CPMP/QWP/158/01 Revision
EMEA/CVMP/115/01 Revision
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) | |
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TRANSMISSION TO THE CPMP/CVMP | |
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DISCUSSION IN THE QUALITY WORKING PARTY (QWP) | |
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TRANSMISSION TO CPMP/CVMP | |
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DISCUSSION IN QWP FOLLOWING INDUSTRY REPRESENTATION MODIFICATION TO TABLES 3 AND 5 | |
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DATE FOR COMING INTO OPERATION | |
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Changes are in:变更
l Table 3 (Final isolation and purification of 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 of containers/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 closures for 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 of the major commodities used by the pharmaceutical industry. It may be present as an excipient, or used for reconstitution of products, during synthesis, during production 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 grades of water quality are required depending on the different pharmaceutical uses. Control of the quality of water, in particular, the microbiological quality, is a major concern and the pharmaceutical industry devotes considerable resource to 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 European Pharmacopoeia (Ph Eur) contains standards for grades of water for pharmaceutical use including Water for injections (WFI) and Purified Water. The use of reverse osmosis (RO) as a means of preparing WFI has been the subject of ongoing 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 for WFI production, a major international symposium was organised to discuss the issue. The meeting concluded that there was insufficient evidence at the present time to support the use of RO to produce WFI and in view of the safety concerns, WFI should be prepared only by distillation as laid down in the Ph Eur.
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 meeting agreed that further guidance on the use of the different grades of pharmaceutical water would be beneficial to the industry as the Ph Eur monographs themselves do not address some of the aspects of when particular grades should be used. Furthermore as a result of this activity a new Ph Eur monograph entitled ‘Highly Purified Water’ has been adopted and will be implemented 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/CVMP Quality Working Party and Inspectors Working Party have recently reconsidered the use of RO water for the preparation of WFI. They have concluded on the available evidence, that the production of water by RO and associated technologies is considered to lack the robustness of distillation and concerns remain about the potential risks associated with, for example, fouling of the membrane (chemical and biological), failure of membrane integrity and lack of effective validation. Hence the current view is the Highly Purified Water is not 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 is intended to provide guidance to the industry on the pharmaceutical use of different grades of water in the manufacture of active pharmaceutical ingredients 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 is not intended to cover situations where, for example, medicinal products are prepared extemporaneously or where preparations are reconstituted/diluted with water prior to use by a pharmacist (e.g. oral antibiotic mixtures) or in the case 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. REQUIREMENTS OF THE EUROPEAN PHARMACOPOEIA 欧洲药典要求
The European Pharmacopoeia 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. Potable Water is not covered by a pharmacopoeial monograph but must comply with the regulations on water laid down by the competent authority. Testing should be carried out at the manufacturing site to confirm the quality of the water. Potable water may be used in chemical synthesis and in the early stages of cleaning pharmaceutical manufacturing equipment unless there are specific technical or quality requirements for higher grades of water. It is the prescribed source feed water for 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 for Injections (WFI) is water for the preparation of medicines for parenteral administration when water is used as a vehicle (water for injections in bulk) and for dissolving or diluting substances or preparations for parenteral administration before use (sterilized water 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 the chemical purity of WFI presents few major problems. The critical issue is that of ensuring consistent microbiological quality with respect to removal of bacteria and bacterial endotoxins. Distillation has a long history of reliable performance and can be validated as a unit operation, hence it currently remains the only official method for WFI.
注射用水的化学纯度控制有几个主要问题。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 is obtained from water that complies with the regulation on water intended for human 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 are of neutral glass, quartz or suitable metal and which is fitted with an effective device to prevent the entrainment of droplets. The correct maintenance of the apparatus is essential. During production and storage, appropriate measures are taken to ensure that the total viable aerobic count is adequately 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 complies with the tests for Purified Water with additional requirements for bacterial endotoxins (not more than (nmt) 0.25 IU of endotoxin per ml), conductivity and Total 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. Purified Water is water for the preparation of medicinal products other than those that require the use of water which is sterile and/or apyrogenic. Purified Water which satisfies the test 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 Water is prepared by distillation, by ion exchange or by any other suitable method, from water that complies with the regulations on water intended for human consumption 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. Highly Purified Water is intended for use in the preparation of products where water of high biological 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 Purified Water is obtained from water that complies with the regulations on water intended for human consumption laid down by the competent authority. Current production methods include, for example, double-pass reverse osmosis coupled with other suitable techniques such as ultrafiltration and deionization. Highly Purified Water meets the same quality standards as WFI but the production methods are considered less reliable than distillation and thus it is considered 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 OF WATER FOR PHARMACEUTICAL USE 药用水质量
Validation and qualification of water purification, storage and distribution systems are a fundamental 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的基本部分，是GMP检查中必不可少的部分。
The grade of water used at different stages in the manufacture of the active pharmaceutical ingredients and pharmaceutical products should be discussed in the pharmaceutical dossier. The grade of water used should take account of the nature and intended uses 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 following tables 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. Water present as an excipient in the final formulation 制剂中作为辅料出现的水
Water is the most commonly used excipient in medicinal products: the minimum quality of water selected depends on the intended use of the product. Table 1 summaries the main categories of sterile products. WFI is required for those products intended for parenteral administration and this includes solutions for haemofiltration 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 convenience the pharmaceutical industry often uses WFI for the preparation of ophthalmic, sterile nasal/ear and cutaneous preparations. In such situations, Highly Purified Water represents a useful alternative with the added advantage of satisfying 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: Sterile Medicinal Products 无菌制剂
Sterile medicinal products 无菌制剂 | Minimum acceptable quality of water 最低水质 |
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Haemofiltration Solutions Haemodiafiltration Solutions Peritoneal Dialysis Solutions Irrigation Solutions | |
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Table 2 summarises the main categories of non-sterile dosage forms. With the exception of some nebulizer preparations, Purified Water is the acceptable grade of water for 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 |
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Rectal/Vaginal Preparations | |
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* In certain disease states e.g. cystic fibrosis, medicinal products administered by nebulisation are required to be sterile and non-pyrogenic. In such cases WFI or sterilized 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 some products such as veterinary teat dips it may be acceptable to use potable water where justified and authorised taking account of the variability in chemical composition 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 used during manufacture of active pharmaceutical ingredients and medicinal products excluding 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 acceptable grade of water will depend heavily on the stage at which it is to be used during manufacture, the subsequent processing steps and the nature of the final product. Tables 3 and 4 summarise the acceptable quality of water for the manufacture of active pharmaceutical ingredients and for sterile and non-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: Water used 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 | | 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. | |
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| No requirement for sterility or apyrogenicity in API or the pharmaceutical product in which it will be used | |
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| No requirement for sterility or apyrogenicity in API or the pharmaceutical product in which it will be used | |
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Final isolation and purification | No requirement for sterility or apyrogenicity in API or the pharmaceutical product in which it will be used | |
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Final isolation and purification | API is not sterile, but is intended for use in a sterile, non-parenteral product | |
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Final isolation and purification | API is sterile and not intended for parenteral use | |
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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 |
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Final isolation and purification | API is sterile and apyrogenic | |
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* Purified Water should be used where there are technical requirements for greater chemical purity.
如果有更高的化学纯度要求，应使用纯化水。
** The Applicant would need to demonstrate that potential variations in the water quality, particularly with respect to mineral composition, would not influence the composition 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: Water used during manufacture of medicinal products which is not present in the final formulation
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 |
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Used in formulation prior to non-sterile lyophilisation | |
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Used in formulation prior to sterile lyophilisation | |
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* For some veterinary premix products e.g. granulated concentrates it may be acceptable to use potable water where justified and authorized taking account of the variability 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 used for cleaning/rinsing of equipment, containers and closures 设备、包装容器清洁/淋洗用水
In general, the final rinse used for equipment containers/closures should use the same quality of water as used in the final stage of manufacture of the API or used as an excipient 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 used for 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 | | Minimum Acceptable quality of water 最低水质 |
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| | Use same quality of water as used in the API manufacture |
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Initial rinse including CIP* of equipment, containers and closure, if applicable | Pharmaceutical products-non sterile | |
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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 |
| | 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 | | |
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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 |
| | 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 | |
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* CIP = Clean In Place
在线清洁
** Some containers, e.g. plastic containers for eyedrops may not need an initial rinse, indeed this may be counter-productive since particulates counts could be increased as a result. In some cases e.g. blow-fill-seal processes rinsing cannot 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 equipment is dried after rinsing with 70% alcohol, the alcohol should be diluted in water of 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 a subsequent depyrogenisation step is employed the use of Highly Purified Water may 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。
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发表于 2014-5-11 08:59:41
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