ISPE指南：关键公用系统GMP合规性翻译讨论

蒲公英

ISPE发布了最新关于《关键公用系统GMP合规性》指南，为了方便蒲友学习讨论，组建了微信群讨论，同时开此帖同步，欢迎大家积极参与，将本帖收藏置顶


讨论须知：


1、英文和中文对照，翻译部分，欢迎大家纠错，翻译文本，也欢迎大家补充观点


2、留言，就要有观点、有内容，为了方便网友阅读，诸如：谢谢分享、顶.....之类的回复


3、分享内容按照原文顺序，随着翻译进度陆续在本帖发布，感兴趣者可以关注


谢谢大家参与支持









1 Introduction 引言

1.1 Overview概述

Regulatory compliance of Critical Utilities (CU) is important to maintaining overall facility compliance, but due to their hidden nature, CU can become vulnerable to noncompliance. CU consistently receive close scrutiny by inspectors primarily because of the level of associated risk to product. If contamination is present in the CU systems, the risk of product contamination increases significantly since in many cases, one or more of the following are true:

关键公用系统（CU）的合规性对于维持整体设施的合规性很重要，但是由于其隐藏的性质，CU可能会容易不合规。CU一直受到检查人员的严格审查，主要是因为与产品相关的风险水平。如果CU系统中存在污染，则产品污染的风险会大大增加，因为在许多情况下，以下一项或多项是存在的：

Water from the CU is used as an excipient directly in product

Compressed gas is used in direct contact with product

Water and/or compressed gas are used in cleaning product-contact surfaces

Clean steam is used in the sterilization of product or product-contact surfaces

来自CU的水直接用作产品中的辅料

压缩气体与产品直接接触

水和/或压缩气体用于清洁产品接触表面

清洁蒸汽用于产品或产品接触表面的灭菌

Governmental inspectorates have been largely silent for decades on their specific expectations of users during an inspection of CU. An inspection guide was written by the FDA for high purity water systems in 1993 (Guide to Inspections of High Purity Water Systems [1]). This guide, although valuable in earlier years, has led to many discussions regarding non-contemporary water system designs and validation approaches, to name a few issues, and does not provide the depth of scope to prepare organizations for an inspection in today’s pharmaceutical industry. In addition, there are no compliance or inspection guides issued by any inspectorate for other CU such as compressed gases or steam.

数十年来，政府检查机构在对CU进行检查时，一直对用户的特定期望保持沉默。FDA在1993年为高纯水系统编写了检查指南（《高纯水系统检查指南》 [1]）。该指南尽管在前几年很有价值，但它导致了许多关于非当代水系统设计和验证方法的讨论，产生了一些问题，在当今制药行业，并不能为组织机构准备检查提供深度的信息。此外，任何检查机构都没有针对其它CU（例如压缩气体或蒸汽）发布合规性或检查指南。

ISPE sees the need in the pharmaceutical industry for guidance in the CU area (specifically water, steam, and compressed gases) for achieving and maintaining GMP compliance, and for demonstrating that compliance during a regulatory inspection. This Good Practice Guide (GPG) is intended to fill that void by providing knowledge based on the collective experiences of the authors gained from operational and regulatory inspections. To make this Guide internationally useful, the authors have included information acquired from experience with the inspectorates of Brazil, Canada, China, the European Union, India, Japan, the United Kingdom, and the United States.

ISPE认为，制药行业需要在CU领域（特别是水、蒸汽和压缩气体）提供指导，以实现并保持GMP合规性，并在监管检查过程中证明其符合性。通过根据作者从运营和监管检查中获得的集体经验，本良好实践指南（GPG）旨在提供知识，填补这一空白。为了使本指南在国际上有广泛用途，作者纳入了从巴西、加拿大、中国、欧盟、印度、日本、英国和美国的视察机构的经验中获得的信息。

This GPG is not a regulatory document, and should not be interpreted to reflect inspectorate guidance. Additionally, it is not the goal of this GPG to provide tips on how to pass an inspection; rather the intent is to provide guidance on achieving and maintaining compliance, and to assist organizations in preparing the documents, personnel, and meeting rooms to help ensure inspections are efficiently conducted, making good use of the limited resources of regulators.

本GPG并非法规文件，不应解释为反映监察机构的指南。此外，此GPG的目的不是提供有关如何通过检查的提示；相反，其目的是为实现和保持合规性提供指导，并协助组织准备文件、人员和会议室，以确保充分利用监管机构的有限资源，来帮助确保有效地进行检查。

蒲公英

2.7Process Gases 工艺气体
2.7.1General 通则

High purity gases intended for product-impact applications (except clean compressed air) include nitrogen, oxygen, carbon dioxide, and other suitable gases, or combinations of these gases. Often, compressed or liquid gases (e.g., nitrogen, oxygen) are delivered by external manufacturers. Bulk high purity gas supply systems may be equipped with backup bottles for critical uses. Care should be taken when automating these backup systems so that the manufacturer is notified (for example, an alarm is triggered) when the backup bottles have been engaged/used. In such an event, the batch production record should indicate the use of the bottles. Bottles should receive a similar level of scrutiny as other raw materials.
影响产品的高纯度气体（清洁的压缩空气除外）包括氮气、氧气，二氧化碳和其它合适的气体，或这些气体的组合。通常，压缩或液态气体（例如氮气、氧气）是由外部生产商提供的。散装的高纯度气体供应系统可能配有用于关键用途的备用瓶。自动化这些备用系统时应格外小心，以便在使用备用瓶时通知生产商（例如，触发警报）。在这种情况下，批生产记录应表明瓶子的使用情况。瓶子应受到与其它原材料相似的审查。

Common applications for these gases are:

这些气体的常见应用是：

•Blow down for drying pipes and equipment 吹干管道和设备

•Tank sparging (including fermentation and cell culture) 罐鼓泡（包括发酵和细胞培养）

•Incubation 培养

•Tank blanketing and transfer overpressure 罐填充和超压转移

Many points mentioned in Section 2.6 for clean compressed air also apply to other gases wherever there is direct product contact (including containers and closures) or contact with a product-contact surface not cleaned in a subsequent operation, and in all classified manufacturing space into which the process compressed air is exhausted. The gene and cell therapy medicines industry along with biotechnology manufacturing utilize medical gases and process air for product contact.

在第2.6节中提到的许多有关洁净压缩空气的要点，也适用于其它气体：无论它们与产品直接接触（包括容器和密封件），还是与在后续操作中未清洁的产品接触表面接触，以及在所有需要排出工艺压缩空气的洁净生产区域中。涉及产品接触时，基因和细胞疗法药物行业以及生物技术生产使用医用气体和工艺空气。

大海

关注关注，学习学习

蒲公英

1.2Purpose 目的

The purpose of this GPG is twofold: to help pharmaceutical organizations achieve and maintain their CU systems in a state of control and to help organizations efficiently demonstrate these systems’ GMP compliance to auditors and regulatory inspectors. By making inspections more efficient, our hope is that regulators’ limited resources will be deployed more widely, resulting in enhanced patient safety.

本GPG的目的是双重的：帮助制药企业在受控状态下实现并维持其CU系统，并帮助企业向审计师和监管检查员有效证明这些系统符合GMP要求。通过提高检查效率，我们希望监管者有限的资源将得到更广泛的利用，从而提高患者的安全性。


1.3Scope 范围

CU systems are utilities with the potential to impact product quality or performance in a significant way. The primary CU discussed in this GPG is the water system, as it is highly complex and prone to noncompliance. (Appendix 1 contains examples of typical regulatory citations specific to water systems.) The other utilities covered are Pure Steam, compressed air, and compressed medical gases.
CU系统是公用系统，可能会在很大程度上影响产品质量或性能。本GPG中讨论的主要CU是水系统，因为它非常复杂且容易出现违规情况。（附录1包含特定于水系统的典型法规引用示例。）其它涵盖的公用系统包括纯蒸汽、压缩空气和压缩医疗气体。

This GPG provides an overview of the processes and documentation needed to implement and maintain a validated utility system, for example, assessing the risks of upstream noncritical parameters (Section 3.3), the value of proactively scheduling water system sanitizations (Section 4.2), and determining a suitable statistical distribution model for monitoring water system data (Section 4.5). Furthermore, Chapter 5 discusses the challenges of legacy water systems.
本GPG概述了实施和维护已验证的公用系统所需的过程和文档，例如，评估上游非关键参数的风险（第3.3节），主动安排水系统消毒的价值（第4.2节），以及确定用于监测水系统数据的合适的统计分布模型（第4.5节）。此外，第5章讨论了旧水系统的挑战。

Topics such as the importance of maintaining up-to-date system drawings (Section 3.4) and sampling water in the same manner as water use during manufacturing (Appendix 3) provide inspection preparation activities specific to CU systems. Also included in this GPG are broadly applicable best practices, such as inspection hosting and an inspection readiness checklist (Appendix 2). These are presented here to make the GPG comprehensive, since they are not covered in other ISPE Guides. However, activities pertaining to CU inspections described in depth by other ISPE Guides (such as the ISPE Baseline® Guide: Volume 5 – Commissioning and Qualification [2], and the ISPE Good Practice Guide: Sampling for Pharmaceutical Water, Steam, and Process Gases [3]) are discussed at a higher level in this GPG. The objective of this redundancy is to make this GPG as stand-alone as possible without sending the user searching to find other GPGs with the critical content needed during preparation for an inspection.

相关主题，如维护最新系统图纸（第3.4节）和以与生产工艺中用水相同的方式对水进行取样（附录3）的重要性等，提供了针对CU系统的检查准备活动。本GPG还包括广泛适用的最佳实践，例如检查接待和检查准备清单（附录2）。此处介绍这些内容是为了使GPG更加全面，因为其它ISPE指南中并未涵盖这些内容。但是，如其它ISPE指南（例如ISPE基准指南：第5卷–调试和确认[2]，和ISPE良好实践指南：制药用水、蒸汽和工艺气体的取样[3]）详细介绍的与CU检查有关的活动，在本GPG中进行了更高级别的讨论。冗余的目的是使本GPG尽可能独立，而无需发送用户搜索来查找其它GPG，这些其它GPG具有检查准备期间所需的关键内容。

It is worth noting that compliance begins with properly engineered systems; however other ISPE Guides fully cover this aspect. As such, this GPG does not address the design of CU systems, but serves as a companion document to these ISPE Guides (for example, ISPE Baseline® Guide: Volume 4 – Water and Steam Systems [4]).

值得注意的是，合规性始于设计合理的系统。但是其它ISPE指南完全涵盖了这一方面。因此，本GPG并未解决CU系统的设计问题，而是作为这些ISPE指南（例如ISPE基准指南：第4卷–水和蒸汽系统[4]）的协同文档。

Although HVAC is considered by many to be a CU, it is not included in this GPG. Such systems are often considered to be an integral part of clean room operations and subject to additional quality attributes and operational issues, and so tend to be associated with inspections of aseptic processing operations rather than CU. In addition, media supply systems are normally considered as an excipient (except compressed air for oral solid dosage forms manufacturing), but HVAC systems are not. Thus, the viewpoint when inspecting HVAC systems is different compared to the CU systems mentioned in this Guide.

尽管许多人认为HVAC是CU，但此GPG中并未包含HVAC。此类系统通常被视为洁净室操作的组成部分，并受到其它质量属性和操作问题的影响，因此通常与无菌处理操作的检查相关联，而不是与CU相关。此外，介质供应系统通常被视为一种辅料（用于口服固体剂型生产的压缩空气除外），而HVAC系统则不是。因此，与本指南中提到的CU系统相比，检查HVAC系统的观点是不同的。

胜利者

谢谢

蒲公英

1.4Key Terms 关键术语

This section introduces key terms as they are used in the context of this Guide. Refer to Appendix 7 for an expanded listing of definitions.
本节介绍在本指南的上下文中使用的关键术语。有关定义的扩展列表，请参见附录7。

Critical Utilities (CU) 关键公用系统（CU）

Utilities that have the identified potential to impact product quality or performance in a significant way.
公用系统：具有确定的潜力，从而可以在很大程度上影响产品质量或性能。

Deviation (ICH Q7 [5]) 偏差（ICH Q7 [5]）

Departure from an approved instruction or established standard.
偏离已批准的指导或已建立的标准。

蒲公英

Drinking Water 饮用水

Drinking water is not covered by a compendial monograph but must comply with the quality attributes of the US EPA NPDWR[ EPA NPDWR: US Environmental Protection Agency National Primary Drinking Water Regulations
EPA NPDWR：美国环境保护局国家主要饮用水条例

] [6] or comparable regulations of the European Union (EU) [7], World Health Organization (WHO) [8], or Japan [9]. It may be derived from a variety of sources including a public water utility, a private water supply (e.g., a well), or a combination of more than one of these sources.

饮用水不属于法规专论，但必须符合美国EPA NPDWR [6]的质量属性或欧盟（EU）[7]、世界卫生组织（WHO）[8]或日本的类似法规 [9]。它可能来自各种来源，包括公共供水公司、私人供水（例如井），或这些来源中的一种以上的组合。

蒲公英

蒲公英 发表于 2020-11-29 13:08
Drinking Water 饮用水

Drinking water is not covered by a compendial monograph but must comply w ...

来自群讨论：饮用水很有意思，好像企业很少关心具体指标，纯化水原水是否符合“饮用水”标准

蒲公英

Medical Gases (FDA [10, 11]) 医用气体（FDA [10，11]）

“Compressed medical gases (CMG or medical gases) include gaseous and liquid (cryogenic) forms stored in high-pressure cylinders that are administered as a gas. Types of compressed medical gases include, but are not limited to, oxygen, carbon dioxide, helium, nitrogen, nitrous oxide, medical air, and combinations of these gases.”

“The term ‘medical gas’ means a drug that— (A) is manufactured or stored in a liquefied, nonliquefied, or cryogenic state; and (B) is administered as a gas.”
“压缩医用气体（CMG或医用气体）包括存储在高压气瓶中的气态和液态（低温）形式，并以气体形式管理。压缩医用气体的类型包括但不限于氧气、二氧化碳、氦气、氮气、一氧化二氮、医用空气以及这些气体的组合。”
““医用气体”一词是指以下药物：（A）以液化，非液化或低温状态生产或储存；（B）以气体管理。”

快活王

蒲公英 发表于 2020-11-29 13:46
来自群讨论：饮用水很有意思，好像企业很少关心具体指标，纯化水原水是否符合“饮用水”标准

在ECA的新闻中，他对水源的质量和指标提出了他的看法。见下文：
CriticalImpurities in Pharmaceutical Water

制药用水中的关键杂质

The quality of the sourcewater used to produce pharmaceutical water plays an important role for both thedesign of the treatment and the validation of the water system. FDA WarningLetters over the past few years have shown that compliance with thespecification of pharmaceutical water is not enough. A validation of thetreatment process is expected. This includes documentation of the processcapacity to produce pharmaceutical water according to specification. If we donot know the quality of the source water, however, the purification capacity isnot known either. As a consequence, fluctuations of the quality ofthe source (feed) water quality may lead to water that does notcomply with the specification after purification. Or it is not known up towhich quality level of the source water pharmaceutical water that complies withthe specification can be produced. Therefore, it is important to know theimpurities respectively their concentration in the source (feed) water.

用于生产制药用水的水源质量，对于处理方法的设计和水系统的额验证来说，都是很重要的。从过去几年的FDA警告信可以看出，制药用水的规格还是不能符合要求。制水工艺应该进行验证，其中包括根据质量标准制备工艺用水的工艺能力。然而，如果我们不了解水源的质量，净化能力也就无从可知。因此，水源质量的不同就会导致净化后的水可能不符合标准。也就不能得知什么质量水平的水源可以生产出符合质量的制药用水。因此，了解水源中各个杂质的浓度是很重要的。

The production ofpharmaceutical water is always based on drinking water. The specifications fordrinking water however (for Germany, stipulated in the Trinkwasserverordnung;for the U.S., in the National Primary Drinking Water Regulation) are definedvery broadly compared to Pharmacopoeial specifications.

制药用水的生产经常以饮用水做水源。然而，与药典标准相比，饮用水的标准（在德国，是在Trinkwasserverordnung里定义的，在美国是在国家基本饮用水规定里）定义得非常宽泛。

The quality of the drinking water varies widely as well, asdrinking water may come from different sources (ground water or surface water).Even the ground water quality varies locally, e. g., depending on the season.This is why water purification plants for the pharmaceutical industry are notready-made goods, but individual solutions that have to be developed by thefuture user and the plant supplier together. The plant supplier will always askabout the quality of the drinking water so that he can offer the appropriateprocessing technologies.

因为饮水水源的不同（地下水或者地表水），则饮用水的质量也相差很大。甚至同一地区的地下水质量也有差异，例如，季节差异。这就是为什么制药行业的制水车间并不是一个可预订的产品，而是根据未来用户和设备供应商制订个性化解决方案。车间提供者总是会要求饮用水的质量，所以能提供合理的工艺技术。

In particular, he will need the following information. For thispurpose, it is useful to provide the plant engineer with various drinking wateranalyses over a minimum period of twelve months.
For the design of a pharmaceutical water plant, the indicatorparameters according to the Trinkwasserverordnung(conductivity,iron, manganese, sulphate and pH value) are important, as the amount of theionic load determines the treatment process. For instance, a single-stage ordouble-stage reverse osmosis may be sufficient to obtain adequate quality atlow conductivity levels. Iron and manganese are limited by the drinking waterordinance, but will lead to irreversible membrane damage at the reverse osmosisplant when their limits (according to the Trinkwasserverordnung)are exceeded.

特别要说明的是，他需要以下信息。因此，向制水系统工程师提供至少12个月期间不同的饮用水分析是很有帮助的。对制药用水工厂的设计来说，根据Trinkwasserverordnung制订的指示参数（电导率、含铁量、含锰量、硫酸含量和pH值）是很重要的，因为离子负载的数量决定处理工艺。例如，在低电导率水平下，一个单级或双级的反渗透装置就可以获得合格质量的水。铁和锰是由饮用水条例限制，但其超过极限（根据trinkwasserverordnung），会对反渗透膜造成不可逆的损伤。

Furthermore, information on the total hardness is indispensable,as it has a major influence on the design of the softening plant - as well ason carbonate hardness or base capacity which are used to calculate the amountof dissolved carbon dioxide. This parameter restricts the use of EDI or mayrequire further treatment, such as membrane degassing.

此外，有关总硬度的信息是必不可少的，因为它会严重影响软化装置的设计-以及用于计算溶解的二氧化碳的碳酸盐硬度的能力。这个参数限制了EDI的使用或可能需要进一步的处理，如薄膜排气。

Depending on the origin of the drinking water, a responsible plantengineer should measure the colloid index (SDI 15) before designing the plant.Especially with surface water, higher amounts are to be expected. A colloidindex of more than 5%/min can already have a negative impact on the operationof a reverse osmosis plant (membrane blocking and/or fouling) and may requireadditional treatment techniques, such as ultrafiltration before the main plant.While the colloid index is never determined via the water supplier, thesilicate content is often indicated in the drinking water analysis. A silicatecontent of more than 25 ppm can become critical for a combination of reverseosmosis and EDI and should also be determined in case it is not indicated inthe analysis.

根据饮用水的来源，一个负责任的工厂设计师应该在设计工厂之前测量胶质价，尤其是地表水，其中的含量更高。高于5%/每分的胶质价就足以对反渗透装置产生负面影响（膜堵塞或者结垢）并可能需要额外处理技术，例如在主系统之前安装超滤。虽然水供应商从来没有测定过胶质价，但饮用水分析中会显示硅酸盐含量。硅酸盐含量超过25ppm可能会对反渗透膜和EDI的组合有关键影响，如果在分析报告中没显示的话，也应该进行测定。

All microbiological parameters have been regulated in the Trinkwasserverordnung.However, you should always remember that the supplier guarantees the qualityonly up to the point of transfer. With regards to the total bacteria count inparticular, regular tests are necessary in order to identify seasonalfluctuations.

所有的微生物参数已经在trinkwasserverordnung中定义。然而，你应该牢记，你要牢记供应商保证的质量只到传送点为止。关于总细菌计数，特别是定期测试是必要的，以确定季节性波动。

以上翻译内容来源于Julia公众号。

samuel6

可以先分享 ISPE 這本書嗎？看各位大大簡介，覺得應該對於製藥業很有幫助，謝謝親。a8516029@yahoo.com

蒲公英

快活王 发表于 2020-12-1 08:12
在ECA的新闻中，他对水源的质量和指标提出了他的看法。见下文：
CriticalImpurities in Pharmaceutical  ...

谢谢，特别喜欢和鼓励您这样的分享交流方式，提供一些有价值的内容，供更多蒲友参考，希望继续关注，保持讨论

蒲公英

Potable Water 饮用水

Water that is suitable for drinking.
适合饮用的水。

Pure Steam 纯蒸汽

Steam that is produced by a steam generator which, when condensed, meets requirements for Water for Injection (WFI).
由蒸汽发生器产生的蒸汽，经冷凝后可满足注射用水（WFI）的要求。

Purified Water (PW) 纯化水（PW）

A classification of water according to compendial standards.
根据药典标准对水进行分类。

Water for Injection (WFI) 注射用水（WFI）

As defined in the US Pharmacopeia (USP) [12]

“Prepared from water complying with the quality attributes of “Drinking Water.” Purified by distillation or a purification process that is equivalent or superior to distillation in the removal of chemicals and microorganisms.”
根据美国药典（USP）的定义[12]
“由符合“饮用水”质量标准的水制备。通过蒸馏、或在除去化学药品和微生物方面等同于或优于蒸馏的纯化工艺，进行纯化。”

As defined in European Pharmacopoeia (Ph. Eur.) [13]
根据欧洲药典[13]的定义。

“Water for the preparation of medicines for parenteral administration when water is used as a vehicle (WFI in bulk) and for dissolving or diluting substances or preparations for parenteral administration (sterilized Water for Injection).”
“当水用作媒介（散装WFI）时，用于制备肠胃外给药药物的水，以及溶解或稀释用于肠胃外给药的物质或制剂的水（无菌注射用水）。”

蒲公英

群里问：drinking water和Potable Water区别？欢迎参与讨论一下

蒲公英

群友观点：WFI PW的日常理化项目太多了，况且几乎都没有出现不合格过，浪费大量检验成本，明明有些系统有在线TOC，非要离线检测，检测也就算了，回顾也用离线的来做。慢慢的，在线的也就成了摆设，或约等于摆设

蒲公英

楼上：在线和离线的数据差不少，TOC、电导什么的，但是在线和离线的检测设备设计是不一样的，这就好比PAT和离线检验，一个用于控制，一个用于监控，判断和放行还是看“监控”数据，但是很有意思的一点是，有时候离线检测数据不合格，偏差调查调在线数据看，反过来印证当时的数据是符合要求的，对中间产品或终产品质量没有影响，

快活王

蒲公英 发表于 2020-12-4 13:42
群友观点：WFI PW的日常理化项目太多了，况且几乎都没有出现不合格过，浪费大量检验成本，明明有些系统有在 ...

说说我的观点吧。
如果在线的检测经过了校验，且不存在污染的风险的话，在线的检测结果完全可以代替离线的检测。
由于离线检测具有较多的不可控性，例如器具、操作、空气的影响、放置的时间等内容，在线监测越来越受官方的认可和推荐。
但是在线监测往往不会代表所有的点，他们往往是安装在总送或者总回上，可以监测水系统的运行情况，但是无法代表POU（用水点）的水质质量，例如我总回TOC合格，不代表我用水点TOC合格，特别是某些还要外连软管的用水点，有更高的风险。
所以往往是在线和离线合作监测的，但是如果一个点已经有了在线的数据，则不需要重新进行离线监测，即使进行离线监测，也只是定期进行对比，看看在线和离线的数值是否接近。
如果企业是土豪，每个用水点都安装了在线监测（终端，例如软管后，这个可不好做到），那可以不进行离线监测。
个人建议，经供参考。
里面部分内容参考了ISPE 制药用水、蒸汽和工艺用气的监测。

ytgr

谢谢分享，好好学习！

蒲公英

2、Critical Utilities Viewed from a Regulatory Perspective 从监管角度看关键公用系统
A Critical Utility (CU) is defined by ISPE [14] as: “Utility that has the identified potential to impact product quality or performance in a significant way.” This GPG focuses on water systems (specifically PW, WFI, and Pure Steam); however it is relevant to also address some of the systems/utilities that feed water systems, specifically potable water and pretreated water, as these grades of water are important to overall compliance. Process gases are touched on in this Guide as well, albeit to a lesser extent as they typically do not present the same degree of difficulty in maintaining compliance.

ISPE [14]将关键公用系统（CU）定义为：“具有确定的潜力，可以影响显着影响产品质量或性能的公用系统。”本GPG专注于水系统（特别是PW，WFI和纯蒸汽）；但是，也有必要解决一些为水系统提供源水的系统/公用系统，特别是饮用水和预处理水，因为这些等级的水对整体合规性很重要。本指南中也涉及了工艺气体，尽管程度较小，因为它们通常在保持合规性方面没有相同的难度。

CUs are special in that they can be considered a raw material, and therefore are subject to GxP requirements. However, with the continuous generation and distribution of water and steam, and the constant availability of compressed gases including air, it is not feasible to take the traditional approach of identifying these materials by a discrete lot number, testing the lot, and releasing for production. Continuously produced utilities are typically used before all results are available.

CU的特殊之处在于它们可以被视为原材料，因此要符合GxP要求。但是，随着水和蒸汽的不断产生和分配，以及包括空气在内的压缩气体的不断供应，采用传统方法通过离散的批号识别这些物料，检验批次并放行以生产的传统方法是不可行的。在获得所有结果之前，通常已经使用了连续产生的公用系统。

Additionally, since these CU have a broad impact across multiple products and processes at a manufacturing site, they are considered to entail a significantly higher risk to product quality and subsequently, to patient safety.

此外，由于这些CU对生产工厂的多种产品和工艺具有广泛的影响，因此认为它们对产品质量以及随后对患者安全的风险要高得多。

For these reasons, regulatory scrutiny of CU systems often includes more elements of the quality system that address monitoring, control, maintenance, and calibration than is seen for a noncritical utility system.

由于这些原因，与非关键公用系统相比，CU系统的监管审查通常包括质量系统中涉及监测、控制、维护和校验的更多元素。

蒲公英

2.1Drinking/Potable Water 饮用水

Drinking water, also referred to as potable water, must comply with appropriate regulatory requirements (such as defined by US EPA [6], WHO [8], etc.) and is the minimum quality of water to be used in pharmaceutical manufacturing (i.e., various pharmacopeias, and GMPs found in the FDA 21 CFR Parts 210 [15] and 211 [16], and elsewhere[ Note that at the time of this writing, the EMA document “Guideline on the quality of water for pharmaceutical use” [17] is pending implementation.
请注意，在撰写本文时，EMA文件“制药用水质量指南” [17]尚待实施。
]).
饮用水，必须符合适当的法规要求（如美国EPA [6]，WHO [8]等定义），并且是制药生产中使用的最低水质（即 ，各种药典和FDA 21 CFR Part 210 [15]和211 [16]等中的GMP）。

Since this is the only specifically mentioned water in the GMP regulations, it is clearly important to regulatory authorities that a lower quality of water not be used in pharmaceutical manufacturing and that the users have taken steps to ensure that a lower, potentially unsafe quality of water is not inadvertently utilized. This puts the burden of proof on the users of this water to ensure the quality meets minimum requirements and is suitable for its intended use.
由于这是GMP法规中唯一特别提及的水，因此对于监管机构而言，很重要的一点是，制药生产工艺中不得使用质量较低的水，并且用户应采取措施，以确保不会无意中使用质量较低、可能不安全的水。这使得水的使用者有了举证责任，以确保其质量达到最低要求，并适合其预期用途。

梦幻咖啡

下载学习，谢谢楼主。