1. INTRODUCTION
Water is widely used as a raw material, inactive ingredient, medicinal vehicle, and solvent in the processing, formulation, and manufacture of pharmaceutical products (dosage forms), active pharmaceutical ingredients (APIs), API intermediates, compendial articles, and analytical reagents as well as in cleaning applications.
水被广泛用作原料、非活性成分、药物载体和溶剂，用于制药产品(剂型)、活性药物成分(API)、API中间体、药典用品和分析试剂的加工、配方和制造以及清洁应用。
This is an informational chapter on pharmaceutical water topics and includes some of the chemical and microbiological concerns unique to water and its preparation and uses. The chapter provides information about water quality attributes (that may or may not be included within a water monograph) and processing techniques that can be used to improve water quality. It also discusses water system validation and gives a description of minimum water quality standards that should be considered when selecting a water source including sampling and system controls. It is equally important for water systems to be operated and maintained in a state of control to provide assurance of operational stability and therefore the capability to provide water that meets established water quality standards.
这是一个关于制药用水主题的信息章节，包括水及其制备和使用所特有的一些化学和微生物问题。本章提供了关于水质属性的信息(可能包括在水质专论中，也可能不包括在内)和可用于改善水质的处理技术。它还讨论了水系统验证，并给出了在选择水源时应考虑的最低水质标准的描述，包括采样和系统控制。同样重要的是，供水系统在可控状态下运行和维护，以确保运行的稳定性，从而确保提供符合既定水质标准的水的能力。
This informational chapter is intended to be educational, and the user should also refer to existing regulations or guidelines that cover U.S. and international [International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) or World Health Organization (WHO)] good manufacturing practice (GMP) issues, as well as operational and engineering guides and/or other regulatory guidance for water [e.g., from the Food and Drug Administration (FDA), Environmental Protection Agency (EPA), or WHO]. This chapter is not, and should not be considered, an all-inclusive document on pharmaceutical waters. It contains basic information and points to be considered for the processing, holding, monitoring, and use of water. It is the user’s responsibility to ensure that:
本信息章的目的是教育性的，用户还应参考涵盖美国和国际上[国际人类用药技术要求协调委员会(ICH)或世界卫生组织(WHO)]发布的良好生产规范(GMP)的现有法规或指南，以及操作和工程指南和/或水的其他监管指南[例如，食品和药物管理局(FDA)，环境保护署(EPA)或世卫组织]。本章不是，也不应该被认为是关于制药水的全面文件。它包含了处理、保存、监测和使用水时需要考虑的基本信息和要点。用户有责任确保:
1.The selection of the type and specifications of water is appropriate for its intended use.
水的类型和规格标准的选择应适合其预期用途。
2.Water production and quality meet applicable governmental regulations and guidance.
水的生产和质量符合适用的政府法规和指导。
3.The pharmacopeial specifications for the types of water used in monographed articles are met.
符合专论正文中所使用的水的类型药典标准。
4.Water used in the preparation of reagents for analysis or the performance of required tests meets USP requirements.
用于制备分析试剂或执行所需测试的水符合USP要求。
Control and monitoring of the chemical and endotoxin purity of waters are important for complying with the requirements of the monographs in this compendium. Attributes listed in USP monographs should be considered the “minimum” requirements. More stringent requirements may be needed for some applications to ensure suitability for particular uses. Basic guidance on the appropriate applications of waters can be found in the monographs and is also discussed further in this chapter.
Control of the microbiological quality of water is also important for many of its uses. This attribute is intentionally not specified in most water monographs. Microbiological control is discussed throughout this chapter, but especially in sections 4. Validation and Qualification of Water Purification, Storage, and Distribution Systems, 5. Design and Operation of Purified Water and Water for Injection Systems, 6. Sampling, 8. Microbial Evaluations, and 9. Alert and Action Levels and Specifications.
控制和监测水的化学和内毒素纯度是重要的，以符合本药典各论的要求。USP各论中列出的属性应被视为“最低”要求。对于某些应用可能需要更严格的要求，以确保对特定用途的适用性。关于适当水的使用基本指导可在各专题中找到，本章也将进一步讨论。对水的许多用途来说，控制水的微生物质量也很重要。故而，在大多数水专论中，不再特意指出此属性。微生物控制贯穿本章，特别是第4节-水净化、储存和分配系统的验证和确认。5-纯净水和注射用水系统的设计和操作;6-取样; 8-微生物评估;9-警戒和行动限和规格。
This chapter contains various chemical, microbiological, processing, and engineering concepts of importance to users of water. Water system validation, process control levels, and specifications are also presented later in this chapter.
本章包含了对用户来说很重要的各种化学、微生物、加工和工程概念。水系统验证、过程控制水平和规范也将在本章后面介绍。
2.SOURCE WATER CONSIDERATIONS
Source water is the water that enters the facility. The origin of this source water can be from natural surface waters like rivers and reservoirs, deep-bed well waters, sea waters, or some combination of these, potentially including multiple locations of each type of source water. Thus, source water can be supplied from these various origins (public or private), from municipalities’ on-site water sourcing, or by external delivery such as a truck. It is possible that source water may not be potable and safe to drink. Such water may require pretreatment to ensure that it meets drinking water standards. It is the responsibility of the users of any source water to ensure that the water used in the production of drug substances (API), as well as water for indirect drug product contact or for purification system feed water purposes meets, at a minimum, drinking (potable) water standards as defined by the requirements of the National Primary Drinking Water Regulations (NPDWR) (40 CFR 141) issued by the U.S. EPA or the drinking water regulations of the European Union (EU) or Japan, or the WHO drinking water guidelines (see 3.3.1 Drinking Water). These regulations establish limits on the types and quantities of certain chemical and microbiological contaminants and ensure that the water will contain safe quantities of chemical and microbial species.
源水是进入设施的水。源水的来源可以是自然地表水，如河流和水库，深床井水，海水，或这些的某种组合，可能包括每种类型水源的多个位置。因此，水源水可以从这些不同来源(公共或私人)、从市政当局的现场水源或通过外部运输，如卡车提供。水源可能不适合饮用和不安全。这类水可能需要预处理以确保符合饮用水标准。用户有责任确保任何来源的水用于生产药物物质(API),以及间接药物产品接触或用水净化系统给水符合目的,至少, 饮用水(适合饮用)应符合相关国家标准所定义的要求（由美国环保署发布的国家饮用水条例的要求(NPDWR) (40 CFR 141)、欧盟(EU)或日本的饮用水法规,或世界卫生组织饮用水准则(见3.3.1饮用水)。这些条例规定了某些化学和微生物污染物的种类和数量的限制，并确保水将含有安全数量的化学和微生物类型。
Where water supplies are from regulated water utility companies, less stringent monitoring may be possible because the attributes may be tested regularly and ensured by the supplier (see 9.4.5 Source Water Control). Water being withdrawn from a nonregulated supply should be sampled and tested appropriately at a suitable frequency that takes into account local environmental and seasonal changes and other quality fluctuations. Testing should ensure conformance with one of the drinking water standards discussed above.
如果供水来自受监管的水务公司，则可能不太严格的监测，因为供应商可以定期测试并确保这些属性(见9.4.5水源水控制)。在考虑到当地环境和季节变化以及其他质量波动的情况下，从不受管制的供水中提取的水应以适当的频率进行取样和适当测试。检测应确保符合上述饮用水标准之一。
The use of water complying with one of these designated drinking waters as a source water allows water pretreatment systems to only be challenged to remove small quantities of potentially difficult-to-remove chemicals. Control of objectionable chemical contaminants at the source water stage eliminates the need to specifically test for some of them [e.g., trihalomethanes and elemental impurities (see Elemental Impurities—Limits 232)] after the water has been further purified, assuming there is no opportunity for recontamination.
使用符合这些指定饮用水中的一种作为水源的水，使得水预处理系统仅需要去除少量可能难以去除的化学物质。在水源阶段对不良化学污染物的控制，假设后续工艺中没有再污染的机会，这消除了在水经过进一步净化后对其中一些污染物(例如三卤甲烷和元素杂质(见元素杂质-限值× 232 ×))进行专门检测的必要性。
Source waters can be used for nonproduct contact purposes such as for non-contact cooling systems. Such water may not normally be required to meet drinking water standards. Under such circumstances, the quality standards for this water when used in a pharmaceutical facility should be subject to quality standards established by the user and defensible to regulatory agencies.
水源水可用于非产品接触用途，如非接触冷却系统。这类水通常不需要达到饮用水标准。在这种情况下，在制药设施中使用这种水的质量标准应服从用户建立的质量标准，并可向监管机构辩护。
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3.WATERS USED FOR PHARMACEUTICAL MANUFACTURING AND TESTING PURPOSES
There are many different grades of water used for pharmaceutical purposes. Several are described in USP monographs that specify uses, acceptable methods of preparation, and quality attributes. These waters can be divided into two general types: bulk waters, which are typically produced on-site where they are used; and sterile waters, which are produced, packaged, and sterilized to preserve microbial quality throughout their packaged shelf life. There are several specialized types of sterile waters that differ in their designated applications, packaging limitations, and other quality attributes. Monographed waters must meet the quality attributes as specified in the related monographs, and any Notes appearing in those monographs should be considered and addressed.
用于制药用水有不同等级。一些等级在USP专著中描述，指定用途，有可接受的制备方法和质量属性。这些水可分为两种一般类型:散装水，通常在使用它们的现场生产;和无菌水，生产，包装，灭菌，以在其包装的货架寿命期保持微生物质量。有几种特殊类型的无菌水，它们在指定的应用、包装限制和其他质量属性上有所不同。专论水必须符合有关专论中规定的质量属性，在这些专论中出现的任何注释都应予以考虑和处理。
With the exception of Bacteriostatic Water for Injection, the monographed bulk and sterile waters have a statement indicating that there are no added substances, or no added antimicrobial agents. In the case of antimicrobial agents, the purpose is to ensure that the sterile water product is rendered sterile based solely on its preparation, packaging, and storage. In the case of the more general statement, “no added substances”, this requirement is intended to mean “no added substances that aren’t sufficiently removed”. Two specific examples support this intention, but there are many examples. First, the use of softeners is commonplace. A softener replaces calcium and magnesium ions ▲(also known as hardness ions)▲ 1S (USP41) with sodium, so technically you are adding two sodium ions for each hard ion. The purpose of sodium displacement is to protect downstream equipment from the hard water. The sodium ions are eventually removed sufficiently, and this is proven when the water sample passes the test in Water Conductivity 645. Another specific example is the use of ozone as a sanitant that is added to the storage tank for microbial control. This could be considered an added substance, unless the ozone is destroyed before use, as is normally the case. Other notable examples include the addition of chlorine to kill bacteria in the pretreatment system, use of bisulfite to chemically reduce chlorine to chloride and protect downstream equipment, and use of a nitrogen blanket for protection from atmospheric contamination.
除抑菌注射用水外，单独的散装水和无菌水均有无添加物质或无添加抗菌剂的说明。有抗菌剂的情况是，其目的是确保无菌水产品仅根据其制备、包装和储存而达到无菌状态。更通常的“无添加物质”的情况下，此要求意在表示“无未充分去除的添加物质”。这样的例子很多，有两个具体的例子支持这种释义。首先，软化剂的使用很普遍。软化剂用钠置换钙和镁离子 (也称为硬度离子)，所以从技术上讲，是在两个钠替换一个硬度离子。钠离子最终被充分去除，排钠的目的是保护下游设备不受硬水的影响。当水样能够符合 水电导率< 645 >的测试时，就证明了这一点。另一个具体的例子是使用臭氧作为一种消毒剂，添加到储罐中以控制微生物。除非像通常情况那样，臭氧在使用前被破坏，这可以被认为是一种添加物质。其他值得注意的例子包括在预处理系统中添加氯以杀死细菌，使用亚硫酸氢盐以化学方式将氯还原为氯化物并保护下游设备，以及使用充氮保护免受大气污染。
There are also other types of water for which there are no monographs. These are waters with names given for descriptive purposes only. Many of these waters are used in specific analytical methods. The descriptive titles may imply certain quality attributes or modes of preparation, but these nonmonographed waters may not necessarily adhere strictly to the stated or implied modes of preparation or specified attributes. Waters produced by other means or controlled by other test attributes, or even a monographed water, may equally satisfy the intended uses for these waters. It is the user’s responsibility to ensure that such waters, even if produced and controlled exactly as stated, are suitable for their intended use. Wherever the term “water” is used within this compendium without other descriptive adjectives or clauses, the intent is that water of no less purity than USP Purified Water be used (see 3.1.1 Purified Water). A brief description of the various types of waters commonly associated with pharmaceutical applications and their significant uses or attributes follows.
还有其他类型的水没有专论。这些水的名称仅用于描述目的。这些水中有许多用于特定的分析方法。描述性标题可能暗示某些质量属性或制备模式，但这些非专论水不一定严格遵守所述或特指的制备模式或指定属性。由其他方法产生的水或由其他测试属性控制的水，甚至是专论的水，都可以同样满足这些水的预期用途。用户有责任确保这些水，即使完全按照规定生产和控制，也适用于其预期用途。在本大纲中使用“水”一词时，不使用其他描述性形容词或从句，其目的是使用不低于USP纯化水的水(见3.1.1纯化水)。下面简要说明与制药应用有关的各种类型的水及其重要用途或属性。
Figure 1 may be helpful in understanding some of the various types of waters, their preparation, and uses.
图1可能有助于理解一些不同类型的水，它们的制备和用途。
3.1Bulk Monographed Waters and Steam
The following waters are generally produced in large volumes using a multiple-unit operation water system. These waters are typically distributed in a piping system for use at the same site.
以下水通常使用多单元操作水系统大量生产。这些水通常分布在同一地点使用的管道系统中。
3.1.1PURIFIED WATER
Purified Water (see the USP monograph) is used as an excipient in the production of nonparenteral preparations and in other pharmaceutical applications, such as the cleaning of nonparenteral product-contact components and equipment. Unless otherwise specified, Purified Water is also to be used as the minimum water quality for all tests and assays in which “water” is indicated (see General Notices, 8.230.30 Water in a Compendial Procedure). This applies regardless of the font and letter case used in its spelling.
纯净水(见USP专论)在非注射剂的生产和其他制药应用中用作辅料，如非注射产品接触组件和设备的清洗。除非另有规定，在所有标明“水”的测试和分析中，也应使用纯净水作为最低水质(见总则，8.230.30药典程序中的水)。无论在拼写中使用什么字体和字母大小写，这都适用。
The minimal quality of source water for the production of Purified Water is Drinking Water whose attributes are prescribed by the U.S. EPA, EU, Japan, or WHO. This source water may be purified using unit operations that include deionization, distillation, ion exchange, reverse osmosis, filtration, or other suitable purification procedures. Purified Water must meet the requirements for ionic and organic chemical purity and must be protected from microbial contamination. Purified Water systems must be validated to reliably and consistently produce and distribute water of acceptable chemical and microbiological quality. Purified Water systems that function under ambient conditions are particularly susceptible to the establishment of biofilms of microorganisms, which can be the source of undesirable levels of viable microorganisms or endotoxins in the water.
These ambient Purified Water systems require frequent sanitization and microbiological monitoring to ensure that the water reaching the points of use has appropriate microbiological quality.
生产纯净水的最低质量水源是饮用水，其属性符合美国环保署、欧盟、日本或世界卫生组织的规定。这种水源水可以通过除离子、蒸馏、离子交换、反渗透、过滤或其他适当的净化程序进行净化。纯化水必须满足离子和有机化学纯度的要求，必须防止微生物污染。纯化水系统必须经过验证，以可靠、稳定地生产和分配化学和微生物质量合格的水。在受控环境条件下运行的纯化水系统特别容易受到产生的微生物生物膜的影响，这可能是水中活性微生物或内毒素的不良水平的来源。这些环境纯净水系统需要经常进行消毒和微生物监测，以确保到达使用点的水具有适当的微生物质量。
The Purified Water monograph also allows bulk packaging for commercial use elsewhere. In contrast to Sterile Purified Water, packaged Purified Water is not required to be sterile. Because there is potential for microbial contamination and other quality changes in this packaged nonsterile water, this form of Purified Water should be prepared and stored in a manner that limits microbial growth, and/or should be used in a timely fashion before microbial proliferation renders it unsuitable for its intended use. Also, depending on the material used for packaging, extractable compounds could be leaching into the water from the packaging. Although this article is required to meet the same chemical purity standards as the bulk water, extractables from the packaging will likely render the packaged water less chemically pure than the bulk water. The nature of these impurities may even render the water an inappropriate choice for some applications. It is the user’s responsibility to ensure fitness for use of this packaged article when it is used in manufacturing, clinical, or analytical applications where the purer bulk form of the water is indicated.
纯化水各论也允许散装包装的商业用途在其他地方。与无菌纯化水相比，包装的纯化水不需要无菌。由于这种包装的非无菌水可能存在微生物污染和其他质量变化，这种形式的纯化水应以限制微生物生长的方式制备和存储，并/或应在微生物增殖使其不适合其预期用途之前及时使用。此外，可萃取化合物可能从包装浸出到水中，这取决于用于包装的材料。虽然这种产品需要满足与散装水相同的化学纯度标准，但从包装中提取的物质可能会使包装水的化学纯度低于散装水。这些杂质的性质甚至可能使水成为某些应用的不适当选择。当使用包装水应用在应更纯净的散装形式的水的情形，如用于生产、临床或分析应用时，用户有责任确保其适用性。
