ISPE_9.仪器和控制.doc

INSTRUMENTATION AND CONTROL仪器及控制9. INSTRUMENTATION AND CONTROL9. 仪器及控制9.1 INTRODUCTION9.1 简介Instrumentation and controls are often used within pharmaceutical water systems to:通常用制药水系统中的仪器及控制来： control the operation of equipment and components 控制设备和组件的运行 monitor and document the performance of critical equipment 监控并用文件记录关键设备的性能 monitor and document pharmaceutical water quality 监控并用文件记录制药用水的质量The concepts and regulatory philosophy of defining critical versus non-critical parameters is discussed as it relates to instrumentation and controls. This definition could be summarized as:当它关系到仪器和控制时，就要讨论关键和非关键参数的概念和调控原则了。定义可以总结如下：All instruments and control systems should be commissioned following Good Engineering Practices. Critical instruments and control systems should be commissioned and qualified.“所有的仪器和控制都应当遵循良好工程规范来进行委认。关键的仪器和控制系统应当进行委认及资格验证。”There is no regulatory requirement that requires the use of On-Line instrumentation. A monitoring program may include a combination of On-Line instrumentation, manual documentation, and laboratory analysis. 没有法规要求命令使用在线仪器。监测程序可能是在线仪器、文件手册及实验室分析的一个结合。If On-Line instrumentation is used to measure or record a critical parameter, action and alert limits may be established. The methods of addressing spikes are also discussed.如果用在线仪器来测量或记录关键参数，可以建立行为及警报限。显示“峰形”的方法也要讨论。Automation can have a significant impact on the cost and performance of a pharmaceutical water system. There is no single optimum level of instrumentation and control for all systems. The optimum level for a given system balances the benefits of improved process control, improved documentation, and lower labor costs against the cost of procuring, installing, validating, and maintaining the instruments and control systems. In many cases, the level of automation for a pharmaceutical water system should be consistent with that utilized for the manufacturing process it supports.自动化会对制药水系统的成本及性能产生显著影响。对所有系统而言，仪器和控制并没有一个单一的最佳水平。给定系统的最佳水平是利益平衡，利益包括改进的工艺控制、改良的文件及相对仪器和控制系统的获得、安装、验证及维护成本而言降低劳动力成本。很多时候，制药水系统的自动化水平应当与所用制造工艺支持的水平一致。9.2 PRINCIPLES9.2 原则a)To achieve GMP compliance, the manufacturer must demonstrate, through documented evidence, that the pharmaceutical water system is in control and consistently produces and delivers water of acceptable quality.为了顺应GMP，制造商应当用文件证据证明制药用水系统在控制中，并且始终能够生产和输送合格的水。b) Although many quality attributes can be continuously monitored using On-Line instrumentation, there is no compendial or regulatory requirement for On-Line monitoring of pharmaceutical water quality. A monitoring program typically includes a combination of On-Line instrumentation, manual documentation of operational parameters, and laboratory analysis of water samples.虽然许多质量特性可以用在线仪器连续监控，但是制药用水水质的在线监控并没有药典规定或法规要求。典型的监控程序是在线仪器、操作参数的文件手册，以及水样实验室分析结果的结合。c) Instruments and control systems are critical and must be qualified when they are used to measure, monitor, control, or record a critical process parameter. A critical parameter is a processing parameter that affects the final water quality.仪器和控制系统很关键，当期测量、监测、控制或记录关键过程参数时必须经过资格验证。关键参数是影响最终水质的过程参数。For example, the temperature of the final water product may be considered critical for microbial control. In this case, the temperature controls (e.g., sensors and alarms) would be considered critical. However, it is not necessary to consider the temperature of the heating media (e.g., steam) as a critical parameter.例如，最终的产品水的温度对微生物防治来说就是关键的。这时候，就认为温度控制（例如传感器和警报）是关键。但是，没有必要以为加热介质（例如蒸汽）的温度也是关键参数。Documentation should clearly indicate which instruments are critical and which are not. It is also advisable to identify non-critical instruments as such on the field device.文件应当明确指出哪些仪器是关键，哪些不是。在现场装置上标示出非关键仪器也是明智之举。d) All instrument and control systems should be designed, installed, calibrated, and maintained appropriately according to Good Engeering Practice. All critical instruments and controls require qualification.设计、安装、校准及维修所有仪器和控制系统时都应适当符合良好工程规范。所有关键仪器和控制都需要确认。e) Items that should be recorded in the system documentation include maintenance procedures and maintenance work performed, procedures for sampling and analysis, reporting the results, and trend analysis of the laboratory data. The monitoring program during start-up typically defines maintenance frequency and alert and action levels for the process variables.系统文件中应当记录的项目包括维护规程、进行的维护工作、取样和分析规程、结果报告以及实验室数据的趋势分析。一般启动期间的监控程序要根据不同工艺对维护频率以及警报和行动级别做一下规定。9.3 GENERAL INSTRUMENTATION REQUIREMENTS9.3 一般仪器要求9.3.1 Instrument Selection and Installation9.3.1 仪器的选择和安装a) Instruments should be selected for accuracy and reliability over the entire process range. 应当在整个工艺范围内针对精确性和可靠性选择仪器。Instruments should be selected and installed in a way that reduces the potential for contamination.选择和安装仪器应当减少污染的可能性。 Water contact surfaces should be constructed of materials that are compatible with the water they contact. Materials of construction and surface finishes (see Chapter 8) are commonly specified for instruments installed in distribution systems. 接确水的表面应当用与所接触水相容的材料制造。建造材料和表面抛光（见第8章）一般要针对安装在分配系统内的仪器作详细规定。 Sensors in direct contact with waters with strict microbial limits should be of sanitary design. Nonsanitary instrumentation is commonly used in feed water and pretreatment systems. 直接接触有严格微生物限制的水的传感器应当进行无菌设计。非无菌仪器一般用于进水和预处理系统。 Instruments may be installed directly in the water system or in a side stream that may, or may not, be returned to the main system. 仪器可以直接安装在水系统中，或安装到能，或不能返回主系统的侧流中。 Deadlegs should be avoided. 应当避免盲管。c) When possible, instruments should be installed such that exposure to harsh process conditions, such as pH and temperature extremes, is avoided. For example, In-Line sensors used to monitor effluent from a deionizer should be positioned such that exposure to regeneration chemicals is avoided.如果有可能，安装仪器应当尽量避免暴露于恶劣的加工条件下，比如极端的pH及温度。例如，用来监控去离子器流出液的在线传感器安装的位置就应当避免暴露于再生化学试剂中。Instruments that are not compatible with passivation agents, sanitization agents, or sanitization temperatures should be installed so that they may be easily removed or bypassed. Such devices may need to be sanitized off line.安装与钝化剂、消毒剂或消毒温度不相容的仪器时应当能够轻松取除或绕过。此类装置可能需要离线消毒。d) Instruments should be installed in accordance with manufacturers requirements to ensure proper operation. For example, flow meters should be installed in the proper orientation and with the correct upstream and downstream straight run of pipe. The impact of process and ambient conditions on an instruments accuracy and reliability should be addressed.安装仪器应当符合制造商的要求从而确保其正常运转。例如，流量计就应当以正确方位安装，并且有正确的上游和正游直接流经管道。应当注明工艺及环境条件对仪器精确度和可靠性的影响。e) Conductivity cells are especially sensitive to the presence of air or steam bubbles, which can be present where there is turbulence, cavitation, or flashing. Such locations should be avoided. 电导率池对存在的空气或蒸汽气泡特别敏感，那些气泡可能存在于有湍流、空穴或闪蒸的地方。此类位置应当避免。f) Accessibility for maintenance should be considered, but improving control response is usually more critical. Poor response time may be a consequence of the poor placement of a device and, in most cases, can be improved by installing the device closer to the point of measurement.应该考虑维修时方便接进，但是通常改善控制响应更为关键。设备安装的位置不好可以导致响应时间弱，大多情况中，这可以通过将设备安装到离测量点更近的地方即可改善。9.3.2 Instrument Calibration9.3.2 仪器校准a) The calibration of critical instruments should follow a regular program, which provides evidence of consistently acceptable performance. Non-critical instruments may be calibrated on a frequency deemed appropriate for the service.关键仪器的校准应当遵循正规程序，这样可以证明其性能始终可接收。非关键仪器可以以一个对使用来说恰当的频率来进行校准。b) Calibration should follow approved procedures and the results should be documented. Each component in a control loop should be calibrated individually or the loop may be calibrated in its entirety. All calibrations should be traceable to certified standards (e.g., NIST).校准应当遵循已经批准的规程，并且应将结果记录成文件。控制回路中的每个组件都应当单独校准，或者也可以整体校准。所有的校准都应当可溯源至公认标准（比如NIST）。c) Vendor-supplied calibration certificates should reference the applicable instrument serial numbers. The impact of shipment and installation on the vendors calibration should be addressed. 应当参考供应商校准证书中的适用仪器序列号。应当指出运输及安装对供应商校准的影响。9.3.3 Types of Instrumentation9.3.3 仪器的种类9.3.3.1 Conductivity9.3.3.1 电导率 a) Although non-ion specific, conductivity is a valuable tool for measuring the total ionic quality of water and is a critical parameter for many high purity water systems. Conductivity limits for Purified Water and WFI are specified in the USP.虽然有非离子性，但是电导率依然是测量水中总离子量的有效手段，并且是很多高纯度水系统的关键参数。纯化水和WFI的电导率极限在USP中有详细规定。b) On-Line conductivity instrumentation is frequently used to monitor and control the performance of many types of purification equipment and to continuously monitor the quality of pharmaceutical waters. On-line conductivity instrumentation may also be used for final quality assurance testing, thus eliminating the need for periodic laboratory analysis of water samples.在线电导率仪经常被用来监控多种纯化设备的性能，以及连续监测制药用水的质量。在线电导率仪也可以用作最终质量保证检测，因此取消了实验室定期分析水样的必要。c) Temperature has a profound impact upon conductivity measurement. To eliminate this temperature dependence, most instruments include a temperature sensor in the conductivity probe and one or more algorithms to correct the actual measurement to a standard temperature. However, due to he inaccuracy inherent in temperature compensation algorithms, compensated conductivity measurements are not suitable for critical quality assurance testing of USP purified water and WFI. When In-Line conductivity measurements are used for final quality assurance testing of USP purified water and WFI, a non-compensated conductivity value and the water temperature must be measured as required by the USP. Compensated conductivity values used strictly for process control and monitoring are not subject to USP requirements.温度对测量电导率有很深的影响。为了消除温度依赖性，大多数仪器都有一个含量温度传感器在内的电导率控针，及一或两种将实际测量值校准至标准温度的算法。但是，因为温度补偿算法自身不准确，因此补偿电导率测量就适用于USP纯化水和WFI的关键QA检测。当用在线电导率仪对USP纯化水和WFI进行最终QA检测时，USP就要求必须测量一个非补偿电导率值和水温。严格用于过程控制和监测的补偿电导率值并不受USP规定的限制。d) To operate properly, conductivity sensors must be installed such that there is continuous water flow through the sensor and air bubbles or solids cannot become trapped inside the electrodes. Air bubbles will result in lower-than-expected conductivity readings while solids can impact the conductivity in either direction. Clean steam must be condensed prior to conductivity measurement.为了正常运转，安装电导率传感器处必须有连续水流经过传感器，而空气气泡固体不能滞留在电极里。空气气泡将导致电导率读数低于预期值，而固体对电导率的影响则可能向任何一边。清净蒸汽须冷凝后方可测量其电导率。e) Conductivity meters may be used throughout a pharmaceutical water system to monitor and control purification processes or to monitor pharmaceutical water quality. Some examples are:电导率仪在整个制药用水系统中都可以用来监控纯化工艺或监测制药用水的水质。有一些例子： Feed water monitoring can detect seasonal or unanticipated quality changes that could impact pretreatment equipment operation. 进水监测可以检查出季节性或非预期的质量变化，这些变化能够影响预处理设备的运转。 RO influent and effluent monitoring allows calculation and trending of percentage rejection. Changes in percentage rejection may be a sign of membrane failure, scaling or fouling, seal failure, improper pH, inadequate feed pressure, or too high a recovery rate. 监测RO流入液和流出液可以计算排阻百分率及其发展趁势。排阻百分比的变化可能是膜损坏、结垢或积垢、密封失败、pH值不当、进压不够或回收率过高的信号。 Deionizer effluent or in-bed monitoring detects, or predicts, resin exhaustion and allows automatic initiation of regeneration cycles. 去离子器流出液或床内监测检出或预测出树脂耗竭并允许自动进行再生循环。 The conductivity of pharmaceutical water may be monitored after the final treatment step to verify acceptable quality prior to delivery to a storage tank. In addition, conductivity meters are often installed in the return piping of distribution loops downstream of the final point of use. Many systems include provisions for automatic diversion to drain or recirculation back through purification equipment when water quality entering the tank is outside the acceptable range.可以在终处理步骤之后监控制药用水的电导率从而验证输送到储存罐之前的水质的可接受度。此外，电导率仪也经常安装在终使用点分配回路下游的返回管道中。当进入储罐的水质超出可接受范围时，很多系统能将其自动排放或经纯化设备重新循环。9.3.3.2 Total Organic Carbon (TOC)9.3.3.2 总有机碳a) Total Organic Carbon (TOC) is a measure of the carbon dissolved in water in the form of organic compounds. It is a valuable tool for measuring the aggregate level of organic impurities in pharmaceutical water systems. A TOC test with a nominal limit of 500 ppd for USP Purifide Water and WFI is a required test in the USP. 总有机碳（TOC）测量的是以有机化合物形式溶解于水中的碳。它是测量制药用水中有机物凝集水平的一个有效手段。USP规定USP纯化水和WFI要进行TOC测定，标称限是500 ppd。d) TOC meters are relatively sophisticated analytical instruments. The USP provides guidance on how to qualify an instrument and how to interpret the instrument results.TOC仪是一个相对精密的分析仪器。USP中为如何确认仪器及如何解释仪器结果提供了指南。c) In addition to continuous monitoring of equipment performance and pharmaceutical water quality, On-Line TOC meters may be used for final quality assurance testing, thus eliminating the need for periodic laboratory analysis. When used for critical assurance testing of USP purified water and WFI, instrument precision, system suitability, test methodology and calibration procedures must meet USP requirements. Instruments used strictly for process control and monitoring are not subject to USP requirements.除了“连续”监测设备性能和制药用水水质外，在线TOC仪也可以用于最终的QA检测，因此就省去了实验室定期分析的必要。当其用于USP纯化水和WFI的关键保证检测时，仪器精度度、系统适应性、检测方法以及校准规程都必须符合USP规定。严格用于过程控制和监测的仪器则不受USP规定的限制。d) TOC is often monitored at several locations in a pharmaceutical water system. Some examples are: 制药用水系统中，有几个位置经常监测TOC。例如： Feed water monitoring can detect seasonal or unanticipated quality changes that could impact pretreatment equipment operation or the potential for resin or membrane fouling. 进水监测可以检查出季节性或非预期能影响预处理设备运转的质量变化，或者树脂或膜结垢的可能性。 Monitoring TOC downstream of carbon filters, organic scavengers, RO units, and UV lights can verify proper equipment operation and provide advance warning of bed exhaustion, compromised membranes, or the need for lamp replacement. 碳过滤器、有机物净化器、RO设备及UV线下游的TOC监测能够确证设备运转正常，并对床耗竭、膜退化或灯需要更换做出预警。 TOC levels of pharmaceutical water may be monitored after the final treatment step to verify acceptable quality prior to delivery to a storage tank. In addition, TOC meters are often installed in the return piping of distribution loops downstream of the final point of use. Many systems include provisions for automatic diversion to drain or recirculation back through purification equipment when water quality is outside the acceptable range. 制药用水的TOC水平可以在终处理步骤后监测，从而验证输送到储存罐的水质可接受度。此外，TOC仪经常安装在终使用点分配回路下游的返回管道中。当进入储罐的水质超出可接受范围时，很多系统能将其自动排放或经纯化设备重新循环。e) There has been much interest in the possible use of TOC analyzers to indicate endotoxin contamination. While this type of contamination will lead to higher TOC levels, there is no quantitative correlation to TOC levels. TOC results cannot substitute for microbial or endotoxin testing.使用TOC分析器来显示内毒素污染也已经很受关注。虽然此类污染将导致较高TOC水平，但是和TOC水平却没有数量关系。TOC结果不适用于检测微生物或内毒素。9.3.3.3 PHa) pH measurement is relatively straightforward for high conductivity water. Reliable results can generally be obtained using pH indicators or laboratory, field, or On-Line pH meters.就高电导率水而言，pH测量是相对简单的。一般用pH指示剂或实验室、现场或在线pH计即可得到可靠的结果。b) Accurate pH measurement is difficult in many pharmaceutical waters due to the low conductivity. Low conductivity water is susceptible to pH swings due to contaminants introduced from the air, sample containers, and test equipment, as well as instrument difficulties associated with measuring low ionic strength solutions. 在很多制药用水中精确测量pH很困难，这是因为其电导率太低。低电导率的水因为从空气、样品池、及测试设备中引入的污染使其对pH波动非常敏感，这和测量低离子强度的溶液很困难一样。Common locations for On-Line pH measurement and control include:在线pH测量和控制的一般位置包括： Upstream of cellulose acetate RO membranes, where acid is injected to minimize membrane hydrolysis 乙醋纤维素RO膜的上游，此处注入酸以减少膜的水解 Upstream of a degasifier, where acid is injected to increase CO2 removal 脱气器的上游，此处注入酸以增加去除CO2 。While pH limits for purified water and WFI are no longer specified in the USP , On-line pH meters are rarely used for process control of final quality assurance testing of pharmaceutical waters for several reasons:当USP中不再规定纯化水和WFI的pH限度后，在线pH计就很少用于制药用水最终QA检测的过程控制了，这是因为几个原因： Conductivity is a more sensitive measurement of overall ionic quality since changes in pH reflect logarithmic changes in water quality 电导率的测量对整个离子量来说更敏感，因为了pH变化反应到水质上是对数变化 A pH sensors reference electrode contains a buffer solution that may leak through the reference electrode into the water being measured. To prevent contamination of the pharmaceutical water system, a pH sensor is installed in a side stream that flows to drain. The water flow rate through the meter must be controlled and held constant to achieve repeatable results. pH传感器的参比电极中含有缓冲液，它有可以通过参比电极泄漏到测量的水中。为了避免制药用水系统污染，将pH传感器安装在通向排水槽的侧流中。必须控制流经测量计的水速，并保持恒定，从而获得可重复的结果。 pH meters require frequent (daily in some cases) calibration with standard buffer solutionspH计需要用标准缓冲液频率（一天几次）校准9.3.3.4 Ozone9.3.3.4 臭氧a) Dissolved ozone levels should be monitored in storage and distribution systems that utilize ozone for microbial control. Ozone levels can be determined periodically in the laboratory using several wet chemistry methods, or continuously using an On-Line analyzer. On-line analyzers are relatively inexpensive and easy to maintain, but they should periodically be calibrated against laboratory methods.使用臭氧进行微生物防治的储存和分配系统中应当监测溶解的臭氧水平。实验室里可以用几种湿化学法定期测定臭氧水平，或者用在线分析器连续测定。在线分析器相对便宜且易于维护，但是相对于实验室方法应当进行定期校准。b) For effective and safe system operation, ozone levels should be monitored at the following locations:为了安全有效的运行系统，应当在以下几处监测臭氧水平： At the storage tank discharge