Guidelineon the quality of water for pharmaceutical use

制药用水质量指南

This guideline replaces the Note for guidanceon quality of water for pharmaceutical use (CPMP/QWP/158/01 EMEA/CVMP/115/01)and CPMP Position Statement on the Quality of Water used in the production ofVaccines for parenteral use (EMEA/CPMP/BWP/1571/02 Rev.1).

本指南取代“制药用水质量指南说明”（CPMP/QWP/158/01 EMEA/CVMP/115/01）和CPMP《注射疫苗生产用水质量立场声明》（EMEA/CPMP/BWP/1571/02 rev.1）。

一Executive summary 执行摘要

This guideline replaces the Note for Guidanceon quality of water for pharmaceutical use (CPMP/QWP/158/01, EMEA/CVMP/115/01)originally adopted in May 2002, and the CPMP Position Statement on the Qualityof Water used in the production of Vaccines for parenteral use(EMEA/CPMP/BWP/1571/02 rev.1).

本指南取代 2002 年 5 月生效的《制药用水质量指南说明》

（CPMP/QWP/158/01, EMEA/CVMP/115/01），和CPMP《注射疫苗生产用水质量立场声明》（EMEA/CPMP/BWP/1571/02 rev.1）。

The note for guidance has been updated to reflect the followingchanges in the European Pharmacopoeia:

此次对指南说明进行了更新，反映出欧洲药典中的以下变化：

revised monograph for Water for Injections(0169) allowing the possibility to use methods other than distillation forproducing water of injectable quality;

注射用水（0619）专论修订内容，修订后允许使用非蒸馏方法制备注射用水；

new monograph for Water for preparation of extracts (2249);

新订提取用水专论（2249）；

suppression of the monograph for Water, highly purified (1927).

废除高纯水专论（1927）

The guideline has alsobeen updated to reflect current expectations for the minimum acceptable qualityof water used in the manufacture of active substances and medicinal productsfor human and veterinary use.

本指南亦进行了更新，以反映目前对人用与兽用 API 和制剂生产用水的最低可接受质量标准要求。

1、Introduction (background) 概述（背景）

Water is one of themajor utilities used by the pharmaceutical industry. It may be present as anexcipient or used for reconstitution of products, during synthesis, duringproduction of the finished product or as a cleaning agent for rinsing vessels,equipment, primary packaging materials, etc.

水是制药行业所用的主要公用系统之一。它可以作为辅料使用，亦可用于药品调配；可用于合成，亦可用于制剂生产，或作为清洁剂用于淋洗贮罐、设备、内包材等。

Different grades of water quality are requireddepending on the different pharmaceutical uses. Control of the quality ofwater, in particular the microbiological quality, is a major concern and thepharmaceutical industry devotes considerable resource to the development andmaintenance of water purification systems.

不同级别的水质量由药品的不同用途决定。水质检测，尤其是微生物质量，是重要的关注点，制药企业都会投入相当大的资源建设和维护制水系统。

The European Pharmacopoeia (Ph. Eur.) providesquality standards for grades of water for pharmaceutical use including Waterfor Injections (WFI), Purified Water and Water for preparation of extracts.

欧洲药典提供了不同级别制药用水的质量标准，包括注射水（WFI）、纯化水和提取用水。

Until April 2017, the production of Water forInjections (WFI) had been limited to production by distillation only. Followingextensive consultation with stakeholders, the Ph. Eur. monograph for Water forInjections (0169) was revised in order to allow the production of WFI by apurification process equivalent to distillation, such as reverse osmosis, whichmay be single-pass or double-pass, coupled with other appropriate techniquessuch as electro-deionisation, ultrafiltration or nanofiltration. The revisedmonograph was published in the Ph. Eur. Supplement 9.1 and became effective on1 April 2017.

2017 年 4 月前，注射水的制备仅限于使用蒸馏方法。在广泛征求利益相关人意见之后，EP 修订了注射用水专论（0169），允许采用等同于蒸馏的纯化工艺制备 WFI，例如反渗透方法，可以是单通道，亦可以是双通道，配以其它适当的技术如电除盐、超滤或纳滤。修订后的专论已在 EP9.1 中发布，于 2017 年 4 月 1 日生效。

This change brings thePh. Eur. more closely in line with the US Pharmacopeia and the Japanese Pharmacopoeia, allowing production of WFI by distillation or by a purificationprocess proven “equivalent or superior to distillation”, and “by distillationor by reverse osmosis and/or ultrafiltration”, respectively.

该变化使用EP 与 USP 和 JP 更为接近，后 2 者分别允许使用蒸馏和其它被证明“等同或优于蒸馏的”纯化工艺，“通过蒸馏或反渗透和/或超滤”制备 WFI。

In addition, the Ph.Eur. Commission has adopted a new policy for the test for bacterial endotoxins,reflected in the revision of general chapter 5.1.10 Guidelines for using thetest for bacterial endotoxins and the general monograph for Substances forpharmaceutical use (2034). As a consequence, new monographs forsubstances for pharmaceutical use will no longer include the test for bacterialendotoxins (with possible exceptions). This aspect is now covered by thegeneral monograph, which includes recommendations for establishing limits andinformation on how to evaluate the pyrogenicity of substances and where,according to the monographs on Parenteral preparations (0520) and Preparationsfor irrigation (1116), the requirements apply to the finished product.

此外，EP 委员会已通过了新的细菌内毒素检查方针，反映在通则 5.1.10“细菌内毒素检测使用指南”和“药用物质（2034）”通论的修订版本中。这样，新的药用物质通论将不再包括细菌内毒素检测（可能有例外）。目前该内容由通论覆盖，其中包括了建立限度的建议和如何评估药用物质热原性的信息。根据注射剂（0520）专论和灌注剂（1116）专论，上述这些要求均适用于制剂。

Theopportunity has also been taken to update terminology and requirements toreflect current expectations.

同时我们还借此机会更新了术语和要求，以反映出目前的期望。

2、Scope 范围

This document isintended to provide guidance to the industry on the pharmaceutical use ofdifferent grades of water in the manufacture of active substances and medicinalproducts for human and veterinary use and should be considered for newmarketing authorisation applications, as well as any relevant variationapplication to existing marketing authorisations.

本文件旨在为制药企业提供人用和兽用 API 和制剂生产中所用的不同级别制药用水的指南。新的上市许可申报，以及对现有 MA 的任何相关变更申报均应考虑本指南。

This guidance alsoapplies to Advanced Therapy Medicinal Products (ATMPs). Where applicable,guidance is provided to include preparation of critical starting materials suchas viral vectors and on cell based medicinal products where terminalsterilisation is not possible. For additional specific guidance for AdvancedTherapy Medicinal Products, applicants and manufacturers are advised to consultthe EC guidelines on Good Manufacturing Practice (GMP) specific to AdvancedTherapy Medicinal Products (ATMPs).

本指南亦适用于先进治疗药品（ATMP）。在适用时，指南包括有关键起始物料的制备，如病毒载体和无法进行最终灭菌的基于细胞的药品。关于 ATMP 的其它专用指南，建议申报人和生产者查询 EC 的 ATMP GMP 指南。

Where relevant, the principles of this guideline may also be appliedto investigational medicinal products.

本指南亦可用于临床试验用药品（如相关）。

This guidance is notintended to cover the water used in situations where medicinal products areprepared extemporaneously or where preparations are reconstituted/diluted withwater prior to use by a pharmacist/user (e.g. water for reconstituting oralantibiotic mixtures, water for diluting haemodialysis solutions) or in the caseof veterinary products, by the user (e.g. powder for use in drinking water).

本指南不包括临时制备药品或药师/使用者在使用之前重新调配/稀释制剂的情况（例如，重新调配口服抗菌混合物所用的水，稀释血液透析溶液所用水），以及用户配制兽药时所用水（例如，用于饮用水的粉末）。

This guidelinecomplements the “Questions and answers on production of water for injections bynon-distillation methods – reverse osmosis and biofilms and control strategiesEMA/INS/GMP/443117/2017 GMP/GDP Inspectors Working Group” which has beenpublished following the implementation of the revised monograph for Water forInjections (0169) and it is intended that the guideline and Q&A should beread together.

本指南补充在注射用水（0169）修订之后为其实施所发布的“非蒸馏方法（反渗透和生物膜）制备注射用水和控制策略问答 MA/INS/GMP/443117/2017 GMP/GDP 检查工作组”。本指南应与该问答指南一起解读。

3、 Legal basis 法规依据

Thisguideline has to be read in conjunction with the introduction and generalprinciples sections 4 & 5 of Annex I to Directive 2001/83/EC and theintroduction and general principles section 2 & 3 of Annex I to Directive2001/82/EC.

本指南应与欧盟指令 2001/83/EC 附录 1 第 4&5 节概述和通则，以及指令 2001/82/EC 附录 1 的第 2&3 节通则一起解读。

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