European Medicines Agency Inspections
EMA检查部
London, 5 March 2008
Doc. Ref. EMEA/CHMP/CVMP/QWP/28271/2008
Reflection Paper on
Water for Injection Prepared by Reverse Osmosis
反渗透法制备注射水的讨论
SCOPE 范围
This paper outlines why it is currently not considered acceptable to usereverse osmosis for the production of water for injections (WFI).
本文概括了目前反渗透水尚未不被接受用于注射用水生产的原因。
In view of recent technological advancements in this field, this paperaims to stimulate discussion on this topic.
在对该领域最近的技术发展进行了总结后，本文对此问题进行了讨论。
INTRODUCTION 概述
Today the use of reverse-osmosis to prepare WFI is considered acceptableby the US Pharmacopoiea, however stringent requirements regarding validationand maintenance are required by the US FDA.
目前，采用反渗透法制备注射用水被美国药典认为是可以接受的，但是，US FDA要求对该类系统制订更严格的验证和维护要求。
The European Pharmacopoeia requires that WFI must be prepared bydistillation. Reverse osmosis is not considered acceptable in the EEA,according to the recommendations of the Note for Guidance on Quality of Waterfor Pharmaceutical Use (CPMP/QWP/158/01 - EMEA/CVMP/115/01).
欧洲药典要求注射用水必须采用蒸馏方法制备。根据“药用水质指南解释”(CPMP/QWP/158/01 - EMEA/CVMP/115/01)，反渗透方法在EEA是不被接受的。
Considering economical and practical industrial aspects, it is oftenclaimed that this technological approach should be accepted by EEA CompetentAuthorities. The major objections concern range of separation for reverseosmosis, validation and maintenance of devices and microbiological aspects.
出于经济考虑以及实用性，经常有人说EEA药监当局应该接受该技术。反应意见主要担心的事情从反渗透分离技术、水系统的验证和维护以及微生物方面。
RANGE OF SEPARATION FOR REVERSE OSMOSIS 反渗透分离的范围
Municipal water may contain contaminants such as chlorine and volatileorganic chemicals. Because these contaminants are physically smaller in sizethan water, the semi-permeable membrane used in reverse osmosis cannot preventthem from passing through with the treated water. Moreover, there are no testmethods currently available that would effectively identify all possible toxiccontaminants in water.
市政供水可能会含有一些污染物，例如氯和挥发性有机化学物。由于这些污染物的尺寸一般比水分子小，反渗透所用的半透膜无法阻止其通过膜进入处理后的水中；并且，目前也没有检验方法可以有效地识别出水中所有可能的有毒污染物。
VALIDATION AND MAINTENANCE OF DEVICES 水系统的验证和维保
The reverse osmosis device must be validated to prepare a quality of wateridentical with water prepared by distillation. It appears that many devicesavailable on the market are not designed for such a use.
反渗透装置必须经过验证其可以生产与蒸馏制备水一样品质的水。实际上市售的许多装置并不是为此目的而设计的。
Maintenance of systems used for reverse osmosis is considered criticalparticularly regarding mechanical resistance of organic membranes subjected tohigh pressure and because of microbiological concerns. The development ofceramic membranes may allow these problems to be resolved.
反渗透系统的维护被认为是非常关键的，特别是考虑到有机膜要承受较高压力，以及微生物的原因。陶制膜或许可以解决该问题。
MICROBIOLOGICAL ASPECTS 微生物方面
The major microbiological problem is biofilm formation. 主要的微生物问题是会形成微生物膜
l Biofilm formation onboth sides of the RO membrane begins within minutes of the unit being switchedon.
l 在系统开户后数分钟内，RO膜两侧都会生成生物膜
l The biofilm on theupstream side concentrates a wide variety of metabolic by-products. Theconcentration is sufficient for these to pass through the membrane.
l 进水侧的生物膜浓缩了大量代谢副产物，其浓度之高足以使其通过反渗透膜
l Biofilm consists of awide variety of gram positive and gram negative bacteria.
l 生物膜由大量革兰氏阳性菌和革兰氏阴性菌组成
l Pathogenic bacteriaare commonly found in biofilms, especially Mycobacteria.
l 在生物膜中常会发现致病菌，特别是分歧杆菌
l Biofilms cannot bedestroyed. Any attempt by using biocides, temperature, etc. results in a rapidincrease in growth following treatment.
l 生物膜不会被摧毁。使用杀菌剂、升温等方式只会使得菌快速滋长
l Biofilm can form onthe permeate side of the membrane in the following ways:
l 以下情况可能使出水侧形成生物膜
n Through microscopicholes and tears in the membrane.
n 通过膜上的微孔和破洞
n If the permeate sideof the membrane is not sterile.
n 如果RO膜的出水侧不是无菌条件
n Through flexing andbending as pressure increases due to decreasing flux as the biofilm builds up.
n 由于进水侧生物膜增加，膜通透率降低，使膜面凹陷弯曲
l Biofouling ofmembranes will begin within a few minutes of operation of the system.
l 系统开启后几分钟内反渗透膜上即开始形成生物垢
l The biofilm willbuild up and become increasingly resistant to sanitisation by hot water orchemicals because of the glycocalyx material.
l 生物膜会增加并由于糖被的原因对热水或化学消毒产生越来越大的抗性
l RO is a percentageremoval system: the higher the concentration of micro-organisms, the moremetabolic by-products, exotoxins, etc.will pass through the membrane.
l 反渗透系统是一种按比例清除系统：微生物的浓度越高，就会有越多的代谢副产物、内毒素等通过反渗透膜
l The net effect isthat the RO membrane will become, in practice, a bacterial fermenter. Asbacteria in the biofilm grow and metabolise, a range of metabolic by productswill be secreted which will include proteins and carbohydrates, some of whichmay be biologically active. These contaminants are not easily identified andquantified.
l 结果就是反渗透膜会变成微生物滋生器。由于生物膜中菌的生产及代谢，分泌产生许多代谢产物，包括蛋白和碳水化合物，其中一些物质具有生物活性。这些污染很难被鉴别和定量。
CONCLUSION 结论
Today it is not possible to assume that the quality of WFI prepared byreverse-osmosis is as safe as water prepared by distillation according to therequirement of the European Pharmacopoeia.
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