欧盟《制药用水质量指南》2020版（下）

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

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

*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

* 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

*  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。