制药用水质量指南解释

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200205 CPMP/QWP/158/01 Revision & EMEA/CVMP/115/01Revision 制药用水质量指南解释

------非常感谢：Julia London,May 2002

CPMP/QWP/158/01Revision

EMEA/CVMP/115/01Revision

COMMITTEE FOR PROPRIETARY  MEDICINAL PRODUCTS (CPMP)    COMMITTEE FOR VETERINARY  MEDICINAL PRODUCTS (CVMP)

NOTE FOR GUIDANCE ON QUALITY  OF WATER FOR PHARAMCEUTICAL USE    药用水质量指南解释

DISCUSSION IN THE QUALITY  WORKING PARTY (QWP)	October 2000    January 2001
质量工作组讨论	2000年10月    2001年1月
TRANSMISSION TO THE  CPMP/CVMP	February 2001
转达到CPMP/CVMP	2001年2月
RELEASE FOR CONSULATION	February 2001
公开征求意见	2001年2月
DEADLINE FOR COMMENTS	August 2001
征求意见截止	2001年8月
DISCUSSION IN THE QUALITY  WORKING PARTY (QWP)	October 2001
质量工作组讨论	2001年10月
TRANSMISSION TO CPMP/CVMP	November 2001
转达到CPMP/CVMP	2001年11月
ADOPTION BY CPMP/CVMP	November 2001
CPMP/CVMP采纳	2001年11月
DISCUSSION IN QWP FOLLOWING  INDUSTRY REPRESENTATION    MODIFICATION TO TABLES 3 AND  5	April 2002
在行业意见后质量工作组讨论    对表格3和5进行修订	2002年4月
ADOPTION BY CPMP/CVMP	May 2002
CPMP/CVMP采纳	2002年5月
DATE FOR COMING INTO OPERATION	1 June 2002
生效日期	2002年6月1日

Changes are in:变更

l Table 3 (Final isolation and purificationof API-not sterile but intended for use in sterile parenteral product)

l 表3（无菌肠外制剂用的非无菌原料药的最终分离和纯化）

l Table 5-Initial rinse ofcontainers/closures for sterile products

l 表5-无菌制剂的容器密闭系统的最初淋洗

l Table 5-Final rinse of containers closuresfor sterile parenteral products (addition of footnote).

l 表5—无菌肠外给药产品容器密闭系统的最终淋洗（增加脚注）

NOTE FOR GUIDANCE ON QUALITY  OF WATER FOR PHARAMCEUTICAL USE    药用水质量指南解释

1. INTRODUCTION 介绍

Water is one ofthe major commodities used by the pharmaceutical industry. It may be present asan excipient, 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.

水是制药行业的主要用品之一，可以用作辅料，可以用于产品重组过程、合成过程、制剂生产过程，可以用作容器设备和内包材的清洁剂等。

Different gradesof water quality are required depending on the different pharmaceutical uses.Control of the quality of water, in particular, the microbiological quality, isa major concern and the pharmaceutical industry devotes considerable resourceto the development and maintenance of water purification systems.

根据用途不同对水质有不同要求。水质的控制，特别是微生物质量控制，是主要关注问题。制药行业投入了大量资源来建立和维护水纯化系统。

2. BACKAGROUND 背景

The EuropeanPharmacopoeia (Ph Eur) contains standards for grades of water forpharmaceutical use including Water for injections (WFI) and Purified Water. Theuse of reverse osmosis (RO) as a means of preparing WFI has been the subject ofongoing discussion within the Ph Eur Commission for a number of years. In 1999,in response to requests from national delgations to permit the use of RO forWFI production, a major international symposium was organised to discuss theissue. The meeting concluded that there was insufficient evidence at the presenttime to support the use of RO to produce WFI and in view of the safetyconcerns, WFI should be prepared only by distillation as laid down in the PhEur.

EP有不同级别的水质标准，包括注射用水和纯化水。反渗透作为制备注射用水的方法已经在欧洲药典委员会讨论了多年。1999年，为响应各国代表要求将反渗透水用于注射用水制备的要求，特别组织了一个国际研讨会对此进行讨论。会议认为，现阶段尚无充分的证据来支持使用反渗透方法制备注射用水，因此，出于安全考虑，注射用水只能采用欧洲药典所指出的蒸馏方法制备。

The meetingagreed that further guidance on the use of the different grades ofpharmaceutical water would be beneficial to the industry as the Ph Eurmonographs themselves do not address some of the aspects of when particulargrades should be used. Furthermore as a result of this activity a new Ph Eurmonograph entitled ‘Highly Purified Water’ has been adopted and will beimplemented in the Ph Eur From 1st January 2002.

由于欧洲药典各论中没有规定什么时候需要使用什么级别的水，会议决定将制订一份关于不同级别的药用水的使用指南。另外，决定在新版EP中增加“高纯水”各论，并从从2002年1月1日起开始实施。

The CPMP/CVMPQuality Working Party and Inspectors Working Party have recently reconsideredthe use of RO water for the preparation of WFI. They have concluded on theavailable evidence, that the production of water by RO and associatedtechnologies is considered to lack the robustness of distillation and concernsremain about the potential risks associated with, for example, fouling of themembrane (chemical and biological), failure of membrane integrity and lack ofeffective validation. Hence the current view is the Highly Purified Water isnot acceptable for WFI.

最近，CPMP/CVMP质量工作组和检查工作组重新考虑了采用反渗透作为注射用水制备方法。他们认为，采用反渗透联合其它技术制水工艺不如蒸馏法稳定，关注点仍在于其潜在风险，例如，滤膜上的积垢（化学和微生物），滤膜不完整，缺乏有效验证。因此，目前的观念是高纯水不能用作注射用水。

3. 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 pharmaceuticalingredients and medicinal products for human and veterinary use.

本文件针对人用和兽用制剂和原辅料生产时不同级别用水提供指导。

This guidance isnot intended to cover situations where, for example, medicinal products areprepared extemporaneously or where preparations are reconstituted/diluted withwater prior to use by a pharmacist (e.g. oral antibiotic mixtures) or in thecase of veterinary products, by the user (e.g. sheep dips).

本指南不包括，例如，现场配制制剂、药剂师在药品使用前用水进行重配制/稀释的情况（例如，口服抗生素混合物），以及兽用药品由使用者配制的情况（例如绵羊浸液）。

4. REQUIREMENTSOF THE EUROPEAN PHARMACOPOEIA 欧洲药典要求

The EuropeanPharmacopoeia provides standards for the following grades of water:

欧洲药典提供了以下级别的水标准

l Water for Injections

l 注射用水

l Purified Water

l 纯化水

l Highly Purified Water

l 高纯水

4.1. PotableWater is not coveredby a pharmacopoeial monograph but must comply with the regulations on water laiddown by the competent authority. Testing should be carried out at themanufacturing site to confirm the quality of the water. Potable water may beused in chemical synthesis and in the early stages of cleaning pharmaceuticalmanufacturing equipment unless there are specific technical or qualityrequirements for higher grades of water. It is the prescribed source feed waterfor the production of pharmacopoeical grade waters.
饮用水，没有药典各论，但是必须符合有关当局的法规要求。应在生产场所进行检测以确认水质。除另有更高级别的特定技术或质量要求外，自来水可以用于化学合成较前的步骤，以及生产用设备的前期清洁。它是药典级别用水制备工艺的水源。

4.2. Water forInjections (WFI) is waterfor the preparation of medicines for parenteral administration when water isused as a vehicle (water for injections in bulk) and for dissolving or dilutingsubstances or preparations for parenteral administration before use (sterilizedwater for injections).
注射用水WFI，用于肠外给药产品的生产，作为媒介（散装注射用水），溶液或稀释，或使用前肠外用药的制备（无菌注射用水）。

Production 制备

Control of thechemical purity of WFI presents few major problems. The critical issue is thatof ensuring consistent microbiological quality with respect to removal ofbacteria and bacterial endotoxins. Distillation has a long history of reliableperformance and can be validated as a unit operation, hence it currentlyremains the only official method for WFI.

注射用水的化学纯度控制有几个主要问题(修改为：没有大的问题）。关键的除去细菌和内毒素，保证稳定的微生物质量。蒸馏法历史长，性能可靠，可以作为一个单元操作进行验证，因此目前仍是注射用水唯一的被官方认可的制备方式。

WFI in bulk isobtained from water that complies with the regulation on water intended forhuman consumption laid down by the competent authority, or from purified water,by distillation in a apparatus of which the parts in contact with the water areof neutral glass, quartz or suitable metal and which is fitted with aneffective device to prevent the entrainment of droplets. The correctmaintenance of the apparatus is essential. During production and storage,appropriate measures are taken to ensure that the total viable aerobic count isadequately controlled and monitored.

散装注射用水水源可以符合法定要求的饮用水，或是纯化水，其蒸馏设备中与水直接接触的材质就是中性玻璃、石英或适当金属材料，可以防止液滴带入。设备应进行正确维保，在生产和存贮期间，要采取适当措施保证总需氧菌数受到充分控制和监测。

WFI complieswith the tests for Purified Water with additional requirements for bacterialendotoxins (not more than (nmt) 0.25 IU of endotoxin per ml), conductivity andTotal Organic Carbon.

注射用水应符合纯化水检测要求，以及细菌内毒素（不得过0.25IU/ml），电导率和总有机碳要求。

4.3. PurifiedWater is water for thepreparation of medicinal products other than those that require the use ofwater which is sterile and/or apyrogenic. Purified Water which satisfies thetest for endotoxins may be used in the manufacture of dialysis solutions.
纯化水：用于需无菌和/或热原要求水以外的其它制剂生产。纯化水如果满足内毒素测试要求，可以用于透析液生产。

Production 制备

Purified Wateris prepared by distillation, by ion exchange or by any other suitable method,from water that complies with the regulations on water intended for humanconsumption laid down by the competent authority.

纯化水采用符合官方标准的饮用水，通过蒸馏、离子交换，及其它适当的方法制备。

4.4. HighlyPurified Water is intended for use in the preparation of products where water of highbiological quality is needed, except where Water for Injections is required.
高纯水：用于除需要使用注射用水以外的，有高生物质量要求的制剂生产。

Production 制备

Highly PurifiedWater is obtained from water that complies with the regulations on waterintended for human consumption laid down by the competent authority. Currentproduction methods include, for example, double-pass reverse osmosis coupledwith other suitable techniques such as ultrafiltration and deionization. HighlyPurified Water meets the same quality standards as WFI but the productionmethods are considered less reliable than distillation and thus it isconsidered unacceptable for use as WFI.

高纯水使用符合官方标准的饮用水制备。现行制备方法包括，例如，双向反渗透与其它适当的技术如超滤和去离子技术联用。高纯水与注射用水质量相同，但其制备方法被可靠性认为比蒸馏法差，因此不能用作注射用水。

5. QUALITY OFWATER FOR PHARMACEUTICAL USE 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 GMPinspection.

水纯化、存贮和分配系统的验证和确认是GMP的基本部分，是GMP检查中必不可少的部分。

The grade ofwater used at different stages in the manufacture of the active pharmaceuticalingredients and pharmaceutical products should be discussed in the pharmaceuticaldossier. The grade of water used should take account of the nature and intendeduses of the finished product and the stage at which the water is used.

在申报资料中，要讨论在原料药和制剂不同生产阶段所用的水的级别。在决定水的级别时，要考虑制剂的特性、其用途，以及水所使用的阶段。

The followingtables provide some general examples for guidance:

以下表格提供了一些常规范例作为指南

5.1. Waterpresent as an excipient in the final formulation 制剂中作为辅料出现的水

Water is themost commonly used excipient in medicinal products: the minimum quality ofwater selected depends on the intended use of the product. Table 1 summariesthe main categories of sterile products. WFI is required for those productsintended for parenteral administration and this includes solutions forhaemofiltration and haemodiafiltration, and peritoneal dialysis.

水是制剂中最常见的辅料：所选择的最低水质取决于产品的用途。表1总结了无菌产品的主要种类。非肠道给药制剂要求使用注射用水，包括血液过滤、血液透析过滤和腹膜透析液。

For conveniencethe pharmaceutical industry often uses WFI for the preparation of ophthalmic,sterile nasal/ear and cutaneous preparations. In such situations, HighlyPurified Water represents a useful alternative with the added advantage ofsatisfying the industry’s need for large volumes.

为了方便，制药行业通常使用注射用水制备眼药、无菌鼻剂、无菌耳剂和皮外制剂。这种情况下，由于用量大，高纯水是有用的替代品。

Table 1: SterileMedicinal Products 无菌制剂

Sterile medicinal products    无菌制剂	Minimum acceptable quality  of water    最低水质
Parenteral	WFI
非肠道	注射用水
Ophthalmic	Purified
眼科	纯化水
Haemofiltration Solutions    Haemodiafiltration Solutions    Peritoneal Dialysis  Solutions    Irrigation Solutions	WFI
	WFI
	WFI
血液滤过液    血液透析过滤液    腹膜透析液    灌洗液	注射用水
Nasal/Ear Preparations	Purified
鼻剂/耳剂	纯化水
Cutaneouse Preparations	Purified
皮外用药	纯化水

Table 2summarises the main categories of non-sterile dosage forms. With the exceptionof some nebulizer preparations, Purified Water is the acceptable grade of waterfor all non-sterile products.

表2总结了非无菌制剂的主要类别。除少数喷雾剂外，纯化水适用于其它所有非无菌制剂。

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

Non-sterile medicinal  products    非无菌制剂	Minimum acceptable quality  of water    最低水质
Oral Preparations	Purified
口服制剂	纯化水
Nebuliser Solutions	Purified *
喷雾剂	纯化水
Cutaneouse Preparations	Purified **
皮外用药	纯化水
Nasal/Ear Prearations	Purified
鼻剂/耳剂	纯化水
Rectal/Vaginal Preparations	Purified
直肠/阴道用药	纯化水

* In certaindisease states e.g. cystic fibrosis, medicinal products administered bynebulisation are required to be sterile and non-pyrogenic. In such cases WFI orsterilized Highly Purified Water should be used.
有些疾病，如囊肿纤维化，喷雾剂要求无菌无热原。这种情况下，应使用注射用水或无菌高纯水。

**For someproducts such as veterinary teat dips it may be acceptable to use potable waterwhere justified and authorised taking account of the variability in chemicalcomposition and microbiological quality.
在考虑化学成分和微生物质量等可变性前提下，经过合理证明和批准后，兽用滴剂等产品可以使用饮用水。

5.2. Water usedduring manufacture of active pharmaceutical ingredients and medicinal productsexcluding water present as an exipient in the final formulation 原料药和制剂生产用水，不包括处方中用作辅料的水

The acceptablegrade of water will depend heavily on the stage at which it is to be usedduring manufacture, the subsequent processing steps and the nature of the finalproduct. Tables 3 and 4 summarise the acceptable quality of water for themanufacture of active pharmaceutical ingredients and for sterile andnon-sterile medicinal products.

水的级别很大程度上取决于所用于的生产阶段、后续处理步骤和制剂的性质。表3和表4总结了原料药和无菌、非无菌制剂生产用水质量要求。

Table 3: Waterused during the manufacture of Active Pharmaceutical Ingredients (APIs)

表3：原料药生产用水要求

Type of manufacture    生产类型	Product requirements    产品要求	Minimum acceptable quality  of water 最低水质
Synthesis of all  intermediates of API s prior to final isolation and purification steps	No requirement for sterility  or apyrogenicity in API or the pharmaceutical product in which it will be  used.	Potable Water*
最终分离和纯化前所有中间体的合成	原料药或制剂没有无菌或无热原要求	饮用水
Fermentation media	No requirement for sterility  or apyrogenicity in API or the pharmaceutical product in which it will be  used	Potable Water *
发酵培养基	原料药或制剂没有无菌或无热原要求	饮用水*
Extraction of herbals	No requirement for sterility  or apyrogenicity in API or the pharmaceutical product in which it will be  used	Potable Water **
草药提取	原料药或制剂没有无菌或无热原要求	饮用水**
Final isolation and  purification	No requirement for sterility  or apyrogenicity in API or the pharmaceutical product in which it will be  used	Potable Water*
最终分离和纯化	原料药或制剂没有无菌或无热原要求	饮用水
Final isolation and  purification	API is not sterile, but is  intended for use in a sterile, non-parenteral product	Purified Water
最终分离和纯化	原料药为非无菌，但制剂无菌，非肠外给药	纯化水
Final isolation and  purification	API is sterile and not  intended for parenteral use	Purified Water
最终分离和纯化	原料药无菌，不用于非肠道制剂	纯化水
Final isolation and  purification	API is not sterile, but is  intended for use in a sterile, parenteral product	Purified Water with an  endotoxin limit of 0.25EU/ml and control of specified organisms
最终分离和纯化	原料药非无菌，用于无菌非肠道给药制剂	纯化水，内毒素限度0.25EU/ml，控制致病菌
Final isolation and  purification	API is sterile and  apyrogenic	Water For Injections
最终分离和纯化	原料药无菌无热原	注射用水

* Purified Watershould be used where there are technical requirements for greater chemicalpurity.
如果有更高的化学纯度要求，应使用纯化水。

** The Applicantwould need to demonstrate that potential variations in the water quality,particularly with respect to mineral composition, would not influence thecomposition of the extract.
申请人应声明水质的潜在变化，特别是矿物质成份，不会影响提取物的成分。

Table 4: Waterused during manufacture of medicinal products which is not present in the finalformulation

表4：制剂生产过程中用到，但制剂中不包含的水

Manufacture    生产	Minimum acceptable quality  of water    最低水质
Granulation	Purified *
制粒	纯化水
Tablet coating	Purified
片剂包衣	纯化水
Used in formulation prior to  non-sterile lyophilisation	Purified
非无菌冻干前配方中所用	纯化水
Used in formulation prior to  sterile lyophilisation	WFI
无菌冻干前配方中所用	注射用水

* For someveterinary premix products e.g. granulated concentrates it may be acceptable touse potable water where justified and authorized taking account of thevariability in chemical composition and microbiological quality.
一些兽药的预混剂，如，制粒浓缩液，如果在考虑化学成分和微生物质量前提下进行了论证并获得批准，可以使用饮用水。

5.3. Water usedfor cleaning/rinsing of equipment, containers and closures 设备、包装容器清洁/淋洗用水

In general, thefinal rinse used for equipment containers/closures should use the same qualityof water as used in the final stage of manufacture of the API or used as anexcipient in a medicinal product.

用于设备、包装密闭容器最终淋洗的水应与原辅料最后生产步骤所用水质相同。

Table 5: Water usedfor cleaning/rinsing

表5：清洁/淋洗用水

Cleaning/Rinsing of  Equipment, Containers, Closures    设备、包装密闭容器清洁淋洗用水	Product type    产品类别	Minimum Acceptable quality  of water    最低水质
Initial rinse	Intermediates and API	Potable Water
初次淋洗	中间体和原料药	饮用水
Final rinse	API	Use same quality of water as  used in the API manufacture
最终淋洗	原料药	采用与原料药生产同质水
Initial rinse including CIP*  of equipment, containers and closure, if applicable	Pharmaceutical products-non  sterile	Potable Water
最初淋洗，包括在线清洁最终淋洗（适用时）	非无菌制剂	饮用水
Final rinse including CIP *  of equipment, containers and closures, if applicable	Pharmaceutical products-non  sterile	Purified Water or use same  quality of water as used in manufacture of medicinal product, if higher  quality than Purified Water
最终淋洗，包括在线清洁的最终淋洗（适用时）	非无菌制剂	纯化水，如果制剂生产所用水质高于纯化水，则采用制剂生产用相同水质
Initial rinse** including  CIP* of equipment, containers and closures, if applicable	Sterile products	Purified Water
最初淋洗，包括在线清洁的最初淋洗（适用时）	无菌产品	纯化水
Final rinse*** including  CIP* of equipment, containers and closures, if applicable	Sterile non-parenteral  products	Purified Water or use same  quality of water as used in manufacture of medicinal product, if higher  quality than Purified Water
最终淋洗，包括在线清洁的最终淋洗（适用时）	无菌，非肠外给药产品	纯化水，如果制剂生产所用水质高于纯化水，则采用制剂生产用相同水质
Final rinse*** including  CIP* of equipment, containers and closures, if applicable	Sterile parenteral products	WFI****
最终淋洗，包括在线清洁的最终淋洗（适用时）	无菌肠外给药产品	注射用水

* CIP = Clean InPlace
在线清洁

** Somecontainers, e.g. plastic containers for eyedrops may not need an initial rinse,indeed this may be counter-productive since particulates counts could beincreased as a result. In some cases e.g. blow-fill-seal processes rinsingcannot be applied.
有一些容器，例如，滴眼液用的塑料容器可能不需要最初淋洗，因为淋洗可能会使得颗粒增加而适得其反。在有些情况下，鼓风-充填-密封不能进行淋洗。

*** If equipmentis dried after rinsing with 70% alcohol, the alcohol should be diluted in waterof the same quality as the water used for the final rinse.
如果设备在采用70%乙醇淋洗后进行干燥，则乙醇的稀释用水应与最终淋洗用水同质。

**** Where asubsequent depyrogenisation step is employed the use of Highly Purified Watermay be acceptable subject to suitable justification and validation data.

如果后续采用除热原步骤，且经过适当论证和验证，可以使用高纯水。

冬天的雨

学习学习，好资料

huigenghao

谢谢您的分享。

红茶.

人家为什么用70%乙醇，我们用75%乙醇

北重楼

感谢分享！

北重楼

红茶. 发表于 2015-5-15 07:54
人家为什么用70%乙醇，我们用75%乙醇

乙醇浓度70-75%之间都是有效的，关键是要数据说话的，而且我们的配制单位是否一样，我们是V/V，人家的呢

helufen

    谢谢分享！

幸福萍萍

学习学习，谢谢分享

道路漫长黑暗

谢谢分享，反渗透比蒸馏法节约明显吗，看起来一直有推动力量啊。

syhorchid

谢谢分享

Lorrainechao

本人英文水平缺条腿。

beiwei5du

Lorrainechao 发表于 2015-5-15 15:51
本人英文水平缺条腿。

我现在也在加紧学习呢！一起努力吧！

beiwei5du

4.1. PotableWater is not coveredby a pharmacopoeial monograph but must comply with the regulations on water laiddown by the competent authority. Testing should be carried out at themanufacturing site to confirm the quality of the water. Potable water may be used in chemical synthesis and in the early stages of cleaning pharmaceuticalmanufacturing equipment unless there are specific technical or qualityrequirements for higher grades of water. It is the prescribed source feed waterfor the production of pharmacopoeical grade waters.
饮用水，没有药典各论，但是必须符合有关当局的法规要求。应在生产场所进行检测以确认水质。除另有更高级别的特定技术或质量要求外，自来水可以用于化学合成较前的步骤，以及生产用设备的前期清洁。它是药典级别用水制备工艺的水源。

那么这样的话，自来水公司的“饮用水检测报告”就没有法律效应了！

兰台令史

谢谢，非常感谢。