Executive summary

This guideline replaces the Note for Guidance on 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 Quality of Water used in the production of Vaccines for parenteral use (EMEA/CPMP/BWP/1571/02 rev.1).

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

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

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

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

1.Introduction (background)

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.

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.

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

Until April 2017, the production of Water for Injections (WFI) had been limited to production by distillation only. Following extensive consultation with stakeholders, the Ph. Eur. monograph for Water for Injections (0169) was revised in order to allow the production of WFI by a purification process equivalent to distillation, such as reverse osmosis coupled with appropriate techniques such as electro- deionisation, ultrafiltration or nanofiltration. The revised monograph was published in the Ph. Eur. Supplement 9.1 and became effective on 1 April 2017.

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

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 the test for bacterial endotoxins and the general monograph for Substances for pharmaceutical use (2034). As a consequence, new monographs for substances for pharmaceutical use will no longer include the test for bacterial endotoxins (with possible exceptions). This aspect is now covered by the general monograph, which includes recommendations for establishing limits and information on how to evaluate the pyrogenicity of substances and where, according to the monographs on Parenteral preparations (0520) and Preparations for irrigation (1116), the requirements apply to the finished product.

The opportunity has also been taken to update terminology and requirements to reflect current expectations.

2.Scope

This document is intended to provide guidance to the industry on the pharmaceutical use of different grades of water in the manufacture of active substances and medicinal products for human and veterinary use and should be considered for new marketing authorisation applications, as well as any relevant variation application to existing marketing authorisations.

This guidance also applies to Advanced Therapy Medicinal Products (ATMPs). Where applicable, guidance is provided to include preparation of critical starting materials such as viral vectors and on cell based medicinal products where terminal sterilisation is not possible. For additional specific guidance for Advanced Therapy Medicinal Products, applicants and manufacturers are advised to consult the EC guidelines on Good Manufacturing Practice (GMP) specific to Advanced Therapy Medicinal Products (ATMPs).

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

This guidance is not intended to cover situations where medicinal products are prepared extemporaneously or where preparations are reconstituted/diluted with water prior to use by a pharmacist (e.g. water for reconstituting oral antibiotic mixtures, water for diluting haemodialysis solutions) or in the case of veterinary products, by the user (e.g. sheep dips).

This guideline complements the “Questions and answers on production of water for injections by non- distillation methods – reverse osmosis and biofilms and control strategies EMA/INS/GMP/443117/2017 GMP/GDP Inspectors Working Group” which has been published following the implementation of the revised monograph for Water for Injections (0169) and it is intended that the guideline and Q&A should be read together.

3.Legal basis

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

4.Requirements of the European Pharmacopoeia

The European Pharmacopoeia provides quality standards for the following grades of water:

• Water for Injections

• Purified Water

• Water for preparation of extracts

4.1.Potable Water

Potable Water is not covered by a pharmacopoeial monograph but must comply with the regulations on water intended for human consumption of a quality equivalent to that defined in Directive 98/83/EC, or 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 pharmacopoeial grade waters.

4.2.Water for Injections (WFI)

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 (sterilised water for injections).

For a detailed description 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 be introduced at the local manufacturing site, notice should be given to the GMP supervisory authority of the manufacturer before implementation as described in the Compilation of Community Procedures on Inspections and Exchange of Information.

4.3.Purified Water

Purified Water is water for the preparation of medicines other than those that are required to be both sterile and apyrogenic, unless otherwise justified and authorised.

Purified Water which satisfies the test for endotoxins described in Ph. Eur. monograph 0008 may be used in the manufacture of dialysis solutions.

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

4.4.Water for preparation of extracts

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

For a detailed description of the production and control of Water for preparation of extracts refer to Ph. Eur. Monograph 2249.

5.Quality of Water for Pharmaceutical Use

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.

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

The following tables provide some general examples for guidance:

5.1.Water present as an excipient in the final formulation

Water is the most commonly used excipient in medicinal products: the minimum quality of water selected depends on the intended use of the product, according to a risk based approach to be applied as part of an overall control strategy.

Table 1 summarises 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.

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

Table 2 summarises the main categories of non-sterile dosage forms. With the exception of non-sterile vaccines for non-parenteral use and some nebuliser preparations, Purified Water is the acceptable grade of water for all non-sterile products.

^* WFI is recommended in order to ensure the vaccines’ safety and product quality (avoid introduction of undesirable microorganisms in the finished product formulation) unless otherwise justified (i.e. for some non-sterile veterinary vaccines for non-parenteral use, purified water might be accepted).

^** In certain disease states (eg. cystic fibrosis), medicinal products administered by nebulisation are required to be sterile and non-pyrogenic. In such cases, WFI should be used.

^*** 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.

5.2.Water used during manufacture of active substances and medicinal products excluding water present as an excipient in the final formulation

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, according to a risk based approach to be applied as part of an overall control strategy.

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

^* Purified Water should be used where there are technical requirements for greater chemical purity.

^** Refer to the monograph 2249 “Water for preparation of extracts”.

^*** Appropriate specifications have to be set for endotoxins and specified micro-organism testing of the active substance as per the relevant Ph. Eur. chapters.

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

^* For some veterinary premix products eg. granulated concentrates it may be acceptable to use potable waterwhere justified and authorised taking account of the variability in chemical composition and microbiological quality.

5.3.Water used for cleaning/rinsing of equipment, containers and closures

Washing procedures of the equipment, primary containers and closures normally fall within the field of GMP and are not described routinely in the MA dossier, but may, in certain circumstances, be requested by the competent authority.

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 AS or used as an excipient in a medicinal product.

Table 5 summarises the acceptable quality of water used for cleaning/rinsing of equipment, containers/closures for all medicinal products.

^* CIP = Clean In Place

^** 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.

^*** If equipment is cleaned with diluted detergents or/and dried after rinsing with diluted alcohol, the alcohol or the detergent should be diluted in water of the same quality as the water used for the final rinse.

References

1.Note for Guidance on Quality of water for pharmaceutical use (CPMP/QWP/158/01- EMEA/CVMP/115/01).

2.Ph. Eur. monograph “Water for Injections” (0169).

3.Ph. Eur. monograph “Water for preparation of extracts” (2249).

4.Ph. Eur. monograph “Water, purified” (0008).

5.Ph. Eur. monograph “Parenteral preparations” (0520).

6.Ph. Eur. monograph “Preparations for irrigation” (1116).

7.Ph. Eur. monograph “Substances for pharmaceutical use” (2034) .

8.CPMP Position Statement on the Quality of Water used in the production of Vaccines for parenteral use(EMEA/CPMP/BWP/1571/02 Rev.1).

9.ICH Q9 (Quality risk management), EMA/CHMP/ICH/24235/2006.

10.Questions and answers on production of water for injections by non-distillation methods – reverse osmosis and biofilms and control strategies EMA/INS/GMP/443117/2017 GMP/GDP Inspectors Working Group.

11.Ph. Eur. chapter 5.1.10 “Guidelines for using the test for bacterial endotoxins”

12.Compilation of Community Procedures on Inspections and Exchange of Information, (EMA/572454/2014).

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以下为软件翻译，仅供参考

执行摘要

该准则取代了最初于2002年5月通过的“药品用水质量指导说明”(CPMP/QWP/158/01、EMEA/CVMP/115/01)和“CPMP关于生产肠外使用疫苗所用水质量的立场声明”(EMEA/CPMP/BWP/1571/02 Rev.1)。

指南说明已经更新，以反映“欧洲药典”中的以下变化：

经修订的“注射用水专著”(0169)，允许使用蒸馏法以外的其他方法生产可注射质量的水；

编写萃取物的水的新专著(2249)；

“抑制水”专著，高度净化(1927年)。

1.导言(背景)

水是制药业使用的主要商品之一。它可以作为辅料或用于产品的重组，在合成过程中，在成品的生产过程中，或者作为清洗容器、设备、初级包装材料等的清洗剂。

根据不同的药物用途，需要不同的水质等级。水的质量，特别是微生物质量的控制是一个主要问题，制药工业将相当多的资源用于水净化系统的开发和维护。

欧洲药典(Ph.EUR.)提供药品用水等级的质量标准，包括注射用水(WFI)、纯净水和制备提取物的水。

到2017年4月，注射用水的生产仅限于蒸馏生产。在与利益攸关方广泛协商后，欧盟博士。修订了“注射用水专著”(0169)，以便通过类似蒸馏的净化工艺，如反渗透，再加上适当的技术，如电去离子化、超滤或纳滤，生产WFI。修订后的专著发表在欧盟博士期刊上。补编9.1，2017年4月1日生效。

这一变化带来了欧盟博士。更符合“美国药典”和“日本药典”，允许通过蒸馏或经证明“优于蒸馏”和“蒸馏或反渗透和/或超滤”的净化工艺生产WFI。

此外，欧盟博士。委员会通过了一项新的细菌内毒素检查政策，这反映在修订第5.1.10章“细菌内毒素检验准则”和“制药用物质通用专著”(2034年)中。因此，关于药物用途物质的新专著将不再包括细菌内毒素检查(除可能的例外情况外)。这方面现在由一般专著涵盖，其中包括关于确定限制的建议和关于如何评价物质的热致性的资料，以及根据“肠外制剂”(0520)和“灌溉制剂”(1116)的专著，这些要求适用于成品。

还利用这一机会更新术语和要求，以反映当前的期望。

2.范围

本文件旨在为制药业提供指导，说明在制造供人类和兽医使用的活性物质和医药产品时使用不同等级的水的情况，并应考虑采用新的营销授权申请，以及对现有营销授权的任何相关变更申请。

本指南也适用于先进治疗药物产品(ATMP)。在适用的情况下，提供指导，以包括制备关键的起始材料，如病毒载体和细胞为基础的医药产品，而最终绝育是不可能的。关于高级治疗药物产品的额外的具体指南，申请人和制造商建议咨询针对先进治疗药物产品(ATMPS)的EC良好制造实践指南(GMP)。

在相关情况下，本指南的原则也可适用于调查药品。

本指南不打算涵盖以下情况：医药产品是临时配制的，或制剂在药剂师使用前用水进行重组/稀释(例如，用于重组口服抗生素混合物的水、稀释血液透析溶液的水)，或在兽医产品中由使用者(如羊浸)进行重组/稀释。

该准则补充了“关于非蒸馏法生产注射用水的问题和答案-反渗透和生物膜及控制策略”，该问题和答案是在执行“注射用水问题订正专著”(0169)之后公布的，目的是将该指南和Q&A一并阅读。

3.法律依据

本准则必须与第2001/83/EC号指令附件一导言和一般原则第4和第5节以及第2001/82/EC号指令附件一导言和一般原则第2和第3节一并阅读。

4.欧洲药典的要求

“欧洲药典”规定了以下等级水的质量标准：

注射用水

纯净水

提取液制备用水

4.1.饮用水

饮用水不属于药典专著所涵盖的范围，但必须遵守与第98/83/EC号指令或主管当局规定的同等质量的人类用水条例。应在生产现场进行测试，以确定水的质量。饮用水可用于化学合成和清洗制药制造设备的早期阶段，除非对较高等级的水有具体的技术或质量要求。它是生产药典级水的指定水源。

4.2.注射用水(WFI)

注射用水(WFI)是指当水被用作载体(用于散装注射的水)和溶解或稀释物质或肠外给药制剂(注射用消毒水)时，用于制备用于肠外给药的药物的水。

有关注射用水生产和控制的详细说明，请参阅欧盟博士。专著0169。应该注意的是，当在当地的生产现场引入反渗透时，在执行“共同体检查和信息交流程序”所述的实施之前，应向制造商的GMP监督当局发出通知。

4.3.纯净水

纯净水是用于配制除无菌和无菌药物以外的其他药物的水，除非另有正当理由和授权。

符合Ph.EUR所描述的内毒素检查标准的纯净水。专著0008可用于透析液的制造。

有关纯净水生产和控制的详细说明，请参阅Ph.EUR。专著0008。

4.4.提取液制备用水

配制提取物的水是用于制备草药药物提取物(0765)的水，该水符合专著“纯净水”(0008)中散装纯净水或容器中的纯净水的规定，或者是用于人类消费的质量相当于第98/83/EC号指令所界定的质量的水，根据专著所述的生产部分进行监测。

有关制备提取物的水的生产和控制的详细说明，请参阅Ph.EUR。专著2249。

5.药品用水质量

水的净化、储存和分配系统的验证和鉴定是GMP的一个基本组成部分，是GMP检查的组成部分。

在销售授权申请中，应讨论在生产活性物质和医药产品的不同阶段所使用的水的等级。所用水的等级应考虑到成品的性质和预定用途以及用水的阶段。

下表提供了一些一般性的指导实例：

5.1.水作为赋形剂存在于最终配方中

水是医药产品中最常用的赋形剂：根据作为总体控制战略一部分的基于风险的方法，所选择的水的最低质量取决于产品的预定用途。

表1概述了无菌产品的主要类别。用于肠外给药的产品需要WFI，这包括血液滤过、血液透析和腹膜透析的解决方案。

无菌眼、鼻/耳和皮肤制剂应使用旨在确保不育和避免污染物的引入和微生物生长的材料(水)来配制。根据风险评估，这可能要求使用水质高于纯净水的水。

无菌药用产品水生物制剂(包括疫苗和ATMP)的最低可接受质量

表2概述了非无菌剂型的主要类别.除非肠外使用的非无菌疫苗和一些雾化制剂外，纯净水是所有非无菌产品可接受的水等级。

GB/T1459.1-1993非消毒药用产品非肠外净水疫苗的最低可接受质量纯净水雾化溶液净化水*皮肤制剂纯净水*鼻/耳制剂纯净水/阴道制剂净化水*皮肤制剂净水*鼻/耳制剂净化水/阴道制剂净化水*皮肤制剂净化水*鼻/耳制剂净化水/阴道制剂净化水

建议使用WFI，以确保疫苗的安全性和产品质量(避免在成品配方中引入不受欢迎的微生物)，除非另有正当理由(即对于一些非肠外使用的非无菌兽医疫苗，可接受纯净水)。

*在某些疾病状态下(例如。(囊性纤维化)，由星云给药的药物必须是无菌的和非致热的.在这种情况下，应使用WFI。

*某些产品，例如兽医奶嘴，在考虑到化学成分及微生物质素的差异后，在合理及获授权的情况下使用食水，是可以接受的。

5.2.生产活性物质和医药产品时使用的水，不包括作为最终配方中赋形剂的水

可接受的水等级将在很大程度上取决于在制造过程中使用的阶段、随后的加工步骤和最终产品的性质，这是根据一种基于风险的方法，作为总体控制战略的一部分。

表3概述了制造活性物质的最低可接受水质。

制造类型.产品要求.在最终分离和纯化步骤前，AS的所有中间体的水合成的最低可接受质量.对其使用的AS或医药产品的无菌性或无菌性没有要求.饮用水*发酵介质是用于制造化学实体(即半合成产品)的.饮用水*发酵培养基和细胞培养介质用于制造生物制品(即疫苗和重组生物制品)。纯净水的所有步骤包括发酵培养基、细胞培养基、初始纯化、最终分离和纯化。AS用于制造ATMP。也适用于原料药，如用于制造ATMP的病毒载体。WFIExtration中草药无不育性或无生殖性的要求，在AS或医药产品中使用它将用于制备提取物*任何步骤排除最后分离和纯化(例如发酵，(初步净化)如生物及拟用于肠系膜外用途(ATMP除外)。净化水的分离和纯化不要求AS或其将使用的医药产品的无菌性或无育性。饮用水*最终分离和净化AS不是无菌的，而是用于制备非肠外用途的非无菌疫苗。净化的水分离和净化AS不是无菌的，目的是用于无菌的、非肠道外的产品。净水分离和净化AS是无菌的，不打算用于肠系膜外的用途。纯净水分离和净化AS不是无菌的，而是打算用于无菌的、肠外产品。纯净水*最后的分离和净化AS(生物)是在溶液中，而不是无菌的，但它是用于无菌的，无菌的，无菌的；无菌的

如果有更高的化学纯度的技术要求，就应该使用纯净水。

*参见专著2249“编写提取物的水”。

*必须制定适当的规格，以便按照有关的Ph.EUR对活性物质进行内毒素和特定微生物检查。各章。

表4概述了生产无菌和非无菌医药产品的可接受水质。

GB/T1459.1-1988水颗粒纯净水最低可接受质量纯净水在非无菌冻干前用纯净水在无菌冻干粉前用纯净水

一些兽药预混料产品，如。在考虑到化学成分和微生物质量的变化的情况下，在合理和授权的情况下使用饮用水是可以接受的。

5.3.用于清洗/冲洗设备、容器和封口的水

设备、主要容器和闭锁的清洗程序通常属于GMP领域，在MA档案中没有经常说明，但在某些情况下，主管当局可以提出要求。

一般而言，用于设备、容器/封口的最后冲洗应使用与制造砷的最后阶段相同的水质，或作为药用产品中的辅料使用。

表5概述了用于清洗/冲洗所有医药产品的设备、容器/封口的水的可接受质量。

清洗/冲洗设备、容器、灌装水的可接受质量如适用.医药产品-非甾体纯净水或使用与制造医药产品所用的水质相同的水，如质量高于纯净水如适用.非肠外产品清洁水或使用与医药产品生产相同质量的水，如质量高于纯净水，包括设备、容器和封闭物的CIP*，如适用，则为WFI.

CIP=就地清洁

*有些容器，例如盛有滴眼液的塑胶容器，可能不需要初步清洗，这可能会适得其反，因为微粒数量可能因此而增加。在某些情况下，如吹填密封工艺，冲洗不能应用。

*如设备是用稀释洗涤剂清洗或/或用稀释酒精冲洗后干燥的，则酒精或洗涤剂应在与最后冲洗所用的水相同的水质中稀释。

Refreences

1.关于药品用水质量指南的说明(CPMP/QWP/158/01-EMEA/CVMP/115/01)。

2.Ph.EUR.专著“注射用水”(0169)。

3.Ph.EUR.专著“制备提取物的水”(2249)。

4.Ph.EUR.专著“水，净化”(0008)。

5.Ph.EUR.专著“肠外制剂”(0520)。

6.Ph.EUR.专著“灌溉准备”(1116)。

7.Ph.EUR.专著“药用物质”(2034年)。

8.CPMP关于生产肠外使用疫苗所用水质量的立场声明(EMEA/CPMP/BWP/1571/02 Rev.1)。

9.Ich Q9(质量风险管理)，EMA/CHMP/ICH/24235/2006。

10.关于非蒸馏法生产注射用水的问题和答案-反渗透和生物膜及控制策略(EMA/INS/gmp/443117/gmp/gdp检查员工作组)。

11.Ph.EUR.第5.1.10章“细菌内毒素检查使用指南”

12.“共同体监察和信息交流程序汇编”(EMA/572454/2014)。