1. Introduction
1.1 Water is widely used in the pharmaceutical industry. It is often used as a raw material; an ingredient in formulations; to prepare reagents; in cleaning; and in the manufacture of active pharmaceutical ingredients, intermediates and finished pharmaceutical products.
1.2 Water for pharmaceutical use must meet quality requirements and specifications, as published in relevant standards and pharmacopoeias. Water of the required quality for its intended use should be produced by appropriate methods.
1.简介
1.1水在制药行业中应用广泛，常被用作原料、制剂成分、试剂制备、清洗以及原料药、中间体和制剂药品的生产。
1.2药用用水必须符合相关标准和药典中规定的质量要求与规格。应通过适当方法生产出符合预期用途质量要求的水。
2. Scope
2.1 This document provides guidance for the production of water for injection (WFI) by means other than distillation. The principles described in this guideline may be applied to other grades of water, meeting other specifications.
2.2 The document is not exhaustive but aims to provide guidance on the main principles to be considered. Other guidelines and literature should also be consulted (1, 2).
2.范围
2.1本文件为非蒸馏法生产注射用水（WFI）提供指导。本指南中所述原则也可适用于符合其他规格的其他等级的水。
2.2本文件并非详尽无遗，旨在为需考虑的主要原则提供指导，同时也应参考其他指南和文献（1, 2）。
3. Monographs
3.1 Manufacturers should have appropriate specifications for WFI.
3.2 Monographs for WFI are published in The International Pharmacopoeia (1), as well as various national pharmacopoeias, and provide for the minimum requirements for the quality of WFI.
3.3 WFI should meet the specification as published in current monographs of the relevant pharmacopoeia recognized by the national medicines regulatory authority.
3.各论
3.1生产商应制定适当的注射用水规格标准。
3.2《国际药典》（1）及各类国家药典中均载有注射用水的药典标准，规定了注射用水质量的最低要求。
3.3注射用水应符合国家药品监管机构认可的相关药典现行标准中的规格要求。
4. Life-cycle approach
4.1 Good practices during each stage of the life-cycle of WFI should be considered.
4.2 Stages include, but are not limited to, the collection and treatment of source water; treatment of drinking water; treatment of purified water; and the production, storage, distribution, use and control of WFI.
4.3 Principles of risk management (3) and data governance should be applied in each relevant stage of the life-cycle.
4.生命周期方式
4.1应考虑注射用水全生命周期各阶段的良好规范。
4.2这些阶段包括但不限于水源水的收集与处理、饮用水处理、纯化水处理以及注射用水的生产、储存、分配、使用和控制。
4.3风险管理（3）和数据治理原则应应用于生命周期的每个相关阶段。
5. Risk assessment
5.1 An appropriate method for the production of WFI should be used.
5.2 Risks and controls should be identified for each stage of the life-cycle of the production, storage, distribution, use and control of WFI.
5.3 Risks identified should be analysed and evaluated to determine the scope and extent of validation and qualification of the system, including the computerized controls used for the production, control and monitoring of WFI. Risk management should be an ongoing part of the quality management process for WFI. A mechanism to review or monitor events associated with production, storage, distribution and use of WFI should be implemented.
5.4 Where production methods other than distillation are used, specific attention should be given to ensure:
- the appropriateness of user requirement specifications;
- feed-water quality;
- the sequence of purification stages required;
- the extent of pretreatment required;
- appropriately designed and located sampling points;
- controls are in place to prevent “dead legs”; and
- in-line monitoring.
5.风险评估
5.1应采用适当的注射用水生产方法。
5.2需识别注射用水生产、储存、分配、使用和控制全生命周期各阶段的风险及控制措施。
5.3应对已识别的风险进行分析和评估，以确定系统验证和确认的范围及程度，包括用于注射用水生产、控制和监测的计算机化控制系统。风险管理应作为注射用水质量管理过程的一个持续部分。应建立相关机制，对与注射用水生产、储存、分配和使用相关的事件进行审查或监测。
5.4当采用非蒸馏法生产时，应特别注意确保：
- 用户需求标准的适当性；
- 进料水质量；
- 所需纯化阶段的顺序；
- 所需预处理的程度；
- 采样点设计和位置的合理性；
- 制定防止 “死脚” 的控制措施；
- 在线监测的实施。
6. Control strategy
6.1 The WFI system should be appropriately qualified and validated.
6.2 There should be controls to minimize the risk of contamination of WFI produced, stored or circulated.
6.3 An appropriate control strategy should be defined to ensure that all risks identified are eliminated, or reduced to an acceptable level.
6.4 All parts of the system (pretreatment, treatment, storage and distribution) should be appropriately designed and constructed. Materials for construction should not be reactive, additive, absorptive or adversely affect the quality of water and should be suitable for the sanitizing method used.
6.5 Treatment (also referred to as pretreatment) of water entering the system should ensure adequate removal of chemicals (organic and inorganic), particles, matter and microbiological impurities. The treatment should not have a detrimental effect on the materials of construction or downstream components of the water system.
6.6 Techniques such as deionization, electro-deionization, nanofiltration, ultrafiltration, water softening, descaling, prefiltration, degasification, and ultraviolet treatment, along with other techniques, may be considered in conjunction with a single- or double-pass reverse osmosis system.
6.7 These should allow for sanitization (thermal or chemical, or a combination thereof) when required. The method of sanitization should be appropriate, effective and validated. Sanitization should be done at specified intervals, in accordance with a documented procedure.
6.8 Appropriate sampling techniques should be used to sample water for analysis, at defined sampling locations, in accordance with a documented sampling procedure and a schedule.
6.控制策略
6.1注射用水系统应经过适当的确认和验证。
6.2应制定控制措施，以最大限度降低所生产、储存或循环的注射用水受到污染的风险。
6.3应制定适当的控制策略，确保所有已识别的风险被消除或降低至可接受水平。
6.4系统的所有部分（预处理、处理、储存和分配）均应进行适当的设计和建造。建造材料不得具有反应性、添加性、吸附性，也不得对水的质量产生不利影响，且应适用于所采用的消毒方法。
6.5进入系统的水的处理（也称为预处理）应确保充分去除化学物质（有机和无机）、颗粒物、杂质和微生物污染物。该处理过程不得对水系统的建造材料或下游组件产生不利影响。
6.6可考虑将去离子、电去离子、纳滤、超滤、水软化、除垢、预过滤、脱气和紫外线处理(deionization, electro-deionization, nanofiltration, ultrafiltration, water softening, descaling, prefiltration, degasification, and ultraviolet treatment)等技术与单级或二级反渗透(single- or double-pass reverse osmosis)系统结合使用。
6.7必要时，这些系统应允许进行消毒（热力消毒、化学消毒或两者结合）。消毒方法应适当、有效且经过验证。应按照书面程序，在规定的时间间隔内进行消毒。
6.8应按照书面采样程序和时间表，在指定的采样位置，采用适当的采样技术对水进行采样分析。
7. Good practices in the production of water for injection
7.1 WFI should be prepared either from water that complies with World Health Organization guidelines for drinking water (4), national standards for drinking water as a minimum quality feedwater, or purified water.
7.2 The results of water testing should be trended. Trend data should be reviewed routinely, in order to determine the potential for deterioration in the system.
7.3 Appropriate alert and action limits, in addition to specification limits, should be specified. Trend data should be assessed routinely and used to revise limits where appropriate.
7.4 The system should be monitored for its ongoing performance within defined parameters, including but not limited to, conductivity, total organic carbon (TOC) and microbial contamination.
7.5 A combination of online and offline monitoring of WFI should be done, to ensure that the appropriate water specification is maintained. TOC and conductivity should be monitored with online instruments. Use of rapid microbiological methods is encouraged for timely monitoring, and aids with rapid responses to prevent deterioration of the system.
7.6 The outlet of reverse osmosis systems should be monitored, to ensure that potential breaches are identified. This may include monitoring the conductivity of the water, and pressure.
7.7 The system should remain in a validated state throughout its life-cycle.
7.注射用水生产良好实践
7.1注射用水应采用符合世界卫生组织饮用水指南（4）、国家饮用水标准（作为最低质量进料水）的水或纯化水制备。
7.2应对水质检测结果进行趋势分析，并定期审查趋势数据，以确定系统可能出现的劣化情况。
7.3除规格限值外，还应规定适当的警戒限和行动限。应定期评估趋势数据，并在适当时修订限值。
7.4应在规定的参数范围内对系统的持续性能进行监测，包括但不限于电导率、总有机碳（TOC）和微生物污染。
7.5应结合在线和离线监测注射用水，以确保维持适当的水质规格。应使用在线仪器监测总有机碳和电导率。鼓励使用快速微生物检测方法进行及时监测，助力快速应对以防止系统劣化。
7.6应监测反渗透系统的出口，以确保识别潜在的违规情况，包括监测水的电导率和压力。
7.7系统在其整个生命周期内均应保持在验证状态。
References
- The International Pharmacopoeia, 9th ed. Geneva: World Health Organization; 2019 (https://apps.who.int/phint/en/p/docf/, accessed 4 December 2019).
- 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; http://apps.who.int/medicinedocs/documents/s19832en/s19832en.pdf, accessed 4 November 2019).
- 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/Annex2TRS-981.pdf, accessed 4 December 2019).
- Guidelines for drinking-water quality. Fourth edition incorporating the first addendum. Geneva: World Health Organization; 2017 (https://apps.who.int/iris/bitstream/handle/10665/254637/9789241549950-eng.pdf;jsessionid=60F04022DD9AD3A4C214F236B00A5F52?sequence=1, accessed 4 December 2019).
Further reading
Augustine R, Baird A, Bevilacqua A, Cohen N, Coleman RC, Evans J et al. ISPE baseline guide volume 4. Water and steam systems, 3rd ed. North Bethesda (MD): International Society for Pharmaceutical Engineering; 2019.
