ISPE 2.重要设计原理

KEY DESIGN PHILOSOPHIES KEY DESIGN PHILOSOPHIES 重要设计原理 2 KEY DESIGN PHILOSOPHIES主要设计原理 2.1 INTRODUCTION序论 Pharmaceutical water is the most widely used ingredient in drug manufacturing and the main component in equipment/system cleaning.Therefore, systems for the production of pharmaceutical water constitute a key component in every manufacturing facility. The nature of producing pharmaceutical waters is to minimize or eliminate potential sources of contamination. This Guide considers this and the means by which engineers can design out, or ensure control of the risk. 制药用水在药品生产中是使用最广泛的成份，并且在设备/系统清洗中也是主要组份。因此，制药用水的生产系统在所有制药企业中构成一个关键组份。生产制药用水的本质是将潜在的污染源降到最低或者消除。本指南认为其以及工程师使用的工具可以设计或者确保控制风险。 The quality of Pharmaceutical Water and Steam is not only critical from a regulatory point of view, but also from a financial point of view. The Pharmaceutical Water and Steam specification has the largest impact on lifecycle costs of the system. 制药用水和蒸汽的质量不仅是调控观点的关键，在经济观点上也是如此。制药用水和蒸汽技术指标对系统整个过程的成本有巨大影响。 It must be demonstrated that all pharmaceutical waters (non-compendial and United States Pharmacopoeia(USP)monograph compendial waters) can be produced consistently to specification. Establishing the level of microbial control needed in a pharmaceutical water and steam system used in the manufacture of a nonsterile product requires an understanding of both the use of the product and the manufacturing process. 必须 证明 住所证明下载场所使用证明下载诊断证明下载住所证明下载爱问住所证明下载爱问 可以在相同技术指标下始终如一地生产所有制药用水（非药典和USP药典各论用水）。制造非无菌产品时所用的制药用水或蒸汽系统中，建立必须的微生物防治水平，对产品用途和生产工艺都需要了解。 Manufacturers need to define the appropriate water purity based upon sound process understanding and system equipment capability. They must determine the specific purification capability for each processing step, the limitations of the unit operation, and the critical parameters, which affect the specified water/steam quality - chemically, physically, or biologically. Expert QA advice should be sought to provide further details about this important area. 制造商需要依据合理的工艺理解和系统设备性能来确定适当的水质纯度。他们必须确定那些可以影响特定水/蒸汽（化学的，物理学的或生物学的）质量的每个工艺步骤特定的纯化性能、设备操作的限制和关键参数。应该向QA专家征求关于该重要区域更进一步细节的建议。 USP covers two compendial water qualities (USP Purified Water and USP Water for Injection). This Guide supports both these water qualities plus additional non-compendial waters including "Drinking Water". It is common practice to name non-compendial waters (exclusive of "Drinking Water") used in pharmaceutical manufacturing by the final treatment step (i.e., Reverse Osmosis/RO water, deionized water/DI water, etc.). USP包含两种药典规定用水药典规定用水质量（USP纯水和USP注射用水）。本指南即支持这两种水质，另外附加包括“饮用水”在内的非药典规定用水药典规定用水。 通常习惯骨终处理步骤（即，反渗透水/RO水，去离子水/ DI水，等等）来命名在制药生产中使用的非药典规定用水药典规定用水（“饮用水”除外）。 Guidance on establishing specifications for monographed USP water is provided in the United States Pharmacopoeia (USP). Additionally, the FDA Guide to Inspections of High Purity Water Systems (which was developed for FDA personnel) also provides useful information to the user. 关于制定USP各论用水的技术指标的指南在USP中提供。此外，FDA高纯度水系统的检查指南（由FDA工作人员制定）也为用户提供有用信息。 2.2 UNITED STATES PHARMACOPOEIA (USP) 美国药典(USP) USP is a Guide to producing medicinal products for consumption within the US. USP specify standards of quality, purity, packaging, and labeling for a number of waters including two bulk waters, "Water for Injection"and "Purified Water" used in the preparation of compendial (USP) dosage forms. This Guide is concerned with the production of these two compendial (USP) waters and does not address the other "packaged waters"monographed by the USP. USP 24 (and supplements) is the current version, at the time this Guide was prepared. USP是生产在美国国内消费的药品指南。USP具体规定了许多水包括在药典(USP)制剂中使用的两种散装水，“注射用水”和“纯水”在内的许多水的的质量、纯度、包装和标签 标准 excel标准偏差excel标准偏差函数exl标准差函数国标检验抽样标准表免费下载红头文件格式标准下载 。本指南与生产这两种药典(USP)水有关但没有提及USP各论的其他“整装水”。在本指南编纂完成的时候，USP 24（和增刊）是现行版本。 2.2.1 USP Purified Water USP纯水 Official monograph requirements for "Purified Water" require that "Purified Water": “纯化水”的药典各论规定要求“纯化水”： ●​ Is obtained from water complying with the "U.S. Environmental Protection Agency National Primary Drinking Water Regulations, or comparable regulations of the European Union or Japan, and will be referred to subsequently as "Drinking Water". ●​ Contains no added substance ●​ Is obtained by a suitable process ●​ Meets the requirements for Water Conductivity ●​ Meets the requirements for Total Organic Carbon (TOC) ●​ 从符合“美国环境保护局全国初级饮用水条例”，或符合与之相近的欧洲或日本条例的水中获得，并且将随后被作为“饮用水” 参考。 ●​ 不包含添加物质 ●​ 通过适当工艺获得 ●​ 符合水电导率要求 ●​ 符合总有机碳(TOC)要求 2.2.2 USP Water for Injection (WFI) USP注射用水(WFI) Official monograph requirements for "Water for Injection" require that "Water for Injection": “注射用水”的药典各论规定要求“注射用水”： ●​ Meets all of the requirements for "Purified Water" ●​ Is obtained by a suitable process and purified by distillation or Reverse Osmosis ●​ Meets the requirements of the Bacterial Endotoxin test and contains not more than 0.25 USP Endotoxin Unit per ml ●​ Is prepared using suitable means to minimize microbial growth ●​ 符合 “纯化水”的所有要求 ●​ 通过适当工艺获得并经过蒸馏或RO纯化 ●​ 符合细菌内毒素试验的要求并且不包含超过0.25 USP EU/ml的内毒素 ●​ 通过使用适当的方法使微生物生长降到最低来制备 2.2.3 Non-Monographed but accepted requirements 非各论但是公认规定 The USP "General Information" provides background information, which clarifies regulatory intent. The following information is included in Chapter 11: USP“通则”提供了背景信息，它阐明了法规目的。下列信息包含在第11章中： ●​ Purified water systems require frequent sanitization and microbiological monitoring to ensure water of appropriate microbiological quality at the points of use. ●​ Water for Injection is "finally subjected to distillation or Reverse Osmosis", implying that the Still or RO unit is the last unit operation. 'The system used to produce, store and distribute water for injection must be designed to prevent microbial contamination and the formation of microbial endotoxins, and it must be validated." ●​ An action limit of 100 colony forming units per ml (10,000 CFU/100 ml) for "Purified Water" is suggested. ●​ An action limit of 10 colony forming units per 100 ml (10 CFU/100 ml) for 'Water for Injection" is suggested. ●​ Minimum sample sizes are 1 ml for USP Purified Water and 100 ml for WFI. (FDA recommends 100 ml for Purified Water and 250 ml for WFI). ●​ 纯水系统需要频繁的消毒和微生物监测来确保使用点水的微生物质量适宜。 ●​ 注射用水是“最终经过蒸馏或RO”，这意味着蒸馏器或RO设备是最后的单元操作。“用于生产、贮存和分配注射用水的系统必须设计成能阻止微生物污染和微生物内毒素的产生，而且它必须经过验证”。 ●​ 建议“纯水”的行为界限为100 CFU /ml (10,000 CFU/100 ml)。 ●​ 建议“注射用水”的行为界限为10 CFU /100ml (10 CFU/100 ml)。 ●​ USP纯水最小取样量为1 ml，WFI最小取样量为100 ml（FDA建议纯水最小取样量为100 ml，WFI最小取样量为250 ml）。 Note: "It should be emphasized that the above action guidelines are not intended to be totally inclusive for every situation where ingredient waters are to be employed. It is therefore, incumbent upon the manufacturer to supplement the general action guidelines to fit each particular manufacturing situation" [USP24, page 2163]. When designing a pharmaceutical or medical device water system, it is critical for the designer to consult with the manufacturers technical experts to ascertain what purity levels must be achieved. 注意：“应该强调上述行为指导方针并不打算完全包括使用成分用水的所有情况。因此，为适合每个特定的生产情况，制造商有 职责 岗位职责下载项目部各岗位职责下载项目部各岗位职责下载建筑公司岗位职责下载社工督导职责.docx 补充一般行为指导方针。”[USP24, 2163页]。当设计一制药用或医疗用设备水系统时，设计者关键是要咨询制造商技术专家来确定必须达到的纯度水平。 2.2.4 USP testing and instrument requirements USP测试和仪器需求 THREE STAGE CONDUCTIVITY TESTING 三个阶段的电导率测量 Stage 阶段 Method of Measurement 测量方法 Acceptance Criteria 验收标准 One 1 Use In-Line or grab sample and measure the conductivity and operating water temperature. 使用在线或定时收集的样品并测量其电导率和操作水温。 Use the stage 1 table from the latest revision to USP to determine the conductivity limit. 根据USP最新版本，使用1阶段的表来确定电导率界限。 Two 2 Retest at least 100 ml of the stage 1 grab sample for conductivity after vigorous mixing and temperature normalization to 25℃ ±1℃. 充分混匀和温度恢复到25℃±1℃后，再检测至少100 ml 1阶段定时收集样品的电导率 When change does not exceed a net of 0.1 uS/cm over 5 minutes, measure the conductivity. If less than 2.1 u.S/cm the water meets the requirements. 当5分钟后净变化不超过0.1uS/cm，测量电导率。如果小于2.1 uS/cm，则水符合要求。 Three 3 If the stage 2 test does not meet the requirements, retest the sample within 5 minutes while maintaining temperature. Add 0.3ml per 100ml of saturated potassium chloride solution and determine the pH to the nearest 0.1 pH unit. 如果2阶段的检测不符合要求， 当温度保持时，5分钟内再检测样品。每100ml饱和氯化钾溶液加入0.3ml并用精确到0.1 pH单位来测定pH值。 Use the stage 3 table from the latest revision to USP to determine the conductivity limit, if either the measured conductivity is greater than the limit value or the pH value is outside the range of 5 to 7, the water does not meet the requirements. 根据USP最新版本，使用3阶段表来确定电导率界限。如果随便一个测量的电导率大于界限值或pH超出5到7的范围，那么水不符合要求。 CONDUCTIVITY INSTRUMENT REQUIREMENTS FOR ACCEPTABLE REGULATORY 电导率仪器可接受的调控要求 MEASUREMENT 测量 Temperature Measurement 温度测量 ±0.25℃ Accuracy 精确度±0.25℃ Resolution <±0.1uS/cm 分辨率 <±.1uS/cm Conductivity cell constant 电导池常数 ±2% Accurate 精确度±2% Reading accuracy < ±0.1 uS/cm 读数精确度< ±0.1 uS/cm Location of In-Line meters 在线计量器的位置 Must reflect the quality of the water used. Typically, the optimum location in a distributed water loop is following the last "point of use" valve, and prior to the storage tank return connection. 必须反映所用水的质量。分配水回路的最佳位置是在最后“使用点”之后，在贮水槽回路连接之前。 Instrument type 仪器类型 The above procedure is based on the use of a "dip" or "flow through" conductivity cell. Conductivity readings used to control USP compendial waters must be non-temperature-compensated measurements. 上述规程是以“浸泡”或“流过”电导池的使用为根据。用于USP药典规定用水药典规定用水电导率读数必须是无温度补偿的测量结果。 2.2.5 Total Organic Carbon (TOC) and Requirements for TOC Control 总有机碳(TOC)和TOC控制要求 TOC is an indirect measure, as carbon, of organic molecules present in high purity water. USP replaced the USP 22 "Oxidizable Substance" wet chemistry test with an In-Line capable, TOC test. A limit was determined by USP to be 0.5ppm or 500ppb, based on the results of studies and an industry wide survey of pharmaceutical water systems. TOC是间接测量，因为碳是作为有机分子存在于高纯水中的。USP用一能够在线测量TOC替换了USP 22“易氧化物质”的湿化学测量。根据研究的结果和对企业制药用水系统广泛勘测的结果，USP决定其界限为0.5ppm或500ppb。 SYSTEMS AVAILABLE FOR MEASURING TOC 可用于TOC测量的系统 Instruments are available for measuring TOC In-Line from slipstreams and from grab samples manually removed from the water system. Automatic Off-Line sample introduction systems are available for processing large numbers of grab samples. USP have not prevented acceptable technologies from being used, but limit the methods to the following instruments that are capable of completely oxidizing the organic molecules to Carbon dioxide (CO2), measuring the CO2 levels as carbon, discriminating between Inorganic carbon (IC)and the CO2 levels generated from the oxidization of the organic molecules, maintaining an equipment limit of detection of 0.05 mg per liter, or lower, and periodically demonstrating an equipment "suitability". 仪器是可用于在线测量来自切向流和人工从水系统中定时采集样品的TOC。自动离线进样系统可用于处理大量定时采集的样品。USP没有阻止正在使用的适宜方法，但是限定了下述仪器的使用方法，这些仪器能够把有机分子完全氧化为CO2，测量CO2形式中碳的水平，区别无机碳(IC)和有机分子氧化产生的CO2水平，维持设备检测限为0.05 mg/L或更低，并且定期证明仪器的“适应性”。 A number of acceptable methods exist for measuring TOC in high purity water. All share the same basic methodology, the complete oxidation of the organics to CO2 and the measurement of this CO2. 测量高纯水的TOC有许多合适方法。所有共同使用的同一基本方法论，有机物完全氧化为CO2并且测量该CO2。 Three general approaches, based on the above concept are used in a variety of commercially available instruments, which measure Organic Carbon in a water sample by completely oxidizing the organic molecules to Carbon dioxide (CO2) and measuring the CO2 levels as carbon. Four common oxidation methods and four common CO2 measurement methods are used in different combinations in these TOC analyzers.The total carbon (TC) result may be expected to include Inorganic carbon resulting from dissolved CO2 and bicarbonate which must be subtracted from the TC to produce the Total Organic Carbon level in the sample. Some TOC analyzers remove the Inorganic Carbon (IC) by acidifying the samples and either gas stripping or vacuum degassing the CO2. In pharmaceutical waters the IC levels are generally very low and IC removal processes are not usually required. 以上述概念为根据的三种一般方法用于许多种商业效用仪器，这些仪器通过把有机分子完全氧化为CO2并通过测量CO2形式的碳量来测量水样品中的有机碳量。四种常用氧化方法和四种常用CO2测量方法通过不同组合应用于TOC分析器中。在样品中，总碳量(TC)结果可能会包括溶解的CO2和重碳酸盐IC结果，必须从TC结果中减去该IC结果来得到TOC水平。一些TOC分析器通过酸化样品和脱CO2气体或真空脱CO2气体来去除IC。在制药用水中，IC水平一般来说非常低并且通常不需要去除IC的过程。 TYPES OF TOC ANALYZERS 分析器类型 ●​ Laboratory Instruments ●​ In-Line Instruments ●​ Laboratory Instruments capable of operating in-line ●​ 实验室仪器 ●​ 在线仪器 ●​ 可以在线操作的实验室仪器 When USP accepted the well-proven technology for measuring TOC, they applied laboratory quality control procedures to its application. While these techniques are common in a laboratory for setting a wide range equipment for measurement over a specific range, they place unusual limitations on In-Line TOC applications. TOC instruments must be: 当USP接受了测量TOC的经过充分证明的技术方法后，它们就将实验室质控规程应用其中。当这些技术在实验室中普遍用来安装一个宽范围设备来测量超规范围时，它们将在TOC在线应用上设置一个非常限度。TOC仪器必须： ●​ Maintained calibrated to ensure reliable and consistent readings ●​ Periodically checked for "suitability" ●​ Standardized ●​ May be used In-Line or Off-Line ●​ If installed In-Line, the instrument must reflect the quality of the water used ●​ 维持校准状态，确保读数的可靠性和一致性 ●​ 定时检查“适应性” ●​ 标准化 ●​ 可在线或离线使用的 ●​ 如果在线安装，仪器必须反映用水质量 OUT OF RANGE EXCURSIONS 超出偏移范围 Out of range readings may be experienced as the direct result of the above types of organic contaminations.Spikes may also occur as the result of extraneous electrical interference etc. All spikes must be identified and formally explained. 上述类型有机物污染的直接结果就是导致超出范围的读数。由于外部电子干扰等，也可能产生峰形。必须标识出所有峰形并做正式说明。 Procedures to handle out of range spikes should be available. These procedures should address short duration spikes, which occur following continuous acceptable readings and are followed by similar acceptable readings, specifically in In-Line applications. Procedures should list the potential sources and allow the acceptance of such a spike without further investigation if the spike is preceded and succeeded by a number of acceptable readings. 应当有处理超标峰形的规程可用。这些规程应当提出短期峰形，它是发生在连续可接受读数之后，并且随后又是类似的可接受读数，特别是在在线应用中。规程应当列出潜在源，如果这个峰在之前和之后都是许多可接受计数，那么不用进一步也允许接受此类峰形。 Unexplainable spikes may be minimized when using In-Line batch sampling systems by extending the sample analysis period to 30 or 60 minutes rather than using shorter analysis periods. This technique measures more sample in a longer time period, allowing the recorded result to be based on statistical analysis over the extended time period. 用在线批次取样系统时，用30到60分钟阶段的扩大取样分析，而不是用更短的分析阶段可以减少不可解释的峰形。此技术在长时间期限内测量更多样品，认可了 记录 混凝土 养护记录下载土方回填监理旁站记录免费下载集备记录下载集备记录下载集备记录下载 的那些建立在扩大时间期限的统计分析基础上的结果。 In-Line compared with Off-Line TOC Monitoring TOC的在线和离线监测比较 In-Line 在线 Off-Line 离线 Features 特征 Monitor should include built in alarms and be programmable in respect to the "out of spec." excursions. Should have convenient method of conducting Limit Response and Suitability Tests. 监测应当包括嵌入式警报，并且可程控OOS偏移。应当有传导响应限和适应性检查员简便方法。 Laboratory instrument should be capable of achieving robust oxidation levels and should include automatic Off-Line sample introduction systems,for processing large numbers of grab samples. A generous supply of scrupulously clean polymer based sample containers is required.Laboratory instruments will require reagents and carrier gases. 实验室仪器应当能够完成强氧化水平，针对处理大量的定时收集的样品，应当包括自动离线取样引入系统。要求有针对取样器的小心清洁聚合物的大量供给。实验室仪器将需要反应物和载气。 Installed cost 安装成本 Medium, based on above features and a single installed unit. High, if multiple units are installed. 中等，取决于上述特征和一个独立安装装置。高，如果安装多装置的话。 High, based on above features 高，取决于上述特征 Operating cost 操作成本 Low to high, depending on instrument capability for suitability and limit response testing and the number of instruments installed. 从低到高，取决于仪器的适应性能力和响应限测试以及安装仪器数量。 High 高 Recommended test frequency 推荐测试频率 4 to 48/day 4到48/天 The recommended frequency is based on the specific system requirement for trending or concern for "out of spec." excursions and their subsequent investigations. See paragraph on "Special Requirements". 推荐频率取决于特定系统对OOS偏移的趋向或担心以及对它们随后调查的要求。见“特定要求”段落。 1/shift 1/移动 Frequency of Suitability and Limit Response Testing 适应性和界限灵敏度测试频率 Based on documented history 取决于历史文件 1/shift 1/移动 2.2.6 USP 23 Microbial and Endotoxin Testing USP23微生物和内毒素检测 Microbial contaminants and Endotoxins are traditionally sampled at the points of use in a water system. USP 24 has made no changes in this area. 微生物污染和内毒素检测习惯上在水系统使用点取样。USP24在这方面没有变化。 2.2.7 USP 23 pH testing USP23 PH检测 Testing water for compliance with the USP 24 pH limits is required as part of the stage 3 Off-Line conductivity testing. (pH must be confirmed as being in the range of 5 to 7.) Testing may use calibrated Off-Line meters. Calibration should be performed using solutions of a known pH, covering the range of 5 to 7. The frequency of calibration should ensure that the levels of accuracy are maintained. Refer to manufacturer for specific recommendations on both method and frequency. 需要检测水对USP24pH限的顺应性，这是第3阶段离线电导率检测的一部分。（必须确定pH在5到7的范围内）。测试可以用校准过的离线测量计。应当用已知pH在5到7范围内的溶液进行校准。校准的频率应当能确保维护精确度。方法和频率参考制造商的特别建议。 2.2.8 Validated Backup Instrumentation 验证过的备用仪器 Failure of a monitoring instrument should not be precluded when making decisions concerning type, location and the extent of validation. Since each excursion from the acceptable limits must be investigated, In-Line installations should be supplemented with a calibrated laboratory instrument as backup. Validation should include the operation in Off-Line mode as a supplement or alternate to In-Line instrumentation. Off-Line laboratory testing should also include a backup instrument to be maintained calibrated in case of failure of the primary unit. 在确定有关验证的类型、位置和范围时，并不能预先排除监测仪器发生故障。因为必须调查每次对可接受限的偏移，所以应当用一个在线安装的经校准实验室仪器作为后备。验证应当包括离线模式下的运行，它将作为在线仪器的补充或替代品。离线实验室检测还应当包括一个后备仪器，万一原来的装置发生故障，可以用来维护校准。 2.3 SPECIFICATION OF PHARMACEUTICAL WATER QUALITY 制药用水质量技术指标 2.3.1 Specifying Water Quality 水质规定 The quality of water supplied in any pharmaceutical process must be consistent with the quality required for the final product. It may not be sufficient to specify a water quality that meets the specification of the two compendial grades of water outlined in the USP. These grades, USP Purified water and WFI, are minimum standards. A more stringent specification could be required depending on the intended use of the product and on the process used to manufacture that product. It is the responsibility of each drug manufacturer to establish the logic for their water quality specification based on the required quality of the end product. 所有制药工艺中的给水水质都必须符合终产品所需的品质。规定一种水质达到两个USP中规定的水的两个药典级别标准可能并不充分。这些等级，USP纯化水和WFI是最低标准。根据产品的预期用途和产品的制造工艺，就需要一个更严格的规定。每个药品制造商有责任根据终产品所需的水质为他们的水质标准建立条理。 Pharmaceutical water uses can be categorized as: 制药用水的用途可以分为以下几类： ●​ An ingredient in a dosage form manufacturing process ●​ 制剂工艺中的成分 ●​ An ingredient in an Active Pharmaceutical Ingredient (API) process (the term API is used interchangeably with BPC, meaning Bulk Pharmaceutical Chemical) ●​ 原料药工艺中的成分（API）（API这个词可以和BPC互换，BPC是指大宗药用化学品） ●​ Equipment cleaning or rinsing ●​ 设备清洁和冲洗 Water intended for use as a dosage form ingredient must be USP monograph water and must be produced consistently to specification. Evidence of control is required for all critical process parameters that may affect the final drug characterization. USP WFI water would be expected to be used for parenteral manufacture,some ophthalmic and some inhalation products. 用作制剂成分的水必须是USP各论水，并且必须能始终合格生产。所有可能影响最终药品特性关键的过程参数都需要控制根据。希望用于制造无菌制剂、某此眼药和某此吸入剂产品的是USP WFI水。 The monographs for USP Purified and WFI compendial pharmaceutical waters stipulate the baseline requirements for water used in production, processing, or formulation of pharmaceutical activities. 药典药用水中USP纯化水和WFI各论对用于生产、加工或制备药物有效成份的水的基本要求做了规定。 For some applications where there are no requirements for compendia! waters, the manufacturer may establish quality specifications equivalent to USP-WFI or Purified Waters, depending on the specific application. 对药典规定用水药典规定用水药典规定用水没有要求的某些应用，制造商可以根据特定的就用建立等同于USP-WFI或纯化水的质量规定。 Specifications for water used as an ingredient (exclusive of sterile bulks) in the manufacture of API's or as the wash solvent in the