则应基于试验和监测数据分析（至少 6 个月以上的监测）。频率和限度应因地制宜，设置 可行的警戒限和行动限时必须考虑预确认和连续监测的结果。这些限度和采样的地点必须周 期性回顾从而为最初设定的风险提供同步验证。 Those frequencies and limits should be process-based and the results of the qualification should be taken into account. 频率和限度的设定应基于工艺，并参考确认的结果。 Section 4: 第 4 条： New text: Clean rooms and clean air devices should be classified in accordance with EN ISO 14644-1. Classification should be clearly differentiated from operational process environmental monitoring. 新案文：洁净室和空气洁净设备，必须按 EN/ISO14644-1 分级，分级必须与动态环境监测明 确区分。 Interpretation: Classification of clean rooms / clean air devices should be done according to 6 provisions in EN ISO 14644-1. Compared with the prior version, the values for maximum permitted particles have been changed in this section. Especially the values for the maximum permitted number of 5 Dm particles / m3 for grade A have been changed from 1 to 20. For grade A, the corresponding ISO class is 4.8, based on the 5 Dm counts. 释义：洁净室和空气洁净设备分级必须根据 EN/ISO14644-1 的规定进行。与以前的版本相比， 这一节中颗粒最大允许值已经改变了。特别是 A 级区允许的 5 微米的颗粒数目的最高值已经 从每立方米 1 改为 20。 对于 A 级，即 ISO 4.8 级，其分级是基于 5 微米颗粒的计数。对于 D 级，则没有动态指标的限制，公司应在适当的风险分析和历史数据基础上建立自己的限度。 For grade D, no in operation limits are defined; the company should establish in operation limits based on a risk analysis and on historical data where applicable. 对于 D 级，则没有动态指标的限制，公司应在适当的风险分析和历史数据基础上建立自己的 限度。 Section 5: 第 5 条： New text: For classification purposes EN/ISO 14644-1 methodology defines both the minimum number of sampling locations and the sample size. 新案文：出于分级的目的，EN/ISO 14644-1 对最小采样点数量及采样量给出了原则上的定 义。 Interpretation: Minimum amount of sampling points and sampling volume and also interpretation of the results are defined in EN ISO 14644-1 (confidence interval). See also provisions for outliers in appendix B 6.2 of EN ISO 14644-1. 释义：EN ISO 14644-1（置信区间）中定义了最小采样点数量、最小采样量和结果诠释。参 见 EN ISO 14644-1 附录 B6.2 中关于极端值的规定。 ISO 14644-1 Annex f has an informative section on the use of sequential sampling techniques for non-viable particle monitoring. This technique may be useful in reducing the time needed for sampling very large clean-room areas, at rest. This method would not be considered suitable for “in operation” classification. ISO 14644-1 附录 f 中叙述了悬浮粒子监测的连续抽样技术的使用。这种技术可有效的减少在 非常大的洁净室静态采样所需的时间。但此方法不适合用于“动态”分级。 The application of this method may be acceptable but it is unlikely to be the preferred method since most pharmaceutical facilities do not normally have the very large clean rooms of the type discussed in Annex f and therefore it is unlikely that significant time would be saved. 7 这种方法的应用也许会被接受，但它可能不是最佳方法，因为大多数药厂通常不具备在附件 F 提及的非常大的洁净室，因此，不可能节省大量的时间。 Section 6: 第 6 条： New text: Portable particle counters with a short length of sample tubing should be used for classification purposes because of the relatively higher rate of precipitation of particles ≤ 5 μm in remote sampling systems with long lengths of tubing. 新案文：采样管较短的便携式粒子计数器因其对大于 5 微米沉降颗粒采集率比采样管较长的 远程采样系统相对更高一些，因此应在分级时选用。 Interpretation: This section implies that old central particle counters with long tube lengths will no longer be acceptable for clean room classification, as they absorb too many particles (especially 5 μm particles). Therefore, modern portable particle counters with short tubes or (even preferable when possible) those without tubes should be used for classification purposes. The certificate of calibration of the particle counter should mention the tube length and nature of material (inox or polymer). When calibration of the particle counter is performed outside by an external laboratory, the particle counting system should be qualified on site with a comparative measurement with an isokinetic probe. For impact on monitoring, see also section 11. 释义：本节意味着旧的长管中央粒子计数器将不再被洁净室的分级所接受，因为它们损耗太 多粒子（特别是 5 微米的颗粒）。因此，现代的短管或无管便携式颗粒计数器（如果有当然最 好）应被用于分级。该粒子计数器校准证书种应提及管长和材质（不锈钢或聚合物）。当粒子 计数器的校准工作外包给一个外部实验室，粒子计数系统的确认应与一个合格的等速探针进 行比较测量。有关对监测影响，参见第 11 条。 Section 7: 第 7 条： New text: EN ISO 14644-2 provides information on testing to demonstrate continued compliance with the assigned cleanliness classifications. 新案文：EN/ISO 14644-2 提及通过检测来证明可以持续的达到洁净度分级的要求。 Interpretation: This provision concerns clean room re-qualification. The company may choose to perform re-qualification of clean rooms according to provisions in EN ISO 14644-2 (including the proposed frequencies). For re-qualification of grade A areas, it is generally expected to carry out the following activities also performed during initial classification: air velocity, filter integrity, differential pressure every 6 months. Other 8 examples for frequencies: grade B: every 6 months at rest, once a year in operation; other grades: once a year, with maximum delay defined. If the company takes another approach, this should be justified, e.g. based on monitoring data. 释义：这项规定涉及洁净室的再确认。厂家可以选择根据 EN ISO14644-2 所述（包括推荐的 频率）进行洁净室的再确认。对于 A 级区的再确认，在进行初步分类的同时，建议每 6 个月 进行风速，过滤器的完整性及差压检测。以其他频率为例子：B 级：静态每 6 个月一次，在 线检测一年一次，其他等级：每年一次，并确定最大时间间隔。如果公司采取其他方法，必 须进行证明合理性，例如：基于监测数据。 4.2 Clean room / clean air device monitoring 洁净室/洁净空气设备检测 Section 8: 第 8 条： New text: Clean rooms and clean air devices should be routinely monitored in operation and the monitoring locations based on a formal risk analysis study and the results obtained during the classification of rooms and/or clean air devices. 新案文：洁净室和空气洁净设备必须在运行时进行常规监测，监测点的选择应基于正式的风 险分析研究以及通过对洁净室和空气洁净设备分级获得的研究结果。 Interpretation: Frequency, location and number of monitoring locations should be based on a formal risk assessment and not on ISO 14644-1. Data obtained during classification and previous monitoring data should be considered. Critical locations should be covered. 释义：频率，地点和监测点的数量必须基于正式的风险评估，而不是基于 ISO 14644-1。同 时必须参考进行分级时获得的数据和先前的监测数据。关键区域必须涵盖在内。 Section 9: 第 9 条： New text: 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. 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. 新案文：对于 A 级区，粒子监测应当完全贯穿于整个关键工序，包括设备组装，除非能证明 污染物将损害粒子计数器或导致风险，如活的生物体和放射性危害。 对 A 级区的监测必须 9 有适当的频率和样本大小，使得所有的干预措施，瞬态事件和任何环境系统的恶化将被采集 并在超出警戒限时触发警报。 Interpretation: In critical areas with exposed product continuous monitoring, covering the duration of the operations is expected. Continuous means that the system must be able to pick up any potentially occurring event of an unusual number of particles, including an event that occurs for a short time only. Manifold systems might not be suitable for Grade A Zone monitoring due to a lack in responsiveness. It is important that monitoring in grade A comprises equipment assembly, because there is a high impact of the human operator. An SOP should be present defining alert levels and pre-defined corrective measures in cases of alerts and interventions. 释义：建议对关键区域的暴露产品进行持续监测，并覆盖整个操作过程。连续意味着系统必 须能够采集到任何可能由非正常数量的颗粒引起的事件，包括一个仅在很短时间内发生的事 件。流形检测系统因缺乏合适的响应性而不应作为 A 级区的监测手段。重要的是，在 A 级区 的监测包括设备组装，因为人员操作将造成巨大的影响。SOP 必须界定警戒限，并预先制定 在警报和干预事件下的纠正措施。 Section 10: 第 10 条： New text: It is recommended that a similar system be used for Grade B zones although the sample frequency may be decreased. 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. 新案文：建议在 B 级区使用一个类似的系统，尽管采样频率可能会较低。 B 级区应有合适该 区环境的采集量及监测频率，任何系统的恶化和污染水平的变化将被采集到且会在超出限制 触发警报。 Interpretation: Continuous monitoring (see definition under interpretation to section 9) is expected while not fully integral containers are handled in the B zone, e.g. partially stoppered vials within a laminar air flow mobile unit prior to lyophilisation. Manifold systems might not be suitable for Grade B Zone monitoring due to a lack in responsiveness. 释义： B 级区应有而没有完全完备的容器时，比如在冻干前，用于放置部分加塞的小瓶的移 动式层流设备时，应考虑进行连续监测（见第 9 条释义下的定义）。流形系统可能因响应性较 差而不适合做为 B 级区的监测设备。 Section 11: 第 11 条： 10 New text: 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 radii of any bends in the tubing must be considered in the context of particle losses in the tubing. 新案文：空气粒子监测系统可能由数个独立粒子计数器组成; 或由多个单粒子计数器连接到 连续取样点构成的网络;或者是两者的结合。该系统选择必须考虑与颗粒大小相适应。凡使用 远程采样系统的，对管道长度和弯曲半径的选择必须考虑在管道中的粒子损失情况。 Interpretation: This section addresses concerns especially for the sedimentation of 5 μm particles in remote systems (as a rough example, s-shaped bent tubing of 1.5 m length can already absorb about 30% of the 5 μm particles.). The company must qualify their particle sampler and sampling system for both particle sizes, 0.5 μm and 5 μm. 释义：本节讨论了在远程系统中，尤其是 5 微米颗粒的沉降问题（做一个粗略的比方，1.5 米长的 S 形弯曲的管道中可以损耗大约 30％的 5 微米的颗粒。）。公司必须确认粒子取样器和 取样系统的粒径为 0.5 微米和 5 微米。 Section 12: 第 12 条： New text: It is not necessary for the sample volume to be the same as that used for formal classification. 新案文：采样量与进行正式分级时没有必要相同。 Interpretation: The important point for sampling during monitoring is to be able to sample quickly (especially in critical areas), to be able to link a particle excursion to an actual event and to be able to generate an alarm so that operators are immediately aware of the alarm situation. Thus sampling of 1 m3 (which often takes 30 minutes) could be inadequate during monitoring of an A zone during operation 释义：重要的一点是，在监测时应能够快速采样（尤其是在关键区域），使之能够联系起来得 到一个真实的粒子数偏移状况，进而建立一个警戒限，使操作者能立即对超过警戒的粒子情 况有所意识。因此，抽样 1 立方米（通常需时 30 分钟）可能不足以监测动态的 A 级区。 Section 15: 第 15 条： New text: 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 11 alert/action limits will depend on the nature of the operations carried out, but the recommended “clean up period” should be attained. 新案文：C 级和 D 级区的动态监测必须遵循质量风险管理的原则。这些规定和警戒/处置限 度的设定应取决于所进行的操作的性质，但至少“清洁阶段”必须进行。 Interpretation: The number of sampling points and the sampling frequency are to be determined by at least a risk assessment, including risk identification, risk analysis and risk evaluation (see also GMP Annex 20). There is no need for a continuous monitoring. However, the frequency should be higher than that of Re-Qualification of these areas. 释义：采样点数量及采样频率制定至少应基于风险评估，包括风险识别，风险分析和风险估 算（见 GMP 的附件 20）。没有进行连续监测的需要。然而，采样频率必须比这些区域进行再 确认时高。 4.3 Microbiological monitoring 微生物检测 There are no changes to the provisions for microbiological monitoring (sections 18 and 19). 与微生物监测有关的条款无改变（第 18 条和 19 条）。 However, it is important to note that for critical sampling locations in grade A areas where aseptic operations are performed, every found microorganism should result in a thorough investigation, the microorganism has to be identified and impact on batch release should be considered. An additional comment should be made on the limits for settle plates. These limits are interpreted as limit per settle plate. Also, the same limits apply when sampling time is less than 4 hours, e.g. for operations being shorter than 4 hours. 然而，重要的是要注意到，在进行无菌操作的 A 级区的那