WHO最新制药用水指南中文

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分享：WHO最新制药用水指南中文
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WHO TRS 1022
第 55 次 报告

Annex 3


Good manufacturing practices: water for pharmaceutical use
优良生产规范（ GMP ）： 制药用水

Background 背景

Unlike other product or process ingredients, water is usually drawn from an on demand system and is not subject to testing and batch or lot release prior to use. Thus it is essential that water quality (including microbiological and chemical quality) throughout production, storage and distribution processes is controlled.


与其他产品或工艺成分不同，水通常 是 从按需 制备 的 系统提取， 且 在使用前不受 检测 和 批放行 限制 。因此，对 从 生产、储存和分配 全 过程中的水质 (包括微生物和化学质量 )进行控制是至关重要的。

In recent years, following extensive consultations with stakeholders, several pharmacopoeias have adopted revised monographs on wa ter for injection (WFI) that allow for production by non -distillation technologies. In 2017, the World Health Organization (WHO) Expert Committee on Specifications for Pharmaceutical Preparations (ECSPP)recommended that the WHO Secretariat collect feedbac k on whether or not they should
revise the WHO specifications and good manufacturing practices (GMP) on WFI and, if so, how to do so. Following several consultations, the ECSPP agreed that the monograph in The International Pharmacopoeia (Water for injecti ons ) and the guideline WHO Good manufacturing practices: water for pharmaceutical use (1), should both be revised to allow for technologies other than distillation for the production of WFI.


近年来，经过与利益 相 关方广泛 的 协商，一些药典已经通过了关于注射用水
(WFI) 的修订，允许通过非蒸馏技术生产 WFI 。 2017 年， WHO药物制剂规范专家委员会 (ECSPP) 建议 WHO 秘书处收集 关于 是否应修订 WHO GMP 中 WFI ， 以及 如果应修订 该 如何修订 的 反馈 。经过几次协商， ECSPP 同意修订《国际药典》中 WFI 的专 论和 WHO GMP 指南 :制药 用水 (1) ，以 兼顾 允许使用蒸馏以外的技术生产 WFI 。


In early 2019, the WHO Secretariat commissioned a draft guidance text for the production of WFI by means other than distillation. Following several public consultations, the text was presented to the Fifty -fourth ECSPP. The Expert Committee adopted the Pro duction of water for injection by means other than distillation guideline and recommended that it should also be integrated into WHO’s existing guideline on Good manufacturing practices: water for pharmaceutical use .

2019 年初， WHO 秘书处委托起草了一份关于通过蒸馏以外的方式生产 WFI 的指 南 草案。经过几 轮 公开协商后，该文 件被 提交给第五十四 次 ECSPP 。专家委员会通过了蒸馏以外方法生产注射用水 的 指南 ，并建议将其纳入 WHO 现行指南
《 GMP: 制药用水 》 中 。


This document is a revision of WHO Good manufacturing practices: water for pharmaceutical use , previously published in the WHO Technical Report Series, No. 970, Annex 2, 2011.


本文件是 WHO 技术报告 No. 970, 附件 2《 WHO GMP: 制药用水》 ,2011 年的修订 版 。

目录
1. Introduction and scope 简介和范围 ................................ ................................ ........ 5
2. Background to water requirements and uses 水的需求与使用 ............................ 6
3. General principles for pharmaceutical water systems 制药用水系统的一般原则
................................ ................................ ................................ ................................ ........ 9
4. Water quality specifications 水质量标准 ................................ ............................. 10
4.1 Pharmacopoeial specifications 药典标准 ................................ .............. 10
4.2 Drinking -water 饮用水 ................................ ................................ ........... 10
4.3 Bulk purified water 散装纯化水 ................................ ............................ 15
4.4 Bulk water for injections 散装注射用水 ................................ ............... 18
5. General consi derations for water purification systems 水系统的一般考虑 ...... 20
6.Water storage and distribution systems 水的储存和分配系统 ........................... 25
7. Good practices for water systems 水系统的良好实践 ................................ ......... 25
8.System sanitization and bioburden control 系统消毒和生物负荷控制 .............. 29
9.Storage vessels 储罐 ................................ ................................ ................................ . 31
10.Water distribution 水分配 ................................ ................................ .................... 32
11.Operational considerations including some qualification and validation
principles 系统运行、确认与验证 ................................ ................................ ............ 34
12. Continuous system monitoring 系统持续监控 ................................ ................... 37
13. Maintenance of water sys tems 水系统的维护 ................................ .................... 39
14.System reviews 系统回顾 ................................ ................................ ...................... 40
15.Inspection of water systems 水系统检查 ................................ ............................. 42
References 参考文献 ................................ ................................ ................................ .. 42
Further reading 延伸阅读 ................................ ................................ ......................... 44

Introduction and scope 简介 和范围
1.1 This document concerns water for pharmaceutical use (WPU) produced, stored and distributed in bulk form. It provides information on different specifications for WPU; good practices for the management of the quality of water systems; water treatment (production) systems; water storage and distribution systems; commissioning, qualification and validation; sampling and testing; and the routine monitoring of water.


本文 讨论的 是散装 生产、储存和分配 的制药用水 (WPU) 。本文内容包括 ：WPU 的各种标准、 水系统质量 管理 的良好实践、制备 系统 、储存和分配系统 、调试、确认和验证 、取样 检验 以及监测。


1.2 The focus of this document is on the treatment, storage and distribution of treated water used in pharmaceutical applications. It excludes the production, storage and usage of water in qualit y-control laboratories.


本文重点 在于制药用水 的生产、储存和分配 ，不包括质量控制实验室 用水 的生产、储存和使用。


1.3 This document does not cover water for administration to patients in the formulated state or the use of small quantities of water in pharmacies to compound individually prescribed medic ines.


本文不包括制好供患者摄入的水和药房配制处方药时所用的水。


1.4 The document can be used in whole or in part, as appropriate, to the section and application under consideration.


本文可整体使用， 也可根据 情况 部分使用和应用。


1.5 In addition to this document, the “Further reading” section at the end of th is document includes publications that can serve as additional background material when planning, installing and operating systems intended to provide WPU.

除此之外 ，本文末尾的“ 延伸 阅读” 章节 还包括一些 其它文献资料可供参考 。
1.6 This document is supplementary to the WHO good manufacturing practices for active pharmaceutical ingredients (2), and the WHO good manufacturing practices for pharmaceutical products: main principles (3).


本文件是 对 WHO 《原料药 GMP 》和 WHO 《药品 GMP ：原则 》 的补充。


2. Background to water requirements and uses 水的需求与使用
2.1 Water is a widely used substance in the pharmaceutical industry and other sectors involved in manufacturing pharmaceutical products. It is extensively used as a raw material or starting material in the production, processing and formulation of active pharmaceutical ingredie nts (APIs), intermediates and finished pharmaceutical products (FPP), in the preparation of solvents and reagents, and for cleaning (e.g. washing and rinsing). Water has unique chemical properties due to its polarity and hydrogen bonds. These include a rel atively high boiling point, high specific heat, cohesion, adhesion and density. These include contaminants that may be hazards in themselves or that may be able to react with product substances, resulting in hazards to health. Water should therefore meet a ppropriate quality standards to mitigate these risks.


水是药品 和其他制药 相关 产品广泛使用的物质。它广泛用于原料药 (APIs) 、中间体和成品(FPP) 的产品、工艺 和配方 中作为 原料或起始物料 、 溶剂试剂的制备以及清洗 清洁 。水由于其极性和氢键而具有独特的化学性质 ，包括相对较高的沸点 、高比热 、 凝聚 性、附着力和密度。 水中的 污染物 可能造成 危害 ，或可能与产品 成分 发生反应从而对健康造成危害。因此，水应符合适当的质量标准以 降低 风险。


2.2 The microbiological and chemical quality of water should be controlled throughout production, storage and distribution. While chemical test results can normally be obtained without delay, results from microbiological testing are normally available only after w ater has already been used as microbiological tests may require periods of incubation. The assurance of quality to meet the on -demand expectation of water is therefore essential.

在整个 生产、储存和分配 过程中，应控制水的微生物和化学质量 属性 。化学 检测结果通常可以立即获得，而微生物检测则 因为需要 培养通常被使用之后才能得到 结果 。因此，水的质量 保证 需要满足 其灵活 的使用 需求 ， 这点 是至关重要的。


2.3 To reduce the risks associated with the production, storage and distribution of water, and considering the properties and use, it is essential:


为了减少水的 生产、储存和分配 的风险， 结合 水的性质和用途， 以下 是必不可少的 :


■■ to ensure the appropriate design, installation, operation and maintenance of WPU, pre -treatment, treatment, storage and distribution systems;
确保 制药用水系统 的前处理、 制备 、储存和分配 ， 经过 适当 的设计、安装、操作和维护 ;


■■ to continuously or periodically perform sanitization;
连续不断地 或定期 执行消毒 处理 ;


■■ to take the appropriate measures in o rder to minimize chemical and microbial contamination; and
采取适当措施 以 减少化学和微生物污染 ;


■■ to minimize microbial proliferation and endotoxin formation, where
applicable.
尽可能减少微生物 繁殖 和内毒素的 产生 。


2.4 Different grades of water quality exist. The appropriate water quality, meeting its defined specification (such as described in a pharmacopoeia), should be used for the intended application.
不同等级的水应 根据 其用途 ，符合 相应的标准 (如药典所述 )。

2.5 The application of specific types of water to processes and dosage forms should be considered.
应根据 工艺和剂型，使用 特定类型的水。


2.6 Pharmaceutical manufacturers should use the appropriate grade of WPU during, for example, the manufacture of APIs and different dosage forms, for different stages in washing and cleaning, and in the synthesis of materials and products.
制药企业 使用 的 水的 等级 应 与产品 生产相适应， 例如 ： 原料药和不同剂型的 制造 、清洗清洁 的不同阶段以及 原料和 产品的合成等。


2.7 The grade of water used should take into account the nature and intended use of the intermediate or FPP and the stage in the manufacturing process at which the water is used.
水的等级应考虑到 其在 中间体 、成品以及 生产不同阶段的 性质和预期用途。


2.8 Bulk water for injections (BWFI) should be used, for example, in the manufacture of injectable products, such as dissolving or diluting substances or preparations during the manufacturing of parenteral products, and for the manufacture of water for preparation of injections. BWFI should also be used for the final rinse after the cleaning of equipment and components that come into contact with injectable products, as well as for the final rinse in a washing process in which no subsequent thermal or chemical depyrogenization process is applied.
大批量 的 注射用水 (BWFI) 应用 在，例 如：在注射剂 的生产 中，如 药物 溶解 配制 或生产 准备，以及注射 成品 水的 生产 。也用于接触到 注射产品 生产 的设备和部件 的最终淋洗 ，以及在 后续 工序 中 没有热 力或化学去热原过程的 清洗 中的 最终冲洗。

3. General principles for pharmaceutical water systems制药用水系统的一般原则
3.1 Pharmaceutical water production, storage and distribution systems should be designed, installed, commissioned, qualified, validated, operated and maintained to ensure the consistent and reliable production of water of appropriate quality.
制药用水的 生产、储存和分配 系统应 进行 设计、安装、调试、 确认 、验证、运行和维护，以确保 稳定、 可靠 地生产出 合格 的水。


3.2 The capacity of these systems should be enough to meet both the minimum and peak demand. These systems should be able to operate continuously for significant periods of time in order to avoid the inefficiencies and equipment stresses that occur when equipment cycles turn on and off too frequently.
系统的 产 量应足以满足最低和 峰值 需求。系统应能够 在关键 时段内 连续运行，以避免设备频繁开关 导致效率 低下 和设备负荷 。


3.3 Qualification may include stages such as preparing User Requirement Specifications (URS), Fa ctory Acceptance Tests (FAT), Site Acceptance Tests (SAT), as well as installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ). The release and use of the system should be approved by the quality unit, e.g. qualit y assurance (QA) at an appropriate stage of qualification and validation
(see section 11 below).
确认包括以下阶段，如准备用户需求规范 (URS) 、工厂验收测试 (FAT) 、现场验收测试(SAT) ，以及安装确认 (IQ) 、运行确认 (OQ) 和性能确认 (PQ) 。系统的 放行 和使用应 经过质量部门批准，例如， QA在确认和验证的适当阶段 批准 (见下面第 11 节)。


3.4 Water sources and treated wate r should be monitored regularly for chemical, microbiological and, where appropriate, endotoxin contamination. The performance of water treatment, storage and distribution systems should also be monitored. Records of the results monitored, trend analysis a nd any actions taken should be maintained.

应定期监测源 水和净化 水的化学、微生物 以及 内毒素 （必要时） 。还应监测水 制备、储存和分配 系统的性能。应 记录 监测结果、趋势分析和采取的任何措施。



4. Water quality specifications 水质量 标准
4.1 Pharmacopoeial specifications 药典 标准
4.1.1 Pharmacopoeias include specifications for water used in bulk and in dosage forms. Where this document refers to specifications, such as those in pharmacopoeias, the relevant, current publications should be used. This document does not attempt to duplicate such material. Where subtle points of difference exist betwee n pharmacopoeial specifications, the manufacturer should choose the appropriate specification in accordance with the related marketing authorization submitted to the relevant medicine’s regulatory authority. Pharmacopoeial requirements or guidance for WPU are described in national, regional and international pharmacopoeias ( 4) and limits for various impurities, or classes of impurities, are either specified or recommended. Requirements or guidance are given in
pharmacopoeias on the microbiological and chemi cal quality of water.
药典 标准 包括 散装水和 包装 水。当本文涉及规范时 （ 如药典 ） ，应使用相 应 的现行版 本，本文不 再 复述 。如 药典之间存在细微差异，生产商应根据 上市 许可所在地 药品监管机构选择适当的药典。 不同 国家、地区和国际药典 会对 WPU 的药典要求或指 导 (4) ，并规定或推荐各种杂质或杂质类别的 限值 。 也会 给出水的微生物和化学质量 属性 的要求。


4.2 Drinking -water 饮用水
Note: The requirements for the design, construction and commissioning of drinking water systems are usually controlled through local regulations. Drinking water systems are not usually qualified or validated, but subjected to commissioning .1
注:饮用水系统的设计、建造和调试的要求通常由当地法规控制。饮用水系统通常 不进行确认 或验证 ，但 需要 经过调试运行 。

4.2.1 The quality of drinking -water is covered by the WHO guidelines for drinking -water quality (5) and standards from the International Organization for Standardization (ISO) and other regional and national agencies. Drinking -water should comply with the relevant r egulations laid down by the relevant authority.
饮用水的质量 在 WHO 饮用水质量 指南 (5) 中描述， 标准 由国际标准化组织 (ISO) 以及其他地区 和国家机构的标准所规定。饮用水应符合 相应 当局的 标准 规定。


4.2.2 Drinking -water may be derived from a natural or stored source. Examples of natural sources include springs, wells, rivers, lakes and seas. The condition of the source water should be considered when choosing a treatment to produce drinking - water.
饮用水可能 源于 自然或储存的水源。自然 水源包括 泉水、井 水、河流、湖泊和海洋。在选择生产饮用水的 工艺 时，应考虑水源的状况。


4.2.3 Drinking -water should be supplied under continuous positive pressure b y a plumbing system free from any defects that could lead to contamination.
饮用水应 由持续正压 的 管道系统供应 ，以避免管道 瑕疵而 导致污染。


4.2.4 Drinking -water may be derived from a public water supply system. This includes an off -site source, such as a municipality. Appropriate drinking -water quality should be ensured by the supplier. Tests should be conducted to guarantee that the drinking -water delivered is of drinking quality. This testing is typically performed on water when taken from the water source. Where required, quality may be achieved
through processing on -site.
饮用水 可能源于 公共供水系统。包括 厂外供应 ，如市政 供水 。供应商应确保适当的饮用水质量。应 对供水 进行检测，以保证供水质量。 检测 通常是在从水源取水时进行。如有必要， 应进行 现场 处理以 保证水质 。


4.2.5 Where drinking -water is purchased in bulk and transported to the user by water tankers, controls should be put into pla ce to mitigate any associated risks. Vendor assessment and authorized certification activities, including confirmation of the acceptability of the delivery vehicle, should be undertaken in a similar way to that used for any other starting material.

如果饮用水是散 装并由水车运输给用户 的，则应采取措施 降低 风险。供应商 应 经过 评估和授权，包括 对运输 车辆的 确认 ，应 同其他起始物料 一样管理 。


4.2.6 It is the responsibility of the pharmaceutical manufacturer to assure that the source water supplying the purified water (PW) treatment system meets the appropriate drinking -water requirements. In these situations, the point at which drinking -water quality is achieved should be identified and a water sample taken and tested at defined intervals thereafter.
制药企业有责任确保供应纯化水 (PW) 处理系统的 水 源符合 适当的要求。在这些情况下，应确定 获得的 饮用水质量， 并在规定的时间内 进行 取样 检测 。


1 See documents listed under Further reading.

4.2.7 If drinking -water is used directly in certain stages of pharmaceutical manufacture, such as in the production of APIs or in the feedwater for the production of higher qualities of WPU, then testing should be carried out periodically by the water user’s site; for example, at the point of use, to confirm that the quality meets the standards required for drinking -water. The selection of tests to be performed, and the fre quency of testing, should be based on a risk assessment.
如果在制药生产的某些阶段直接使用饮用水，如原料药的生产或用于生产 更高等级 的制药用水 ，则用水方应定期进行检测 ;例如，在使用点确认 其符合饮用水 标准。 测试的 项目和频率应基于风险评估 确定 。


4.2.8 Where drinking -water is produced through the treatment of raw water by a system on -site, the system co nfiguration and water -treatment steps used should be described.
如果饮用水是通过 现场 系统 对未 净化的 水生产的，应说明系统配置和水处理步骤。


4.2.9 Examples of typical processes employed to produce drinking -water may include:
饮用水 生产 的典型工艺的包括 :


■■ desalination;
海水淡化 ;


■■ filtration;
过滤 ;


■■ softening;
软化 ;


■■ disinfection or sanitization, such as by ozone or sodium hypochlorite
(chlorine);

消毒 或杀菌 ，如用臭氧或次氯酸钠 (氯)消毒 ;


■■ iron (ferrous) removal;
除铁 (铁离子 );

■■ precipitation; and
沉淀


■■ the reduction of concentration of specific inorganic and/or organic materials.
降低 特定无机和 /或有机物质浓度。


4.2.10 Controls should be implemented to minimize the microbiological contamination of sand filters, carbon beds and water softeners. The techniques selected should be appropriate and may include backflushing, chemical and/or thermal sanitization and frequent regeneration.
应实施控制措施，尽量减少砂滤、 活性炭过滤器 和软化器的微生物污染。所 用 技术应适当，可包括反冲洗、化学和 /或热消毒和 定期 再生。


4.2.11 The quality of drinking -water should be monitored routinely to account for environmental, seasonal or supply changes which may have an impact on the source wate r quality.
应定期监测饮用水的质量，以 识别 环境、季节或供应的变化可能对源水质 量 产生 的影响。


4.2.12 Where drinking -water is stored and distributed by the user, the storage and distribution systems should minimize the degradation of the water quality prior to use.
After any such storage, testing sh ould be carried out routinely and in accordance with a defined procedure. The storage and distribution of drinking -water should be done in a manner to ensure a turnover or recirculation of the water, if possible.
当饮用水由用户 进行存储和分配时，存储和分配系统应在使用前尽量减少水质变差 。在此类 储存后 ，应按照规定的程序进行常规检测。如 有可能，饮用水的储存和分配应确保水的 循环。


4.2.13 The equipment and systems used to produce and store drinking -water should be able to be drained or flushed, and sanitized.
用于生产和储存饮用水的设备和系统应能排 尽或冲洗 、 消毒。


4.2.14 Storage tanks should be closed with appropriately protected vents and should allow for visual inspection.

储罐应关闭， 并有适当保护的 通风口 ，且能够 进行 目视检查。


4.2.15 Distribution pipework should be able to be drained or flushed, and sanitized.
分配管路 应能 排尽或冲洗、消毒 。


4.2.16 The scope and extent of commissioning for the system should be identified and justified.
系统调试的范围和 程度 应经过 确定并论证。


4.2.17 If possible, the results from testing drinking -water should be subjected to statistical analysis in order to identify trends and changes. If the drinking -water quality changes significantly, but is sti ll within specification, the direct use of this water as a WPU, or as the feedwater to downstream treatment stages, should be reviewed for any potential risks. The appropriate action should be taken and documented.
如有可能，应对饮用水检测结果进行统计分析，以确定 其趋势和变化。如果饮用水水质发生显 著变化， 即使 仍在规定范围内， 也应审查 其 作为 制药 用水 直接 或 作为下游处理 工序的进 水 是否 存在 任何潜在风险。 并采取适当的行动且 记录在案。


4.2.18 Changes to an in -house system or to its operation should be made in accordance with change control procedures.
内部 系统或其 运行的变更应按照变更控制程序 管理 。


4.2.19 Additional testing should be considered if there is any change in the raw water source, treatment techniques or system configuration.
如果 水源、净化方法 或系统 构造 有任何变化，应考虑进行额外的测试。


4.3 Bulk purified water 散装 纯 化 水
4.3.1 Bulk purified water (BPW) should meet the relevant pharmacopoeial specifications for chemical and microbiological purity. The appropriate and applicable test procedures should be followed.
散装纯 化 水(BPW) 应符合相关药典的化学和微生物标准。应遵循 相适应 的检测 方法 。

4.3.2 BPW should be prepared from drinking -water as a minimum -quality feedwater.
BPW 至少 应由饮用水 制备 而成。


4.3.3 Any appropriate, qualified purification technique, or sequence of techniques, may be used to prepare BPW. BPW could be prepared by, for example, ion exchange, reverse osmosis (RO), RO/electro -deionization (EDI), ultrafiltration, or any combination of these techniques.
任何适当 的、合格的纯化 工艺 或工艺 顺序均 可用于制备 BPW 。BPW 可以通过 如离子交换、反渗透 (RO) 、反渗透 /电去离子 (EDI) 、超滤或这些技术的组合来制备。


4.3.4 The following are examples of aspects that should be considered when configuring a water purification system or defining URS:
在配置 纯化水 系统或 定义 URS 时，应考虑如下 方面 :


■■ the quality of feedwater and its variation over seasons;
源水 水质及其季节变化 ;


■■ the quantity of water required by the user;
用水量需求 ;


■■ the required water -quality specification;
水质量标准 ;


■■ the sequence of purification stages required;
制备工艺 的顺序 ;


■■ the number and location of sampling points
取样 点的数 量和位置


■■ desi gn of sampling points in such a way so as to avoid potential contamination;
取样点的设计，以避免潜在的污染 ;


■■ unit process steps provided and documented with the appropriate instrumentation to measure parameters such as flow, pressure, temperature, conductivity and total organic carbon;

提供单元工艺步骤，并 通过 适当的仪器测量 记录 参数，如流量、压力、温度、电导率和总有机碳 ;


■■ material of construction;
材质 ;


■■ sanitization strategy;
消毒 策略 ;


■■ main components;
主要组件 ;


■■ interlocks, controls and alarms; and
联动 、控制和警报 ;


■■ appropriate software, electronic data management, system security and audit trail.
适当的软件，电子数据管理，系统安全和审计跟踪。


4.3.5 Ambient -temperature systems such as ion exchange and ultrafiltration are especially susceptible to microbiological contamination, particularly when equipment is static during periods of no or low demand for wa ter. Sanitization at defined intervals (e.g. based on the data collected from the system validation and system behaviour), as well as other controls, should be defined to prevent and minimize microbiological contamination.
诸如离子交换和超滤等 室温系统特别容易受到微生物污染， 尤其 是当设备 因不用水 或需水量低 而 处于静止状态时。 应规定 定期 (基于收集 的系统 验证和系统 性能数据 ) 消毒 以及其他控制措施，以防止和减少微生物污染。


4.3.6 Methods for sanitizing each stage of purification should be appropriate and validated. The removal of any agents used for sanitization should be proven.
各纯化 阶段的消毒方法应 恰当 并经过验证。应证明 消毒用 的试剂 被去除。


4.3.7 The following controls, for example, should be considered in order to minimize microbial contamination:
应考虑以下控制措施 减少微生物污染 ，例如 :

■■ the maintenance of water flow at all times in the storage and distribution system to prevent water from stagnating;
在储存分 配系统中 始终保持流速 ;


■■ control of temperature in the system, for example, by heat exchangers or room cooling in order to reduce the risk of microbial growth;
控制 水系统内的温度，通过热交换器或房间冷却，以减少 系统 微生物 滋生 的风险 ;


■■ the provision of ultraviolet disinfection at appropriate locations in the system;
在系统 中 适当地点 采用 紫外线消毒 ;


■■ the use of water -treatment system components that can periodically be
thermally sanitized above 70 °C for a defined period of time, or chemically sanitized using, for example, ozone, hydrogen peroxide and/or peracetic acid; and
水系统组件 可以定期进行 70 °C以上 热消毒 或 化学消毒 ， 如：臭氧、过氧化氢和 /或过氧乙酸等 ；


■■ a combination of thermal and chemical sanitization, if required.
如必要， 也可采用 热消毒和化学消毒相结合 方式 。


4.3.8 BPW should have appropriate alert and action limits for chemical and microbiological purity determined from a knowledge of the system and data trending.
BPW should be protected from recontamination and microbial proliferation.
纯化水 应根据系统和数据趋势 制定 适当的化学和微生物 报警 限和 行动限 ，应防止污染和微生物 滋生 。


4.4 Bulk water for injections 散装 注射用水
4.4.1 BWFI should meet the relevant pharmacopoeial specifi cations for chemical and microbiological purity (including endotoxins). BWFI is the highest quality of pharmacopoeial WPU.
BWFI 应符合相关药典的化学和微生物 标准 (包括内毒素 )。BWFI 是药典中 最 好的 制药用水。

4.4.2 BWFI is not a final dosage form. It is an intermediate bulk product suitable to be used as an ingredient during formulation.
BWFI 不是最终 的成品 水。它是 作为配方成分 的中间产品。


4.4.3 As a robust technique should be used for the production of BWFI, the following are examples of what should be considered when configuring a water purification system or defining URS:
注射用水 的生产 应采用 成熟 可靠的技术，以下是在配置系统或定义 URS 时的 考虑点 :


■■ the quality of feedwater and its variation over seasons;
进水水质及其季节变化 ;


■■ the quantity of water required by the user;
用水量需求 ;


■■ the required water -quality specification;
水质量标准 ;


■■ the sequence of purification stages required, where appropriate;
制备工艺的顺序 （需要 时）;


■■ based on the selection of components, material of construction and type of system, the appropriate URS, qualification and validation;
组件 选择 、材质和 系统 类型 、适当的 URS 、确认和验证 ;


■■ the optimum generator size or generators with variable control to avoid
over -frequent start/stop cycling;
选择 最佳大小或可变控制 的 发生器 ，以避免过于频繁的启 /停;


■■ blow -down and dump functions;
排污和 排尽 功能 ;


■■ cool -down venting to avoid contamination ingress;
冷凝排放以 避免污染进入 ;


■■ appropriately located sampling points designed in such a way so as to
avoid potential contamination;

取样点的设计，以避免潜在的污染 ;


■■ appropriate instrumentation to measure parameters as required;
配制适当 的仪器所需的参数 ;


■■ sanitization strategy;
消毒 策略 ;


■■ interlocks, controls and alarms; and
联动 、控制和警报 ;


■■ electronic data storage, system security and audit trail.
电子数据存储、系统安全和审计跟踪。


4.4.4 BWFI may be prepared, for example, by distillation as the final purification step. Alternatively, BWFI may be produced by means other than distillation.
Techniques such as deionisation, electro deionization, nanofiltra tion, ultrafiltration, water -softening, descaling, pre -filtration and degasification, ultraviolet treatment, along with other techniques, may be considered in conjunction with a single or double pass RO system. For full details, see Production of water for injection by means other than distillation as published in the WHO Technical Report Series, No. 1025, Annex 3, 2020 ( 6).
注射用水制备 通过蒸馏作为最后的 制备 步骤。也可以通过蒸馏以外的方法 制备 。如去离子、电去离子、纳滤、超滤、软化、除 锈、 初滤和脱气、紫外线处理等 连同 其他技术，可考虑与单道或双道 RO 结合使用。 更多 详细信息，见 WHO 技术报告 ， No. 1025 ，附件 3用蒸馏以外的方法生产注射用水 ，2020 (6)


4.4.5 BWFI should have appropriate microbial and chemical alert and action limits and should also be protected from recontamination and microbial proliferation.
注射用水应 有适当的微生物和化学 报警限和行动限 ，应防止污染和微生物滋生 。


5. General considerations for water purification s ystems水系统的一般考虑

5.1 Pharmaceutical manufacturers should apply the current principles of quality risk management ( 7) in selecting and using the appropriate water purification systems. An appropriate method for the production of WPU should be used.
制药企业 应采用 质量风险管理原则 (7) 选择和使用水系统。应采用适当的方法 生产 制药用水。


5.2 Risks and controls should be identified for each stage of the production, storage, distribution, use and monitoring of WPU.
应对制药用水生产、储存、分配 、使用和监测的每个阶段 的风险 进行识别和 控制 。


5.3 Risks identified should be evaluated in order to de termine the scope and extent of validation and qualification of the system, including the computerized systems used for the production, control and monitoring of WPU.
应进行风险 识别 和评估，以确定系统 (包括 制药用水 生产、控制和监测的计算机化系统 )验证和确认的范围和程度。


5.4 Risk management should be an ongoing part of the quality management process for WPU. A mechanism to review or monitor events associated with the production,storage, distribution and use of WPU should be implemented.
应在制药用水质量管理中进行持续的风险管理 。应 对制药用水 的 生产、存储、分配 和使用的过程进行 回顾和监测 。


5.5 Procedures fo r managing changes and deviations should be followed. Where applicable, the appropriate risk and impact assessments should be carried out in such a way that changes and deviations are managed.
应遵循变更和偏差管理程序 ，必要时 应进行适当的风险和影响评估。


5.6 The chosen water purificatio n system, method or sequence of purification steps must be appropriate in order to ensure the production of water of the intended grade.
Based on the outcome of the risk assessment, the following should at least be considered when selecting the water treat ment system and method:

水系统 的选型 、制备 工艺和顺序 应能 确保生产出的 预期等级 的水。 基于 风险评估，在水系统 选型 时，至少应考虑以下几点 :


■■ the qualit y of the available feedwater and the variation over time (seasonal changes);
源水 质量 及其 随时间 (季节性 )的变化 情况 ;


■■ the availability of suitable support facilities for the system (e.g. electricity,
heating, steam, chilled water and compressed air);
系统 需有适当的 辅助 设施 (如：电力、 加热 、蒸汽、冷冻水和压缩空气 );


■■ the extent of pre -treatment required;
所需预处理的程度 ;


■■ the sequence of purification steps required;
所需的 制备 步骤的顺序 ;


■■ the design and location of sampling points;
取样点 的设计与位置 ;


■■ the sanitization strategy;
消毒 策略 ;


■■ the availability of water -treatment equipment on the market;
市场上水 系统设备 的供应情况 ;


■■ the reliability and robustness of the water -treatment equipment in operation;
水系统 的可靠性和稳 定 性;


■■ the yield or efficiency of the purification system;
系统的 产能 或效率 ;


■■ the ability to adequately support and maintain the water purification equipment;
对系统的 支持和维护 的 能力 ;


■■ the continuity of operational usage considering hours/days/years and planned downtime;

系统 运行的连续性 （小时 /天 /年）和计划停机 ;


■■ the total life -cycle of the syst em (including capital, operation and maintenance);
系统的全生命周期 (包括资金、运行和维护 );


■■ the final water quality specification; and
最终水质 标准 ;


■■ the minimum, average and maximum quantity of water required by the user.
需求 的最小、平均和最大水量。


5.7 The specifications for water purification equipment, storage and distribution systems should take into account at least the following:
制水 、储 存和分配 系统的 选型 应至少考虑以下因素 :


■■ the location of the plant room;
机房的位置 ;


■■ the extremes in temperature that the system will encounter;
系统将会遇到的极端温度 ;


■■ the risk of contamination, for example, from materials of construction (contact materials) and the environment;
污染的风险，例如， 材质 (接触 物)和环境 ;


■■ the adverse impact of adsorptive contact materials;
材质的 吸附性 ;


■■ hygienic or sanitary design, where required;
卫生或 清洁 设计 （如必 要）;


■■ corrosion resistance;
耐蚀性 ;


■■ freedom from leakage;
密封性 ;

■■ system configuration to avoid or minimize proliferation of microbiological
organisms;
系统配置 应避免或减少微生物的 滋生 ;


■■ tolerance to cleaning and sanitizing agents (thermal and/or chemical);
耐清洗和消毒剂 (热 力和/或化学 性的);


■■ the sanitizatio n strategy;
消毒 策略 ;


■■ system capacity and output requirements; and
系统容量和 产出要求 ;


■■ the provision of all necessary instruments, test and sampling points in order to allow for all the relevant critical quality parameters of the complete system to be monitored.
提供所有必要的仪器、测试和 取样点，以便对整个系统的所有相关关键质量参数进
行监控。


5.8 The design, configuration and layout of the water purification equipment, storage and distribution systems should also take into account the following physical considerations:
制水 、储存和分配系统的设计、配置和布局还应考虑以下物理因素 :


■■ the ability to collect samples;
便于取样 ;


■■ the space available for the installation and environment around the system;
系统 的安装空间和环境 ;


■■ structural loadings on buildings;
建筑物的结构载 荷;


■■ the provision of adequate access for maintenance and monitoring; and
足够 的维修和监测通道 ;


■■ the ability to safely handle regeneration and sanitization chemicals.

安全 进行 再生和 化学 消毒。


6. Water storage and distribution systems 水的储存和分配系统
6.1 Where drinking water is stored and distributed, the appropriate controls should be determined and implemented in order to mitigate risks. This applies to all stages in the supply, storage and distribution of drinking -water.
在饮用水储存和分配的地方，应 有适当的 措施以降低 饮用水供应、储存和分配的所有阶段的风险。


6.2 The water storage and distribution systems for PW and BWFI should be appropriately designed, installed, qualified, operated and maintained in order to ensure the storage and distribution of water is of consistent quality to the user points.
纯化水 和 注射用水的 储存和分配系统应经过适当的设计、安装、 确认、运行 和维护，以确保 使用点 的水质 稳定 。


7. Good practices for water systems 水系统的良好实践
7.1 The components of wa ter systems, including but not limited to pipework, valves and fittings, seals, diaphragms and instruments, should be appropriate and remain suitable during the full range of operational conditions such as temperature and pressure of the system at rest, in operation and during sanitization. The construction materials should be
of adequate quality.
水系统的组 件，包括但不限于管道、阀门和连接件、密封件、膜片和仪表，应在系统 停止、运行和 消毒 期间 ， 保持 的温度和压力等全部运行条件 处于 适宜的状态。 建造材质 应符合相应 质量。


7.2.1 As a minimum, the following design and construction practices should be considered.

至少应考虑以下设计和施工规范。


For drinking water storage, supply and distribution systems on -site
场地的 饮用水储存、供应和分配系统


Materials of construction should be selected based on the following requirements:
材质应 符合以下要求 :


■■ ability to operate at the temperatures/pressures required;
能够在要求的温度 /压力下 运行 ;


■■ lack of impact on the final water quality;
对最终水质没有影响 ;


■■ resistant to sanitizing chemicals;
耐化学 消毒 ;


■■ threaded and flanged joints are permitted;
可用 螺纹和法兰连接 ;


■■ sample valves should preferably be of sanitary design.
样品阀最好是卫生设计的。


Note that the system may have a design life at the end of which it should be replaced or adequately modified .
请注意，系统可能 是有设计寿命 的， 必要时需要更换和维修 。


For purified water and bulk water for injection systems
纯化水和注射 用水 系统


Note: Construction standards are generally aligned with potable water standards up to the process stage (e.g. RO) .
注:在制备工艺前（ 如 RO ） ，施工标准通常与饮用水一致。


■■ Materials of construction should be appropriate. It should be non -leaching, non -adsorbing, non -absorbing and resistant to corrosion. Stainless -steel grade 316L or polyvi nylidene chloride (PVDC) is generally recommended. The choice of material should take into account the intended sanitization method.

材质 应不浸出、不吸附、不吸收、耐腐蚀 ， 一般推荐不锈钢 316L 或聚偏二氯乙烯
(PVDC) ，材质 的选择应考虑预定的 消毒 方法。


■■ Stainless steel systems should be orbitally welded, with manua l welds where necessary. Inter -weldability between materials should be demonstrated with the maintenance of weld quality through a defined process. Documentation for such a system should be kept and should include, as a minimum, the qualification of the we lder, set -up for welding (e.g. machine), work session test pieces (coupons or weld samples), proof of quality of gas used, welding machine calibration record, weld identification and heat
numbers, and logs of all welds. Records, photographs or videos of in spection of a defined proportion of welds (e.g. 100% of manual welds, 10% of orbital welds).
不锈钢系统应采用 自动 焊接，必要时可采用手工焊接。应通过规定的 程序 来证明，以 确保焊接质量。 相应 文件应存档，至少包括 ： 焊工 资质、 焊接 准备 (如机器 )、焊样测试 (样品或 焊样 )、焊接 气体的质量 证明 、 焊机校准记录 、焊 点及 编号、 所有焊缝 的 日志。 按规定 比例焊缝 的 检查 记录、照片或录像 (如：手工焊缝 100% 检查 ，自动焊检查 10%)


■■ Joints should be made using sanitary connections, for example, hygienic clamp joints. Threaded joints should not be permitted. Polyvinylidene fluoride or polyvinylidene difluoride (PVDF) systems should be fusion joined and visually inspected.
接头 应采用卫生连接，例如 ：卫生卡箍接头 ，不允许使用螺纹连接。 PVDF 系统应 采用融合连接 和目视检查。


■■ Passivation should be considered for stainless steel systems, for example, for non -electropolished surfaces (after initial installation and after significant modification) in accordance with a documented procedure defining th e solution to be used, its concentration, the temperature and contact time.
不锈钢系统 应进行钝化处理 。例如，对非电抛光表面 (在初 次安装和重大维修 后)，应按照书面 规定 浓度、温度和接触时间进行钝化 。


■■ Internal finish should be smooth.

内部要光滑。


■■ Flanges, unions and valves should be of a hygienic or sanitary design. Valves should be diaphragm type forged or machined body, with points of use constructed so that they can drain. Sample valves should be sanitary type with the surface roughness of 1.0 micrometer RA or lower for PW and WFI systems and are typically installed betwe en process stages and on the distribution loop return. The appropriate checks should be carried out in order to ensure that the correct seals and diaphragms are used and that they are fitted and tightened correctly.
法兰、 接头和阀门应采用卫生设计。阀门应该 采用 膜片式锻造或机加工阀体，其 内部应能排尽。对于 纯化水和 注射用水 系统，取样 阀应是卫生级的，表面粗糙度为 1.0 微米或更低，通常安装在 各制备单元 之间 和分配 循环 回路上。应进行适当的检查，以确保使用正确的密封和膜片，并确保安装 正确 和紧固。


■■ The system should be installed to promote drainability with a recommended minimum slope of 1/100.
系统的 安装 应利于排尽 ，推荐 坡度 最小 1% （译者解释 ：坡面的垂直高度 h和水平方向的距离 l的比 ）。


■■ Where appropriate, pressure or hydro -tests for leaks, spray -ball functionality test and flow turbulence should be considered.
在适当的情况下，应考虑 气压 或水压泄漏 测试 ，喷 淋球功能测试和 湍流。


■■ Provision should be made for in -line measurement for total organic carbon (TOC), conductivity, pressure , flow and temperature.
应具有 总有机碳 (TOC) 、电导率、压力、流量和温度的在线测量。


■■ Documents should provide evidence of system components and qualification. These include as applicable drawings, original or certified copies of certificates of conformity for materials of construction , records of on -site tests performed, weld/joining records, calibration certificates, system pressure test records and records of passivation.

应提供系统组 件和资质 的文件 证据。包括图纸、 材质证明 的原件或 复印件 、现场测试记录、焊接记录、校准证书、系统压力测试记录和钝化记录。


8. System sanitization and bioburden control 系统消毒和生物负荷控制
8.1 Water -treatment, storage and distribution systems should be subjected to controls that will reduce the risk of contamination and the proliferation of microbiological organisms.
水制备、储存和分配 系统应 当有 控制措施 ，以减少污染和微生物 滋生的 风险 。


8.2 Controls may include using c hemical and/or thermal sanitization procedures as appropriate for production, storage and distribution systems. The procedure and conditions used (such as times and temperatures, as well as the frequency), should be defined and proven to be effective for s anitizing all relevant parts of the system. The techniques employed should be considered during the design stage of the system as the procedure and technique may impact on the components and materials of construction.
控制 包括在生产、储存和分 配系统中 采用适当的化学和 /或热 力消毒程序。 应明确 所用的程序和条件 (如时间和温度 、频率 )，并证明 其有效性 。在系统的设计阶段 就应 当所采用的 消毒 方法 ， 以避免对 系统组件 和材质 产生影响。


8.3 Systems that operate and are maintained at elevated temperatures (e.g.
>70 °C) are generally less susceptible to microbiological contamination than systems that are maintained at lower temperatures. When lower temperatures are required due to the water treatment processes employed, or the temperature requirements for the water in use, special precautions should be taken to prevent the ingress of contaminants including microorganisms (see section 9.2 for guidance).

当系统 在较高 温度 (如 :>70 °C) 下运 行 和维护时， 相对 比 低温 下更 不 易受到微生物污染。当需要 采用 低温 制备使用 时，应采取预防以防包括微生物在内的污染物进入 (参见 9.2 节的指导 )。


8.4 Where the chemical sanitization of the water systems is part of the biocontamination control programme, a validated procedure should be followed in order to ensure that the sanitizing process selected is effective and that the sanitizing agent has been effectively removed.
如果水系统 采用 化学消毒 方法 控制 微 生物污染 ，程序 应 经过验证，以确保消毒 效果且 消毒剂 能被有效去除。


8.5 Records of sanitization should be maintained.
消毒 应有 记录。


8.6 Other control techniques to be considered may include:
其他控制 可能包括 :


■■ The maintenance of a continuous circulation of water maintaining
turbulent flow evidenced by, for example, a Reynolds number of > 4000.
证明 水循环维持湍流流动，如雷诺 系数 > 4000 。


■■ Ensuring hygienic design, including the use of zero dead leg diaphragm
valves where possible, and minimizing dead legs elsewhere. Areas of possible dead legs should be measured and calculated.
保证采用 卫生 设计 ，包括尽可能使用 无死角 隔膜阀，并尽量减少其他 死角， 对
所有可能的死角进行 测量计算。


■■ Installing pipework in a manner to allow for full drainage, if required. A
guidance figure for the slope is not less than 1/100.
如果需要， 管道 的安装应能 完全排 尽 ，坡度 不小于 1%


■■ Considering the use of ultraviolet lamps in the system where needed with
independent monitoring.
考虑在 需要独立监控 的 系统使用紫外线灯。

■■ Maintaining the system at an elevated temperature (e.g. > 70 °C), if
required.
如必要 ， 使系统维持在较高温度 (如> 70 °C)。


9. Storage vessels 储罐
9.1 Storage vessels should be appropriate for their intended use.
储罐应适合其预期用途。


9.2 As a minimum, the following should be considered:
至少 应考虑以下事项 :


■■ the design and shape to ensure drainage of water from the vessel, when
required;

设计和形状要保证容器中水 能在 需要时被排尽 ;


■■ construction materials;
材质 ;


■■ capacity, including buffer capacity, between the steady state, water
generation rate and the potentially variable simultaneous demand from user points, short -term reserve capacity in the event of failure of the water -treatment system or the inability to produce water (e.g. due to a regeneration cycle);
稳定状态 下的容量、缓 冲容量 、产水 率和 使用 量的 变化 ，以及万一 系统 故障或无法生产水 (例如由于再生循环 )情况下的短期储备容量 ;


■■ prevention of stagnant water in the vessel (e.g. the headspace where water droplets can accumulate) and the need for the use of a spray -ball or distributor devices to wet the inner surfaces of the vessel;
防止 储罐内死水 (例如， 顶部会 凝聚 水珠 )，使用喷 淋 球或分配器来湿润内表面 ;


■■ the fitting of bacteria -retentive, hydropho bic vent filters which are tested for their integrity at appropriate intervals;
阻隔细菌 的疏水排气过滤器应 以适当的间隔 测试完整性 ;

■■ the fitting of sanitary design pressure safety valves or bursting discs
provided with external rupture indicators to ensure that loss of system integr ity is detected;
卫生级安全阀或 爆破片 应 带有外部 的破裂指示器，以确保 能识别 系统完整性 问题 ;


■■ the design and sanitization, as required, of level indicators;
液位计 的 安装 应 采用 卫生设计 ;


■■ the design and location of valves, sampling points and monitoring devices
and sensors; and
设计 安装 阀门、 取样点、 监测装置和传感器 ;


■■ the need for heat exchangers or jacketed vessels. Where these are used, double tube sheet or double plate heat exchangers should be considered.
当需要热交换器或夹套 时， 应考虑 使用 双管板或双板换热器。


10. Water distribution 水分配
10.1 The water distribution system should be designed as a loop, with continuous circulation of BPW and BWFI. Where this is not the case, the appropriate justification for using a non -recirculating one -way system should be provided as well as robust measures implemented to monitor these.
分配 系统应设计成回路 使纯化水 和注射用水 保持 循环。如果 不这样 做则应 证明 理由，并采取 可靠 措施进行 监测。


10.2 As a minimum, the following should be considered:
至少 考虑下列事项 :


■■ controls to minimize proliferation of contaminants;
控制 降低 污染 ;


■■ material of construction, joints and impact as a result of sanitization; and
材质 、接缝及 消毒的影响 ;

■■ the design and location of devices, sensors and instruments such as flow meters, conductivity sensors, TOC analysers and temperature sensors.
设备、传感器和仪器的设计和定位，如流量计、电导率、 TOC 和温度传感器。


10.3 Filtration should not be used in distribution loops or at take -off user points.
过滤 器不应 安装在 分配回路或 用水点（ 解释 ：可能 会掩盖污染 不 被发现 ）。


10.4 Where heat exchangers are used, they should be arranged in continually circulating loops or sub -loops in order to avoid unacceptable static water in the system.
如采用换热器，应 安装 在循环回路或 子回路中，以避免 死水 。


10.5 When the temperature is reduced for proc essing purposes, the reduction should occur for the minimum necessary time. The cooling cycles and their duration should be proven satisfactory during the qualification of the system.
当因工艺原因 需要降低 温度时， 处于 低温的时间应尽可能 短。冷 循环及其持续时间应在系统确认 中验证 。


10.6 Circulation pumps should be of a sanitary design with the appropriate seals to prevent contamination of the system.
循环泵应采用卫生设计并密封，以防止系统受到污染。


10.7 Where stand -by pumps are provided, they should be configured or managed to avoid zones where stagnant water is trapped within t he system.
当配备备用泵 时 ，应避 在系统内 形成 死水 。


10.8 Consideration should be given to preventing contamination in systems where parallel pumps are used. There should be no stagnant water remaining in a pump when the pumps is not being used.
使用并联泵 时应考虑 到 防止污染 产生，当某 一个 水泵 停用 时不应有死 水。


10.9 Components should be identified and labelled. The direction of flow should be indicated.
系统 组件应进行 有标识并 标示 流向。

11. Operational considerations including some qualification and validation principles 系统运行、 确认与 验证
11.1 Water systems should be appropriately qualified and validated (8). The scope and extent of qualification should be determined based on risk assessment. (See also point 3.3. above.)
水系统应进行适当的确认和验证 (8) 。确认的范围和程度应根据风险评估确定。 (请参见上文 第 3.3 节)。


11.2 When commissioning work is done, this should be d ocumented.
Commissioning is not a replacement for qualification.
调试应 形成 文档 ，不能替 代确认 。


11.3 In order to demonstrate the reliability and robustness of a system and its performance, a three -phase approach should be used for validation, covering at least one year o f operation over different seasons. Tests on the source water (drinking -water) should be included within the validation programme and continued as part of the routine monitoring, and these results should meet specifications.
为证明系统性能的可靠和 稳定 ，应采用三阶段方法进行验证， 至少 包括 一年 不同季节 的运行 。验证 方案应包括 对水源 (饮用水 )的检测，并 纳入 持续监测 ，结果应 符合标准 。


Note: A typical phase 1 to 3 approach for a new system is described below. When changes are made to existing systems, the phase(s) and length of each phase, as well as sampling points and frequency of sampling should be based on documented risk assessment .
注意 :下面 为典型 的 新系统 1到 3阶段 验证 方法。当对现有系统 变更 时，阶段 及其时长、取样点和频率应基于风险评估 文档 。


Phase 1 第一阶段

Phase I should cover a period of at least two weeks.
第一阶段应该至少两周。
Procedures and schedules should cover at least the following activities and testing approaches:
程序和 计划 应至少包括以下 :


■■ chemical and microbiological testing in accordance with a defined plan;
按照 确定 的计划进行化学和微生物测试 ;


■■ sample, test and monitoring of the incoming feedwater to verify its quality;
对进水进行 取样、检测和监测 以核实 其质量 ;


■■ sample, test and monitoring after each step in the purification process;
对制备 工艺 中每一步 取样、检测和监测 ;


■■ sample, test and monitoring at each point of use and at other defined sample points including the end of the distribution loop;
对每个使用点和其他点 (包括 回路 末端 ) 取样、检测和监测 ;


■■ verification of operating ranges;
核实运行 范围 ;


■■ operating, cleaning, and maintenance;
操作、清洁和维护 ;


■■ sanitizing procedures and operating ranges;
消毒 及其运行 范围 ;


■■ demonstrate the consistent production and delivery of product water of the required quality and quantity;

证明产水 的质和量持续 符合要求 ;


■■ establishing provisional alert and action levels; and
确定临时 的警戒限和 行动限 ;


■■ test -failure procedure.
测试失败的程序


The system should be monitored intensively for its performance. Water should not be used for product manufacturing during this phase.
应密切监测该系统的 性能 。在此阶段，不应将水 用于产品 生产 。


Phase 2 第二 阶段
Phase 2 should cover at least a further test period of two weeks after the satisfactory completion of Phase 1. The system should be monitored while deploying all the standard operating procedures (SOPs). The sampling programme should be generally the same as in Phase 1. The use of the water for product manufacturing purposes during this phase may be acceptable, provided that Phase 1 and ongoing Phase 2 data demonstrate the appropriate water quality and the practice is approved by QA.
在第一阶段 成功 完成后，第二阶段应包括至少两周的测试期。 此时 应按 修订 的 标准操作程序 (sop) 执行， 并进行 监控 ，取样计划通常 与第一阶段相同。 当 第一阶段和正在进行的第二阶段的数据表明水质 合格 ，在经过 QA 批准 后，本阶段 水可 用于产品生产。


The approach should also:
此外 还包括 :


■■ demonstrate consistent system operation within established ranges; and
证明 系统在既定范围内 温度 运行 ;


■■ demonstrate consistent production and delivery of water of the required
quantity and quality when the system is operated in accordance with the SOPs.
证明系统按 标准操作程序运行时，生产和 输送 的水达到所需的 质和 量。


Phase 3 第三阶段

Phase 3 should follow phase 2 ensuring that the duration of Phase I, 2 and 3 cover at least 12 months. The sample locations, sampling frequencies and tests may be reduced according to a routine plan which should be based on the established procedures and data from Phase 1 and Phase 2. Data should be trended, for example, quarterly and a system review should be undertaken after the completion of Phase 3 as part of the evaluation of system performance capability. The appropriate action should be taken where such a need is identified.
第三阶段 继第二阶段 之后 ，确保第一 、二、 三阶段 为期 至少 12 个月。 取样位置、频率和检测 可根据 既定 程序和第一 、二阶段的数 据减少 。数据应 进行 趋势 分析 ，例如 ： 在第三阶段完成后 每季度 进行 一次 系统回顾 ，以评估 系统性能。 必要时 应采取 相应 的行动。


Water can be used during this phase. The data and information obtained during Phase 3 should demonstrate the reliable performance of the system over this period of time covering the different season s.
此阶段水 可以 使用 。第三阶段数据信息应证明系统在不同季节的可靠性。


12. Continuous system monitoring 系统 持续 监控
12.1 The system should be subject to continuous monitoring.
系统应 进行 持续的监控。


12.2 A monitoring plan should be followed where samples are collected in accordance with a written procedure.
应按照书面程序 进行监测 。


12.3 A combination of online and offline instruments, linked to appropriately qualified alarm systems, should be used. Parameters such as flow, pressure, and temperature should be monitored with online instruments – as well as condu ctivity and TOC, where possible.
Periodic offline testing to confirm the results from online testing is recommended. Other parameters may be monitored through offline testing.

参数应 通过 在线 /离线仪器 监测 并报警 ，如：在线 监测 流量、压力和温度等参数，如果可能，还应 包括 电导率和 TOC 。建议定期进行离线测试 ，以确认在线测试的结果。其他参数可 离线进行监控。


12.4 Offline testing (including physical, chemical and microbiological attributes) should be done in accordance with a predetermined programme.
离线测试 (包括物理、化学和微生物 指标 )应按照预确 计划 进行。


12.5 Samples should be taken from points of use and dedicated sample point s where required. All water samples should be taken using the same methodology as detailed in production procedures, for example, using a hose and with a suitable flushing and drainage procedure in place.
样品应从使用点和 特定 点（必要时） 采集。所有水样均应用相同方法 取样 ，并在文件中详细规定 ，例如 ：使用软管，并 经过 适当的冲洗 、排放 。


12.6 Tests should be carried out to ensure that the relevant pharmacopoeia
specification (and approved company specification, where applicable) has been met.This may include the microbiological quality of water, as appropriate.
检测应 符合相 应 药典 要求 (和批准的公司 要求（ 适用 时） )。可能包括适当的微生物质量。


12.7 The results for identified quality attributes should be subjected to statistical analysis at defined intervals, for example, monthly, quarterly and annually, in order to identify trends. The results should be within def ined control limits, such as 3 sigma.
特定 的质量属性 应按规定的时间间隔进行统计分析， 如 ：每月、每季度和每年。结果应在规定的控制范围内，如 ： 3σ。


12.8 Alert and action levels should be established based on historically reported data.
警戒限 和行动 限 应根据历史 数据 确定。


12.9 Adverse trends and out -of-limit results should be inv estigated for the root cause, followed by the appropriate corrective and preventive actions. Where microbial contamination of BWFI occurs, the micro -organism should be identified.

应对不良趋势和超限结果 进行调查 ， 并采取适当的纠正和预防措施。 注射用水 发生微生物污染时，应 进行 鉴定 。


13. Maintenance of water s ystems 水系统的维护
13.1 WPU systems should be maintained in accordance with an approved and documented maintenance programme. Records should be kept.
系统应按照经批准的维护计划进行 ，并 应有 记录。


13.2 The maintenance programme should take into account at least the following:
维修 计划 至少应考虑下列情况 :


■■ defined frequency for system elements e.g. filters, instruments, gauges;
系统元件的 更换频率 ，如 ： 过滤器 、仪器、仪表 ;


■■ the calibration programme;
校验计划 ;


■■ SOPs for specific tasks;

特定任务 ;


■■ the control and storage of approved spare parts;
备品备件 的管理 和储存 ;


■■ preventive maintenance and maintenance plan and instructions, including
cleaning after maintenance;
预防性 维护 保养计划及 指令 ，包括 维护 后的清洁 ;


■■ a review and approval of systems for use upon completion of work; and
对使用系统 使用 情况 的 回顾 和批准 ;


■■ a record and review of problems and faults dur ing maintenance
维护过程中问题和故障的记录和 审核


14. System reviews 系统回顾
14.1 WPU systems should be reviewed at described intervals (e.g. annually)S.
The review should be documented.
制药用水 系统 应按规定的时间间隔 (例如每年 )回顾 并有记录 。


14.2 The review team should be comprised of representatives from, for example, engineering, utilities, validation, QA, quality control, microbiology, production and maintenance.
审查 小组应由工程、公用 系统 、验证、 QA、 QC、微生物专家 、生产和 维护 部门的代表组成。


14.3 Examples of matters to be included in the review are:
回顾包括 如下 内容 :


■■ changes made since the la st review;
自上次 回顾 以来 的变更 ;

■■ system performance trends and capability;
系统趋势 性能 ;


■■ quality trends;
质量趋势 ;


■■ failure events and alarm history;
故障和报警历史 ;


■■ investigations;
调查 ;


■■ out -of-specification and out -of-limit results;
OOS 和 OOT ;


■■ alert and action limits;
所以警报和行动限制 ;


■■ assessing compliance with current GMP requirements for WPU systems;
制药用水 系统 GMP 符合性评估 ;


■■ verification of documentation being current;
核实 现行 文件 ;


■■ maintenance and calibration history;
维护和校准历史 ;


■■ records such as log books and electronic data; and
日志、电子数据等记录 ;


■■ the appropriateness of the software and the computerized system linked to the water system, for example, SCADA (Supervisory Control and Data Acquisition),including audit trail, authorized users with access and privileges.

软件和 计算机化系统 ，例如 ：SCADA( 控制和数据采集 系统 )，包括审计追踪、 权限和用户。


15. Inspection of water systems 水系统检查
15.1 WPU (BPW and BWFI) systems are subjected to regulatory inspections. Users should conduct audits and self -inspection of water systems at regular intervals. Records should be maintained.
制药用水 (纯化水和 注射用水 )系统需接受法规检查。应定期 对 水系统 进行 审核及 自检，并有记录。


15.2 This document can be used as the basis of an audit and inspection. A tour of the water system, treatment system, storage and distribution system, as well as visible pipework and user points, should be performed to ensure that the system is appropriately designed, installed, qualified, validated, maintained and monitored.
本文件可作为审计和检查的依据。应对水系统、 制备 系统、储存和分配系统以及可见的管道和 使用点 进行 现场检查 ，以确保系统 的 设计、安装、 确认 、验证、维护和监控。


References 参考文献
1. WHO Good manufacturing practices: water for pharmaceutical use . In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: forty -sixth report. Geneva: World Health Organization; 2012: Annex 2 (WHO Technical Report Series, No. 970; https://apps.who.int/iris/bitstream/handle/10665/75168/ WHO_TRS_970.pdf?sequence=1 , accessed 29 July 2020).

2. WHO Good manufacturing practices for active pharmaceutical ingredients. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: forty -fourth report. Geneva: World Health Organization; 2010: Annex 2 (WHO Technical Report Series No. 957; https://apps.who. int/iris/bitstream/handle/10665/44291/WHO_TRS_957_eng.pdf?sequence=1 , accessed 29 July 2020).


3. WHO Good manufacturing practices for pharmaceutical products: main principles. In: WHO Expert Committee on Specific ations for Pharmaceutical Preparations: forty -eighth report.

Geneva: World Health Organization; 2014: Annex 2 (WHO Technical Report Series, No. 986 https://apps.who.int/iris/bitstream/handle/10665/112733/WHO_TRS_986_eng.pdf?sequence=1 , accessed 29 July 2020).

4. The International Pharmacopoeia . Geneva, World Health Organization ( https://www.who.int/medicines/publications/pharmacopoeia/en/ and https://apps.who.int/phint/2019/index.html#p/ home , accessed 1 May 2020).

5. WHO Guidelines for drinking -water quality: fourth edition, incorporating the first addendum; 2017 ( https://www.who.int/water_sanitation _health/publications/drinking -water -quality -guidelines -4-
including -1st -addendum/en/ , accessed 1 May 2020).

6. WHO Produ ction of water for injection by means other than distillation: fifty -fourth report. Geneva: World Health Organization; 2020: Annex 3 (WHO Technical Report Series, No. 1025;
https://www.who.int/docs/default -source/medicines/who -technical -report -series -who -expert -committee -on-specifications -for -pharmaceutical -preparations/trs1025 -annex3.pdf?sfvrsn= caebed51_2 , accessed 29
July 2020).

7. WHO Guidelines on quality risk management. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: forty -seventh report. Geneva: World Health Organization; 2013: Annex 2 (WHO Technical Report Series, No. 981: https://www.who.int/medicines/areas/quality_safety/quality_assurance/Annex2 TRS -981.pdf?ua=1 , accessed 1 May 2020).

8. WHO Guidelines on validation. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: fifty -third report. Geneva: World Health Organization; 2019: A nnex 3 (WHO Technical Report Series, No. 1019; https://www.who.int/medicines/areas/quality_safety/quality_assurance/WHO_TRS_1019_Annex3.pdf?ua=1 , accessed 1 May 2020).


Further reading 延伸 阅读
■■ American Society of Mechanical Engineers. Bioprocessing Equipment Standard. ASME — BPE 2019.

■■ Banes PH. Passivation: understanding and performing procedures on austenitic stainless -steel systems. Pharmaceutical Engineering, 1990: 41.

■■ Guide to inspections of high purity water systems. Maryland, US Food and Drug Administration, 1993 (http://www.fda.gov/ICECI/InspectionGuides ).

■■ Biotechnology. Equipment. Guidance on testing procedures for cleanability. British Standards Publishing. BS EN 12296, 1998.

■■ European Medicine s Agency, 2020. Guideline on the quality of water for pharmaceutical use. EMA/CHMP/CVMP/QWP/496873/2018, Amsterdam, Netherlands ( https://www.ema.europa.eu/
en/documents/scientific -guideline/guideline -quality -water -pharmaceutical -use_en.pdf ).

■■ European Pharmacopoeia: see website for the publishers of the European Pharmacopoeia and supplements ( http://www.pheur.org/ ).

■■ Harfst WH. Selecting piping materials for high -purity water systems. Ultra -pure water, May/June 1994.

■■ International Organization for Standardization (ISO) for drinking water ISO 24512:2007 consisting of the following International Standards:

— ISO 24510, Activities relating to drinking water and wastewater services — Guidelines f or the assessment and for the improvement of the service to users

— ISO 24511, Activities relating to drinking water and wastewater services — Guidelines for the management of wastewater utilities and for the assessment of wastewater services

— ISO 24512, Activities relating to drinking water and wastewater services — Guidelines for the management of drinking water utilities and for the assessment of drinking water services

■■ ISPE Baseline Guide Volume 4: Water and Steam Systems. International Society fo r Pharmaceutical Engineering, 2019.

■■ ISPE Baseline Guide Volume 5: Commissioning and Qualification. Second edition. International Society for Pharmaceutical Engineering, 2019.

■■ Noble PT. Transport considerations for microbial control in piping. Journ al of Pharmaceutical Science and Technology, 1994, 48: 76 –85.

■■ Pharmaceutical Inspection Co -operation Scheme. PIC/S; Inspection of utilities; P1 009 -1. Geneva, Pharmaceutical Inspection Co -operation Scheme, 2002.

■■ Tverberg JC, Kerber SJ. Effect of ni tric acid passivation on the surface composition of mechanically polished type 316 L sanitary tube. European Journal of Parenteral Sciences, 1998, 3: 117 –124.
■■ US Food and Drug Administration. Guide to inspections of high purity water systems, high purity water systems (7/93), 2009 ( http://www.fda.gov/ICECI/Inspections/InspectionGuides/ ucm074905.htm ).

■■ US Pharmacopeia: published annually (see http://www.usp.org/ ).

■■ World Health Organization, 2018. A global overview of national regulations and standards for drinking -water quality ( https://apps.who.int/iris/bitstream/handle/10665/272345/9789241513 760 -eng.pdf?ua=1 ).

■■ World Health Organization, 2018. Developing drinking -water quality regulations and standards: general guidance with a special focus on countries with limited resources ( https://apps.who.int/
iris/bitstream/handle/10665/2729 69/9789241513944 -eng.pdf?ua=1 ).

■■ World Health Organization, 1997. Guidelines for drinking -water quality, 2nd edition: Volume 3- Surveillance and control of community supplies ( https://apps.who.int/iris/bitstream/handle/

10665/42002/9241545038.pdf?sequence=1&isAllowed=y ).
■■ World Healt h Organization, 2018. Management of radioactivity in drinking -water ( https://apps. who.int/iris/bitstream/handle/10665/272995/9789241513746 -eng.pdf?ua=1 ).

■■ World Health Organization, 2019. Microplastics in drinking water ( https://apps.who.int/iris/bitstream/handle/10665/3264 99/9789241516198 -eng.pdf?ua=1 ).

候振轩

感谢分享 首页很清晰

dghonst

候振轩 发表于 2022-3-3 15:27
感谢分享 首页很清晰

之前没发过链接，一开始没弄上去

魅力暴君

感谢分享 首页很清晰

刘良才

留个记号等全了再来