ISPE_07.制药用蒸汽

PHARMACEUTICAL STEAM 制药用蒸气 7. PHARMACEUTICAL STEAM 7. 制药用蒸气 7.1 INTRODUCTION 7.1 序论 This chapter aims to simplify and standardize the process of selection, programming, and design of pharmaceutical steam systems. Guidelines, information, and options are provided, along with advantages and disadvantages, based on the best and most cost effective of current and proven practices and technologies. 本章旨在简化以及标准化制药用蒸气系统的选择、规划和设计。并以现行和已被证明的最好的和成本效应最高的实践和工艺为根据，给出一些指导方针、信息资料和选项，以及优缺点。 The absence of regulations governing the use of steam in pharmaceutical processes has resulted in the proliferation of differing practices and interpretations. Most interpretations are made on the side of conservatism. Unfortunately, in addition to increasing cost without an associated increase in benefits, excessive conservatism can result in system complexity, and possibly reduced reliability. One example is the use of clean steam (non-utility boiler produced steam) where a form of utility steam (utility boiler produced steam) would be adequate to maintain product quality. The installation of a clean steam generator when a simple steam reducing station would suffice results in added equipment and the associated impact on cost, complexity, and reliability. 在制药工艺中指导蒸气使用的法规缺乏导致衍生出不同实践和理解。大多数理解是保守的。不幸的是，这除了增加成本外没有相应的增加利益，过度的保守能够导致系统复杂并且可能减少其可靠性。举个例子，在一种公用蒸气（公用锅炉产生的蒸气）就足以维持产品质量的地方使用清洁蒸气（非公用锅炉产生的蒸气），在一个普通蒸气简化装置就能满足需要时安装一个清洁蒸气发生器，这导致设备增加并在成本，复杂性以及可靠性方面造成相关影响。 In some instances, interpretations are based on inaccurate assumptions of what is important or critical. An example is the over specifying of pretreatment or using WFI as feed to solve the perceived problem. 在某些情况中，理解是建立在不准确假设“什么是重要或关键的”基础上的。举个例子，比如过度规定预处理或使用注射用水作为给水来解决那些已察觉的问。 The chapter establishes standard definitions for terms commonly associated with pharmaceutical steam and provides information that facilitates making correct and cost effective decisions. 本章为制药用蒸气相关的术语制定了标准定义，并为促使作出正确和成本有效的决定提供了信息。 7.2 cGMP ISSUES 7.2 cGMP出版物 The user has the ultimate responsibility for system design and performance, and for ensuring that the proper type of steam is used for a given process. 用户对系统的设计和性能拥有最终并要确保适当类型的蒸气用于给定的工艺。 There is no FDA or USP minimum standard for clean steam. However, cGMPs for large volume parenterals (LVPs) issued in 1976 indicated that feed water for boilers supplying steam that contact components, drug products, and drug product contact surfaces shall not contain volatile additives such as amines or hydrazines. 对于清洁蒸气，FDA或USP没有最低标准。然而，1976年发行的cGMP关于大容量注射液部分明供应蒸气的锅炉的给水、接触组件、药品和药品接触面不能包含挥发性添加剂比如胺或联胺。 Few regulations govern the design and construction of clean steam generators. There are also no regulations governing materials of construction, type or level of instrumentation, surface finishes, or operating temperatures. 很少法规管理清洁蒸气发生器的设计和构造，也没有法规管理构造材料、使用仪器的类型和等级、表面抛光或操作温度。 Among US Government publications, the FDA's Code of Federal Regulations (CFR) provides culinary steam recommendations and stipulations related to heat exchanger and tank air vents design and construction. The Culinary steam recommendations apply to food applications only. 在美国政府出版物中，FDA的联邦管理法规(CFR)提供厨房用蒸气的优点和关于热交换器及水罐排气口设计、构造的规定。建议厨房用蒸气只用于食品应用。 US Public Health Service/Dairy Industry Committee, 3A Sanitary Standards, Number 609-02, adds additional limitations to Culinary steam feed water additives for food applications. It should be noted that boiler feed water additives permitted in food for human consumption may not be acceptable in drinking water or orally ingested drug products. 美国公共卫生部门/乳制品工业委员会，3A卫生标准，编号609-02，为食品应用而对厨房用蒸气给水添加剂增加附加限制。应该注意人用食品中的锅炉给水添加剂不能用于饮用水或口服药品。 7.2.1 Steam Attributes 7.2.1 蒸气特质 7.2.1.1 Quality 7.2.1.1 质量 The term "Quality" when referring to steam indicates the level of steam saturation. There are no FDA or USP regulations relating to minimum "steam quality" or the level of non-condensable gasses present in pharmaceutical steam. (See Section 7.4.) 当涉及蒸气时，“质量”术语表示蒸气饱和标准。没有关于最低“蒸气质量”或在制药用蒸气中不可压缩气体标准的FDA或USP法规。（参看7.4部分） European regulators have defined specific criteria for pharmaceutical steam used for equipment sterilization. (European Standard EN 285 - Steam Sterilizers - reference section 13.3) These cover acceptable levels of saturation or dryness, the level of superheat, and the volume of non-condensable gases present. 欧洲法规对用于设备灭菌的制药用蒸气规定了具体标准。(欧洲标准EN 285-蒸气灭菌器-参考13.3部分)。这些包含饱和或干燥标准、过热标准和不可压缩气体体积。 7.2.7.2 Purity 7.2.7.2 纯度 Purity requirements for steam used in pharmaceutical manufacturing and product development are driven by the product characteristics, manufacturing process, and the intended use of the product. The product manufacturer is responsible for ensuring that steam used to process the product is appropriate. 用于制药生产和产品研制的蒸气纯度要求由产品特性、生产工艺和产品预期用途决定。药品生产商有责任确保将合适的蒸气用于药品生产。 Though steam purity requirements are product specific, it may be impractical to reliably produce special steam for each situation. Manufacturing operations typically generate and distribute only one or two steam purity grades, commonly grouped. 虽然蒸气纯度要求是因产品特性而不同，但为每个情况可靠地生产特殊蒸气是不实用的。生产操作典型地产生和分配一般分组为一种或两种的蒸气纯度等级。 7.3 TYPES OF STEAM 7.3 蒸气类型 Pharmaceutical steam is classified into two (2) types based on their respective sources. These are: 1) Utility-Boiler produced steam, hereafter called Utility Steam. 2) Non-Utility Boiler produced steam, hereafter called Clean Steam. 根据它们各自的来源，制药用蒸气分为两种类型。它们是： 1)公用锅炉产生的蒸气，此后叫做公用蒸气。 2)非公用锅炉产生的蒸气，此后叫做清洁蒸气。 7.3.1 Utility Steam 7.3.1 公用蒸气 Utility steam is characterized with usually having: • Chemical additives to control scale and corrosion • Relatively high pressure with the potential of generating superheat during expansion • Relatively high pH 公用蒸气通常具有以下特征： • 用于控制水垢和腐蚀产物的化学添加剂 • 伴随在膨胀时产生过热潜在性的相对高压 • 相对的高pH值 Chemical additives: Utility steam is produced, in most cases, using conventional fire-tube steam boilers, normally of steel construction. Such boilers are almost always provided with systems that inject additives in the feed water to protect the boiler and steam distribution piping from scale and corrosion. Some of these scale and corrosion inhibitors may, and often do, include amines and other substances that may not be acceptable in steam being used in pharmaceutical processes. The user must determine what additives are used, and verify if they are acceptable in the particular application, i.e., do not add any impurities or create a reaction in the drug product. 化学添加剂：在多数实例中，使用常规钢结构火管蒸气锅炉产生公用蒸气。这种锅炉几乎总是规定在给水中注入添加剂来保护锅炉和蒸气分配管道以免产生水垢和腐蚀。一部分这些水垢和腐蚀抑制剂可能并且经常使用，包括胺和不适用于制药工艺所用蒸气的其他物质。用户必须决定使用哪种添加剂并且验证它们是否可适用于特定应用，比如，不能在药品中添加任何杂质或产生反应。 Utility steam can be filtered to remove particulate matter, but filtration does not remove dissolved substances and volatiles such as amines. 可以过滤公用蒸气除去颗粒物，但是滤器无法去除已溶解物质和挥发物比如胺。 Superheat: Superheated steam is produced in water tube boilers by reheating the steam or by generating the steam at a higher pressure in a fire tube boiler and then reducing the pressure through a regulating valve. When the pressure is reduced, the energy in the higher temperature steam is dissipated to generate steam at the lower pressure and produce superheated steam above the corresponding saturation temperature. Superheat is dissipated downstream of the regulating valve due to heat loss in the line. 过热：在水管锅炉中通过再加热蒸气产生过热蒸气或者在火管锅炉中通过在更高的压力下产生蒸气然后使用调节阀减低压力来产生过热蒸气。当压力减低时，较高温度蒸气中的能量消散会产生较低压力下的蒸气并同时产生超过相应饱和温度的过热蒸气。由于管线的热损失，过热在调节阀的下游消散。 pH control: In order to protect carbon steel from corrosion by the steam, it is necessary to use additives to raise the pH to between 9.5 -10.5. pH控制：为保护碳钢制品不被蒸气腐蚀，有必要使用添加剂将pH值升高到9.5-10.5之间。 7.3.2 Clean Steam (CS) 7.3.2 清洁蒸气(CS) Pharmaceutical clean steam is generated from treated water free of volatile additives, such as amines or hydrazines, and is used for thermal disinfection or sterilization processes. It is considered especially important to preclude such contamination from injectable drug products: 制药用清洁蒸气是从不含有挥发性添加剂（例如胺或联胺）的净水中产生，并用于热灭菌或灭菌过程。从注射用药品中清除这类污染是尤其重要的： Clean steam is characterized as having: • No additives • No generated superheat except when the generated pressure is significantly higher than the use pressure of the steam. (See Section 7.3.1 - Superheat.) • Relatively low pH 清洁蒸气具有下列特征： • 没有添加剂 • 不产生过热，除非产生的压力显著高于蒸气使用压力（参看7.3.1部分-过热） • 相对低pH值 There are many terms used in the pharmaceutical industry to describe Clean Steam. These include Clean Steam, Pure Steam, Pyrogen Free Steam, WFI Steam, and USP Purified Water steam. There is no standard or accepted definition for any of these terms. However, the most commonly used terms are "Pure Steam" and" Clean Steam". In this Guide, the term "Clean Steam" is used in lieu of all others. The condensate of Clean Steam has no buffer, and may have a relatively low pH compared to that of utility steam. 在制药工业中有很多术语用于描述清洁蒸气。这些包括清洁蒸气、纯蒸气、无热原蒸气、注射用水蒸气和USP纯化水蒸气。对任何这些蒸气都没有标准或公认定义。然而，大多数通常使用的术语是“纯蒸气”和“清洁蒸气”。在本指南中，使用“清洁蒸气”术语替代其他所有术语。 清洁蒸气的冷凝液没有缓冲系统，并且与公用蒸气相比它具有相对低pH值。 7.4 BACKGROUND AND INDUSTRY PRACTICES 7.4 背景和工业实践 7.4.1 Purity of sterilizing steam 7.4.1 灭菌蒸气纯度 When steam or the resulting condensed water comes in direct or indirect contact with the drug product, the purity should be equivalent to the water purity acceptable for final rinsing of the drug contact surfaces. 当蒸气或其产生的冷凝水与药品有直接或间接接触时，其纯度应该与最终冲洗药品接触面合格的水纯度相同。 Note: A continuous supply of Dry Saturated Steam at the point of use is considered necessary for efficient steam sterilization. Water carried by the steam in suspension may cause damp loads and superheated steam is considerably less effective than saturated steam when used for sterilization. Non-condensable gases if contained in the steam may prevent the attainment of sterilization conditions in parts of the sterilizer load. 注意：为了有效蒸气灭菌，有必要考虑在用点连续供应干燥饱和蒸气。蒸气带来的悬浮的水可能引起潮湿，当用于灭菌时，过热蒸气比饱和蒸气的效果低的多。如果蒸气中含有不可压缩气体，则可能会防碍灭菌器中的一些部位达到灭菌条件。 7.4.2 Steam used for humidification 7.4.2 用于增湿作用的蒸气 When steam is used for indirect humidification, such as injection into HVAC air streams prior to final air filtration, the steam does not need to be purer than the air that it is being mixed with. However, when humidifying process areas, the potential level of impurities, including amines and hydrazines should be evaluated in order to ascertain the impact on the final drug product. This is particularly important in areas where open processing takes place, such as aseptic filling suites and formulation areas. If the diluted water vapor is found to contribute significantly to the contamination of the drug, a purer grade of steam should be selected. 当蒸气用于间接增湿作用时（如：在最终过滤之前注入HVAC的空气气流），蒸气没有必要比将要混入的空气更纯净。然而，当给加工区增湿时，为了确定对药品终产品的影响，应该评价包括胺和联胺的杂质潜在水平。这对开放的加工区非常重要，例如无菌填充室和合成区域。如果发现稀释的水汽显著地增加药品污染时，应该选择更加纯净级别的蒸气。 7.4.3 Common practices 7.4.3 普通实践 It is common practice to generate pharmaceutical steam from compendial waters and test the steam condense for equivalency to the compendial standard. This practice ignores the ability of the pharmaceutical steam generator to remove impurities. This overprocessing is wasteful and unnecessary. An exception is when the steam quantity is small and the cost and maintenance of a dedicated feed water pretreatment system exceeds the cost of using compendial water. Pharmaceutical Clean Steam is commonly used in applications where utility steam would suffice; such as non-critical room humidification and high purity water heat exchangers. 常见的行为是用药典规定的水来生成制药用蒸气，并以等同的药典标准来检测蒸气的冷凝水。该行为忽略了制药用蒸气发生器去除杂质的能力。过度处理是浪费和不必要的。但当蒸气需求量很少，并且对专用的给水预处理系统的维护成本超过了使用药典规定的水的成本时，这就是个例外。制药用清洁蒸气通常用于公用蒸气可以满足的应用区域，例如非关键房间增湿作用和高纯化水热交换器。 Table lists the commonly accepted industry standards and highlights the trend in the pharmaceutical industry to provide "purer than necessary" steam and over-specified feed water. 列表中列出通常公认的工业标准和制药工业趋势的要点从而提供“比所需更加纯净的”蒸气和过度具体说明的给水。 7.4.4 Industry and Baseline Practices in the Production of steam 7.4.4 蒸气产生企业和基线实践 Table 7-1 Practices in the Production of Steam 表7-1 蒸气产生实践 Intended Use of Steam 蒸气预期用途 Method of generation 产生 Parenteral and Non-Parenteral Dosage form applications where steam is in direct contact with the drug. 蒸气直接接触药品的无菌和非无菌制剂应用 The use of a sanitary clean steam generator with entrainment for the control of endotoxins & liquid carry-over (SCSG) is both baseline and common industry practice. 灭菌清洁蒸气发生器的用途伴随带走内毒素&液体携带污染(SCSG)控制是基线和普通工业实践 Critical step in the manufacture of API where steam is in direct contact with the Active Pharmaceutical Ingredient (API). 蒸气直接影响API的API生产的关键步骤 The use of an SCSG is both baseline and common industry practice. SCSG的用途是基线和普通工业实践 Non-Critical step in the manufacture of an API where added impurities may be removed in a subsequent step. 加入的杂质可以在后续步骤中去除的API生产的非关键步骤 SCSGs are commonly used; however, utility steam is the acceptable baseline application. 通常使用SCSG，然而公用蒸气也是合适的基线应用。 Sterilization of USP water systems. USP水系统的灭菌 WHILE THE USE OF A SCSG IS COMMON PRACTICE, AN ALTERNATIVE APPROACH IS TO USE UTILITY STEAM PLUS HOT USP WATER, FLUSHING & WASTE TESTING. 当SCSG的用途是普通实践时，可选方法是使用公用蒸气加上热USP用水，冲洗&废物测试 Process humidification for dosage form application where steam is in direct contact with the drug, where open processing takes place and where the potential level of amines, hydrazine's etc. in the condensate has been determined to have a detrimental effect on the drug product. 蒸气直接接触药品，进行开放工艺和已确定冷凝液中胺、联胺等的潜在水平对药品有不利影响的制剂增湿过程应用 SCSGs are commonly used and are the Baseline application. 通常使用SCSG并且SCSG是基线和普通工业实践。 Humidification of non-critical HVAC systems such as rooms and areas where the drug is not directly exposed to the room atmosphere. 非关键HVAC系统的增湿，例如药品不直接暴露在房间大气中的房间和区域 SCSGs are commonly used but utility steam may be totally acceptable. 通常使用SCSG，但公用蒸气也能够完全合格 HUMIDIFICATION OF PROCESS & CRITICAL CLEANROOMS. 工艺 & 关键洁净室的增湿 Where open processing takes place and where the potential level of amines, hydrazine's etc. in the condensate has been determined to have a detrimental effect on the drug product the baseline and common practice is the use of a SCSG. However, if it has been determined that the impurities have an insignificant effect on the drug product, a utility steam source would qualify as the baseline approach. 在进行开放工艺和已确定冷凝液中胺、联胺等的潜在水平对药品有不利影响的地方，基线和普通实践是使用SCSG。然而，如果已确定杂质对药品具有无关紧要的影响，公用蒸气来源将作为基线方法确认。 Energy source for non-critical & cGMP heat exchangers. 非关键& cGMP热交换器的能源 It is common practice to use a SCSG as the energy source. The baseline approach would be to use a utility steam source coupled with a cGMP heat exchanger design. 使用SCSG作为能源是普通实践。基线方法是将使用与cGMP热交换器设计配对的公用蒸气能源 Sterilization of fermentation vessels. 发酵容器的灭菌 It is common practice as well as the baseline approach to use utility steam. 这是与使用公用蒸气基线方法一样好的普通实践。 Figure 7-1 Pharmaceutical Steam System Planning 7.5 SYSTEM PLANNING 7.5 系统设计 Pharmaceutical Steam System Planning, shown in the Figure 7-1 is a graphic representation of the system boundaries, limitations, and restrictions. Initial system planning reveals primary boundaries that establish the cornerstone for design criteria. These system boundaries are steam Requirements, System Design, Use Point Criteria, and Distribution System requirements. 在图表7-1中显示的制药用蒸气系统是系统边界、界限和限制的图解表示。最初的系统计划显示为设计标准确立基础的主要边界。这些系统边界是蒸气要求、系统设计、使用点标准和分配系统要求。 The arrows encircling each boundary represent limitations that establish more specific operating strategies and ranges. To allow more flexibility in final planning and detailed design the designer should always indicate ranges of acceptability, rather than a specific value or position. 围绕在每个边界的箭头代表确立更多详细操作对策和范围的界限。为了允许更多适应性在最终计划和详细设计，设计者应该始终标明可接受范围，而不是具体数值或状态。 7.5.1 Steam Requirements 7.5.1 蒸气要求 The planning process starts with the listing of all steam requirements and applications that include: • Company standards including QA/QC requirements and published Sop's • The categorization of use-point by: • Type of application (Humidification, critical or non-critical, API, and Dosage for applications) • Purity selection (this is based primarily on the application and the endotoxin and chemical purity criteria set for the product for which the steam, or its condensate, will be in contact with. The selection must consider underlying factors which have impacts on purity control, installed and operating cost, maintenance, and practicality) • Steam quality (dryness, non-condensable limits, and maximum superheat) 设计过程是从把所有蒸气要求和应用列表开始，蒸气要求和应用包括： • 公司标准，包括QA/QC要求和发行的Sop • 使用点如下分类 • 应用类型（增湿作用，关键或非关键，API，和应用剂量） • 纯度选择（这首先建立在将使用哪种蒸气或其冷凝液产品的应用、内毒素和化学纯度标准设置的基础上。选择必须考虑潜在影响纯度控制的因素、安装和操作成本、维护以及实用性。） • 蒸气质量（干燥、非凝界限和最高过热） 7.5.2 System Design 7.5.2 系统设计 Pharmaceutical steam is generated using different methods. The most appropriate method for each application must be selected. (See the Pharmaceutical Steam Purity Decision Tree, Section 7.6.) The process continues with an evaluation of the steam system requirements (generation) that includes: the selection of the type of generation system that would satisfy each category, which would include: • The types of generation systems available. (If both pyrogen free clean steam and clean steam without endotoxin limits is required, the practicality and economy of producing only the higher grade should be raised.) • The source of utility steam or electrical power (The plant steam requirement for clean steam as well as utility steam and the option of electric powered steam generators should be considered.) • The type and number of systems required based on feedback from the "Distribution System" evaluation. • The condensate sampling needs. • Safety considerations 使用不同的方法产生制药用蒸气。对每个应用必须选择大多数适当方法。（参看制药用蒸气纯度决策树，7.6部分。）用蒸气系统要求（产生）的评估来继续过程，该系统要求包括：产生系统类型的选择将要满足如下每个种类： • 可用产生系统类型（如果无热原清洁蒸气和无内毒素限制的清洁蒸气都需要，那么应该提高只产生较高级别蒸气的实用性和经济性） • 公用蒸气的电源或电力动力（与公用蒸气一样的清洁蒸气的车间蒸气要求和电力蒸气发生器的选项都应该一起考虑。） • 系统的类型和数量要求以“分配系统”评估的反馈为根据 • 冷凝液抽样需要 • 安全性考虑 7.5.3 Use Point Criteria 7.5.3 用点标准 The third step defines the specific delivery requirement ranges for clean steam at the point of use including: • Utilization, which is determined from each overall system peak demand(s), average demand, and the relationships between peak demand time periods and their flow rates. • Pressures and flow levels • Use periods and histogram analysis, if available • Quality • Purity 第三步为在使用点的清洁蒸气规定详细交付要求范围包括： • 使用是由每个完整系统的高峰需求、平均需求和高峰需求时间周期与其流速关系决定 • 压力和流量水平 • 使用周期和柱状图分析，如果可得到 • 质量 • 纯度 7.5.4 Distribution System 7.5.4 分配系统 The fourth step includes the distribution system evaluation, which includes; • Condensate, non-condensable and moisture removal • Pipe size and Insulation requirements including: • Materials of construction, sanitary design requirements and surface finish • Physical location of each use point • Heat and temperature losses • Natural drainage 第四步包括如下分配系统评价： • 冷凝液，非凝液和湿度去除 • 管道型号和绝缘体要求，包括： • 构造材料，清洁设计要求和表面抛光度 • 每个使用点的物理位置 • 热量和温度损失 • 自然排水 Note: Since the steam quality will decline, due to heat losses, with time, the efficiency of the insulation and the length of the distribution system, the quality at the use point will not be expected to reflect the generation quality level. 注意：由于热损失，随着时间、绝缘体效能和分配系统的长度，蒸气质量将下降，因此在使用点的蒸气质量将不能反映产生质量水平。 7.5.5 Re-evaluation of system boundaries and constraints 7.5.5 系统边界和限制的再评价 These sequential steps are repeated and re-evaluated as information in the design process iterates, and further criteria about the overall system boundaries are identified. (See Figure 7-3.) In operations with a requirement for only one grade of steam, the steam system is designed to meet the most stringent requirements of the most demanding product or process. With more than one purity grade of steam, products and processes are often categorized and fed by the most appropriate system. The number of types of steam generated is most often a