欧盟《制药用水质量指南》2020版（中英文对照）！

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）。

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 JapanesePharmacopoeia, 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。

4. Requirements of the European Pharmacopoeia 欧洲药典的要求

The European Pharmacopoeia provides quality standards for thefollowing grades of water:

欧洲药典为以下级别的水设置了质量标准：

·        Water for Injections

·        注射用水

·        Purified Water

·        纯化水

·        Water for preparation of extracts

·        提取用水

4.1. Potable Water 饮用水

Potable Water is notcovered by a pharmacopoeial monograph but must comply with the regulations on waterintended for human consumption of a quality equivalent to that defined inDirective 98/83/EC or laid down by the competent authority. Testing should becarried out by the manufacturer to confirm the quality of the water. Potablewater may be used during the manufacture of active substances and in the earlystages of cleaning pharmaceutical manufacturing equipment unless there arespecific technical or quality requirements for higher grades of water. It isthe prescribed source feed water for the production of pharmacopoeial gradewaters.

饮用水没有药典专论，但必须符合欧盟指令 98/83/EC 中规定的人用饮用水质量要求，或各成员国相关机构规定的标准。生产商应进行检测，以确认水质。饮用水可用于 API 和平，可用于清洁较前工艺用药品生产设备，有特定技术或要求使用更高质量水者除外。它是指定用于制备制药用水的源水。

4.2. Water for Injections (WFI)注射用水（WFI）

Water for Injections(WFI) is water for the preparation of medicines for parenteral administrationwhen water is used as a vehicle (water for injections in bulk) and fordissolving or diluting substances or preparations for parenteral administration(sterilised water for injections).

WFI是注射用药品制备用水，这时水是载体（散装注射水），用于溶解或稀释药用物质或制备注射给药的制剂（灭菌的注射水）。

For a detaileddescription of the production and control of Water for Injections refer to Ph.Eur. monograph 0169. It should be noted that when reverse osmosis is to beintroduced at the local manufacturing site, notice should be given to the GMPsupervisory authority of the manufacturer before implementation as described inthe Compilation of Community Procedureson Inspections and Exchange ofInformation.

注射用水的制备和检测详细信息参见 EP 专论 0169。应注意如果在生产工厂本地使用了反渗透制备方法，则应按“欧盟检查和信息交换程序汇编”所述在实施之前向生产商的GMP监管机构提交通知。

4.3. Purified Water 纯化水

Purified Water is waterfor the preparation of medicines other than those that are required to be bothsterile and apyrogenic, unless otherwise justified and authorised.

纯化水是不需要无菌或除热原的药品制备用水，另有论证和批准者除外。

Purified Water whichsatisfies the test for endotoxins described in Ph. Eur. monograph 0008 may beused in the manufacture of dialysis solutions.

符合 EP 专论 0008 中所述内毒素检测要求的纯化水可用于透析液的生产。

For a detaileddescription of the production and control of Purified Water refer to Ph. Eur.monograph 0008.

纯化水的制备和检测详细信息参见 EP 专论 0008。

4.4. Water for preparation of extracts 提取用水

Water for preparationof extracts is water intended for the preparation of Herbal drug extracts(0765) which complies with the sections Purified water in bulk or Purifiedwater in containers in the monograph Purified water (0008), or is waterintended for human consumption of a quality equivalent to that defined inDirective 98/83/EC which is monitored according to the Production sectiondescribed in the monograph.

提取用水是草药提取物（0765）生产用水，应符合纯化水专论（0008）中散装纯化水或容器中的纯化水章节的要求，或指令 98/83/EC 中规定的人用水质要求。该水应根据专论中生产章节进行监测。

For a detailed description of the production and control of Water forpreparation of extracts refer to Ph.

Eur. Monograph 2249.

提取用水的制备和检测详细信息参见 EP 专论 2249。

5. Quality of Water for Pharmaceutical Use 制药用水质量

Validation andqualification of water purification, storage and distribution systems are afundamental part of GMP and form an integral part of the GMP inspection.

水纯化、存贮和分配系统的验证和确认是 GMP 的必要部分，是GMP 检查中不可分割的一部分。

The grade of water usedat different stages in the manufacture of active substances and medicinalproducts should be discussed in the marketing authorisation application. Thegrade of water used should take account of the nature and intended use of thefinished product and the stage at which the water is used.

API和制剂生产的不同步骤所用水的级别应在上市许可申报资料中进行讨论。所用水的级别选择应考虑制剂的特性和使用途径，以及水被使用的步骤。

The following tables provide some general examples for guidance:

下表中给出了一些通用例子作为指导：

5.1. Water present as an excipient in the final formulation 作为最终制剂的辅料的水

Water is the mostcommonly used excipient in medicinal products: the minimum quality of waterselected depends on the intended use of the product, according to a risk basedapproach to be applied as part of an overall control strategy.

水是制剂中最常用的辅料：所选用水的最低质量取决于药品的用途，应采用基于风险的方法，将其作为整体控制策略的一部分。

Table 1 summarises themain categories of sterile products. WFI is required for those productsintended for parenteral administration and this includes solutions forhaemofiltration and haemodiafiltration, peritoneal dialysis, irrigationsolution and biologics.

表1 中汇总了无菌药品的主要类别。用于注射的药品需要使用 WFI，其中包括血液滤过和血液透析、腹膜透析、冲洗液和生物制剂。

Sterile ophthalmic,nasal/ear and cutaneous preparations should be prepared using materials (water)designed to ensure sterility and to avoid the introduction of contaminants andthe growth of micro-organisms. According to the risk assessment, this couldrequire the use of water of higher quality than purified water.

无菌眼膏、鼻/耳剂和皮肤制剂应使用能保证无菌性的原料（水）进行生产，避免引入污染物，避免微生物繁殖。根据风险评估，这些可能要求使用比纯化水质量更高的水。

Table 1: Sterile Medicinal Products 表 1：无菌药品

表 2 汇总的是非无菌制剂剂型的主要类别

Table 2: Non-sterile Medicinal Products 表 2：非无菌制剂

Non-sterile medicinal	非无菌制剂	Minimum acceptable  quality	最低可接受水质
products		of water
Vaccines for non-parenteral use	非注射疫苗	Purified Water*	纯化水*
Oral Preparations	口服制剂	Purified Water	纯化水
Nebuliser Solutions	雾化溶液	Purified Water**	纯化水**
Cutaneous Preparations	皮肤制剂	Purified Water***	纯化水***
Nasal/Ear Preparations	鼻/耳剂	Purified Water	纯化水
Rectal/Vaginal Preparations	直肠/阴道用药	Purified Water	纯化水

*According to the outcomes of the riskassessment, WFI may be required in some cases for manufactureof non-sterile vaccines where in order toensure the vaccines’ safety and quality (avoiding introduction ofmicroorganisms undesirable in the specific finished product formulation)greater microbiological purity of water is needed.

根据风险评估结果，为确保疫苗的安全性和和高于纯化水微生物纯度的质量（避免在特定制剂中引入不期望的微生物）有些非无菌疫苗的生产可能需要使用 WFI。

**In certain diseasestates (e.g. cystic fibrosis), medicinal products administered by nebulisationare required to be sterile and non-pyrogenic. In such cases, WFI should beused.

在有些疾病状态下（例如，囊性纤维化），需要通过无菌和无热源雾化摄入药品。这种情况下要使用 WFI。

***For some productssuch as veterinary teat dips, it may be acceptable to use potable water wherejustified and authorised taking account of the variability in chemicalcomposition and microbiological quality.

有些药品如兽用乳头浸蘸剂，可能可以使用饮用水，在论证和批准时要考虑化学组成和微生物质量的波动。

5.2. Water used during manufacture of active substances and medicinalproducts excluding water present as an excipient in the final formulation 不作为最终制剂辅料的原料药和制剂生产中所用水

The gradeof water will depend on the stage at which it is to be used during manufacture,the subsequent processing steps and the nature of the final product, accordingto a risk based approach to be applied as part of an overall control strategy.

水的级别取决于其在生产中所用的步骤，后续的处理步骤，以及成品的特性。应采用基于风险的方法，将其作为全面控制策略的一部分。

Table 3 summariseS the minimum acceptable quality of water for the manufacture of activesubstances.

表3 中汇总了API 生产用水最低可接受质量

Table 3: Water used during the manufacture ofActive Substances (AS)

表 3：活性物质（AS）生产用水

* Purified Water should be used where there are technical requirementsfor greater chemical purity.

如果对化学纯度有更高的技术要求，则应使用纯化水

**  Refer to the monograph 2249 “Water forpreparation of extracts”.

参见 EP 专论 2249“提取用水”

***Appropriate specifications have to be set forendotoxins and microbiological quality of the active substance as per the relevantPh. Eur. chapters.

必须根据相关的 EP 章节为AS 制订恰当的内毒素和微生物质量标准

****Appropriate specifications have to be set formicrobiological quality of the active substance as per the relevant Ph. Eur.chapters.

必须根据相关的 EP 章节为AS 制订恰当的微生物质量标准

Table 4 summarises the acceptable quality ofwater for the manufacture of sterile and non-sterile medicinal products.

表 4 中汇总了无菌和非无菌药品生产用水的可接受质量

Table 4: Water used during manufacture ofmedicinal products but not present in the final formulation

表 4：不是最终制剂成分的制剂生产用水

* For some veterinary premix products (e.g.granulated concentrates) it may be acceptable to use potable water wherejustified and authorised taking account of the variability in chemicalcomposition and microbiological quality.

有些兽用预混剂（例如制粒浓缩剂）可使用饮用水，前提是在论证和批准时要考虑化学组成和微生物质量的波动性。

5.3. Water used for cleaning/rinsing ofequipment, containers and closures 设备、容器和密闭器清洁/淋洗用水

Washing procedures of the equipment, primarycontainers and closures normally fall within the field of GMP and are notdescribed routinely in the MA dossier, but may, in certain circumstances, berequested by the competent authority.

设备、内包容器和密闭器的清洗程序一般在 GMP 范围内，一般不会在MA 文档中进行说明，但在特定情形下可能药监当局会索取这方面信息。

In general, the final rinse used forequipment, containers/closures should use the same quality of water as used inthe related manufacturing stage associated with the intermediates or the AS orused as an excipient in that specific medicinal product.

一般来说，设备、容器/密闭器的最终淋洗水应与中间体或 AS 或相关生产步骤所用具有等同质量，或与特定制剂用作辅料的水质相同。

If equipment is cleaned with diluteddetergents and/or dried after rinsing with diluted alcohol, the alcohol or thedetergent should be diluted in water of the same quality as the water used forthe final rinse.

如果设备采用稀释后的清洁剂清洁，和/或在采用稀释后的乙醇淋洗后干燥，则乙醇或清洁剂应稀释用水应与最终淋洗用水的质量相同。

Table 5 summarises the acceptable quality ofwater used for cleaning/rinsing of equipment, containers/closures for allmedicinal products.

表5 中汇总了所有制剂类型的设备、容器/密闭器清洁/淋洗用水的可接受质量

Table 5: Water used for cleaning/rinsing. 表 5：清洁/淋洗用水

*  CIP = Clean In Place 原位清洁

**Some containers, e.g. plastic containers foreyedrops may not need an initial rinse, indeed this may be counter-productivesince particulates counts could be increased as a result. In some cases e.g.blow-fill-seal processes rinsing cannot be applied.

有些容器如滴眼剂所用塑料容器可能不需要初次淋洗，实际上可能适得其反，因为这样可能会增加微粒数量。在某些情况下如吹灌封工艺中，是无法冲洗的。

*** For injection for veterinary use, PurifiedWater may be used for cleaning/rinsing of equipment, containers, closures, ifthe preparation falls into the exempted category from test for bacterialendotoxins (2.6.14) or test for pyrogens (2.6.8) by the Ph. Eur. monograph “Parenteralpreparations” (0520). In this case, a risk based approach to justify the use ofpurified water instead of WFI must be implemented as part of an overall controlstrategy and particularly to ensure sterility and to avoid the introduction ofcontaminants and the growth of micro-organisms in the final product.

对于兽用注射剂，设备、容器、密闭器清洁/淋洗可使用纯化水，如果根据 EP 专论“注射剂（0520）”，该制剂可免于检测细菌内毒素（2.6.14）和热原（2.6.8）。在此情况下，必须基于风险对使用纯化水而不是 WFI 的做法进行论证，将其作为全面控制策略的一部分，尤其要确保无菌性，避免引入污染物，避免制剂中微生物的滋生。