ISPE-10.调试和确认.doc

COMMISSIONING AND QUALIFICATION调试和确认10. COMMISSIONING AND QUALIFICATION10. 调试和确认INTRODUCTION简介Commissioning and qualification comprise the validation process by which a system is put into service and demonstrated to consistently produce water of a specified quality, under various conditions, while operated under set procedures. Although commissioning and qualification are typically separated within a project schedule, they are in essence, one continuous process.调试和确认是一个验证过程，是将系统投入使用并证明其在设定规程的不同条件下运转时始终能生产合格水质的过程。虽然在一个项目进步表中可以将调试和确认分离开，但本质上它们是一个连续过程。The specific activities and processes during commissioning and qualification will not be discussed in this Guide. These are considered by a separate ISPE Baseline Guide on Commissioning and Qualification and pharmaceutical water systems are used as examples throughout. A summary of key concepts are listed below:本指南中不讨论调试和确认期间的特定活动和过程。这些在一个单独关于调试和确认的ISPE基线指南中会有所考虑，并且制药用水系统也在各处被用作例子。关键概念总结如下：a) Due to the interdependence between activities and those involved, excellent communication, planning and coordination between operations, engineering, commissioning, and validation personnel will enable timely and cost-effective project completion.鉴于活动它们涉及的相互依赖性，操作、工程、调试和验证人员之间的沟通、计划和协调将能及时且低本高效地完成。b) Each component of the system should be built in accordance with plans and specifications and should be inspected, tested, and documented by qualified individuals. These activities, and the production of supporting documentation, are defined as Good Engineering Practice (GEP).嵌入的每个系统组件都应当符合计划和规定，并且应当由具有资质的人员检查测试并用文件记实。这些活动以及编制的支持文件都应当按照良好工程规范（GEP）进行规定。c) GEP recommends a minimum level of documentation for all systems and equipment. This encompasses design, fabrication, vendor testing, construction, field inspection, and commissioning. If these documents are appropriately planned, organized, and authorized, they may become an integral part of qualification support documentation, thus avoiding redundancy and saving time and money.GEP为所有系统和设备推荐了最低级别的文件，包括设计、装配、供应商测试、建造、现场检查及调试。如果这些文件都经适当的计划、组织及认可，那么它们就可以整合成确认支持文件，从面避免了重复，节省了时间和金钱。d) Design criteria and documentation requirements should be clearly defined early in the design phase, to ensure clear expectations and appropriate planning, and facilitate timely commissioning and validation. Engineering firms, vendors, and contractors should be required, per the system specifications, to provide the necessary documentation, to avoid unnecessary costs and delays associated with obtaining or creating these documents.在设计阶段初期就应当明确规定出设计标准和文件要求，从而确保目的明确，计划适当且调试和验证推进及时。每种系统规格中，都应当要求工程公司、供应商以及承包商提供必需的文件，从而避免因为取得或起草这些文件产生的不必要的花费和延误。e) During construction, timely review of documentation and periodic walk-throughs can ensure that Installation Qualification requirements are met.建造期间，及时检查文件并定期“导览”能够确保达到安装确认的要求。f) Commissioning takes the system from a state of substantial completion to a state of operation. It is the Phase of a project that includes mechanical completion, start-up, and turnover. Commissioning incorporates a systematic method of testing and documenting the system at the conclusion of construction, and prior to the completion of validation activities.调试是将系统从完成状态带入运行状态。是一个包括机械完工、启动并循环的项目阶段。调试具体表现为建造后验证活动完成前之间的测试和文件记录系统的系统化方法。g) Commissioning documents should not be created and executed for the purpose of regulatory compliance. However, commissioning tests and documentation will typically satisfy many installation and operational qualification requirements.调试文件的编制和执行不应当只是为了顺应法规。但是，调试检测及文件将满足大多数安装和运行确认要求。SYSTEM QUALIFICATION DOCUMENTATION系统确认文件Good Engineering Practice dictates that documentation be developed to provide evidence of the design, and that the water system operations in accordance with the design. This documentation encompasses engineering, installation, inspection, and testing. Such documentation is common to all system commissioning activities and is partially summarized below:良好工程规范规定起草文件来证明设计以及水系统的运行符合设计要求。此文件包括工程技术、安装、检查以测试。此类文件是所有系统调试活动共有的，特别总结如下： A system description stating design intent 说明设计意图的系统描述 A schematic drawing of the system (P&ID) 系统概略图（P&ID） Written system specifications 编写的系统规定 Detailed design drawings 详细的设计图纸 Vendor manuals and drawings 供应商手册和图纸 Field inspection and test reports 现场检查和测试报告 System qualification test results系统确认测试结果Because of their critical impact on pharmaceutical production, water systems require additional emphasis on certain sections of this documentation. Specific design requirements for water and steam systems are contained within the body of this Guide. When compiling documentation related to water systems, particular attention should be paid to the following:由于它们对制药产品的重大影响，水系统需要对这些文件的特定部分做额外强调。水和蒸汽系统的特殊设计要求包括在本指南的主体之内。当编辑文件和水系统有关时，应当特别注意以下几点：a) Schematic documentation may be enhanced by the inclusion of a system isometric diagram (or diagrams) indicating location and numbering of welds, relative elevations, slope of lines, and points of drainage.可以用一个系统等大的图（或多图）来增强图式文件，该图上标明了焊接的搁置和编号、相对高度、管线倾斜度以及排水点。b) The system specification should indicate performance criteria, as well as design parameters. 系统规定中应当指明性能标准，以及设计参数。c) Field inspection and test reports should include cleaning and passivation procedure and record, weld parameter documentation and inspection reports, slope verification, and verification of the absence of dead-legs.现场检查和测试报告应当包括清洁和钝化的规程及报告，焊接参数文件和检查报告、倾斜验证，以及“盲管”缺乏的验证。d) System qualification tests may or may not be subject to a pre-approved protocol addressing qualification test requirements. In either case, test results should be reported in direct comparison to acceptance criteria derived from system design and operating specifications.系统确认测试可能是一个指明确认测试要求的预批准方案，也可能不是。另一方面，报告测试结果时应直接和从系统设计及运行规定中得出的验收标准做直接比较。System qualification tests should include verification of all automated functions, specified temperature control, distribution system velocity, and initial water quality determination.系统确认测试还应当包括所有自动功能、特定温度控制、分配系统速度、以及内部水质确定的验证。Additional details regarding water system qualification may be found in the associated ISPE Baseline Guide on Commissioning and Qualification.关于水系统确认的其它细节可见相关的“ISPE 关于调试和确认的基线指南”。SYSTEM QUALIFICATION SAMPLING PROGRAM系统确认取样程序The qualification of water systems is unique in that performance must be proven over an extended period of time, and is subject to variations in use rate and initial feed water quality. Therefore, the sampling program associated with pharmaceutical water systems validation is unique and specialized.水系统的确认必须唯一的，因为必须经过一个长期的性能证明，并且水系统验证应服从使用率和初始给水水质的变化。因此，制药水系统验证的取样程序是唯一的和专门的。Extensive sampling is required to establish and confirm that the entire system will operate within specified operating ranges, to develop and evaluate the system operation and maintenance procedures, and to verify that the water produced and delivered to the points of use consistently meets the required quality specifications and acceptance criteria. This portion of the program is sometimes termed performance qualification.要求进行广泛的取样以建立并确定整个系统都可在特定的操作范围下操作，并制定和评价系统操作和维护规程，此外还验证生产出的水以及连续的送到用点的水满足质量规格和验收标准。该程序部分有时被称为性能确认。Because of the critical impact that water has upon pharmaceutical quality, the sampling program and evaluation of results is usually subject to a pre-approved plan or protocol, with clearly defined acceptance criteria. Also included should be procedures to deal with deviations from specified parameters and analytical results.由于水超过了制药品质的关键影响，取样程序和结果评估通常应服从带有明确定义的验收标准的预批准的计划或方案。此外还应包括处理特定参数和分析结果的偏差的规程。The sampling program consists of three successive phases, each with a specific purpose and sampling scheme, as outlined below. The initial phase of the sampling program typically begins after the water system is shown to be fully operational, as demonstrated through integrated system testing in Operational Qualification.如下表所示，取样程序由三个连续的阶段构成，每个阶段都有特定的目的和取样计划。如运行确认中的整体系统测试所示范的那样，取样程序的初始阶段在水系统已经显示完全运行后开始。The water generated during the various phase may be used for manufacturing as long as analytical result are acceptable. The intended applications and impact of water quality should be considered in determining how much data is required before use:只要分析结果是合格的，各个阶段生成的水都可用于生产。应考虑到水质的预期应用和影响，以确定使用前需要多少数据：Table 10-1 Sampling Program表10-1 取样程序Phase 阶段Primary Objectives 主要目的Typical Duration 持续时间1 Develop appropriate operating ranges.建立适当的操作范围。 Develop and finalize operating, cleaning, and maintenance procedures. 建立并最终制定操作、清洁和维护规程。 Demonstrate production and delivery of water of the required quality.表明生产和输送水的要求的质量2-4 weeks 2-4周2 Demonstrate consistent operation within established ranges.证明操作在已建立的范围内 Demonstrate consistent production and delivery of water of the required quality.证明生产和输送水的要求的质量一致2-4 weeks 2-4周3 Demonstrate extended performance.证明扩展的性能 Ensure that potential seasonal variations are evaluated and treated. 确保可能的季节变化是经评价和处理的One year 1年10.3.1 Phase 110.3.1 阶段1The purpose of this phase is to establish appropriate operating ranges and provide data for the development of cleaning and sanitization procedures and frequencies. Sampling should be performed after each step in the treatment process and from each point of use. In addition, the incoming feed water to the water system should be tested and verified to comply with the relevant Drinking Water regulations. The FDA Guide to Inspections of High Purity Water Systems suggests daily sampling for two to four weeks, but recognizes that other sampling programs may be acceptable.该阶段的目的是建立适当的操作范围并为制定清洁和消毒规程和频率提供数据。应在处理过程中的每个步骤之后以及每个用点处进行取样。此外，应检测进入水系统的给水，并验证其是否满足相关“饮用水”规程。关于高纯水系统的检查的FDA指南建议每日取样并持续2-4周，但也承认可接受其他的取样计划。In devising the sampling scheme, consideration should be given to the system configuration, maintenance cycles, how the water is drawn for use, and the expected or potential variation in chemistry and microbiological attributes, at each potential sample point. In treatment, chemistry testing is specific for each processing step and microbiological testing between each component is important to determine the microbial load and the components ability to manage the load.在设计取样方案中，应考虑到系统的构型、维护循环、水是如何取来使用的，以及每个可能的取样点预期的或潜在的化学和微生物性质的变化。在处理中，各个加工步骤的化学检测是特定的，并且各个组件之间的微生物检测对于确定微生物载量和组件处理负载的能力是非常重要的。At the end of this phase, the SOPs for system operation and maintenance should be developed and approved for continued interim use during the next phase. System logs, documentation for critical parameters (e.g., conductivity and TOC data, sanitization data, etc.), and responses to critical alarms or action levels should be reviewed, to verify the appropriate procedures are in place. In addition, the process that will be followed to investigate a confirmed test failure should be developed at this time. The intent of this process is to assess whether a failure is localized (i.e., isolated to a specific port) or systematic, and to define how different types of failures will be handled.该阶段结束时，应制定系统操作和维护的SOP，并应经批准可继续暂时用于下一阶段。应检查关键参数（电导率和TOC数据、消毒数据等）的系统日志、文件以及对危机警报的回应或行为水平，以查证适当的规程是否在位。此外，在此时还应建立检查经确认的检测失败遵循的程序。该程序的目的是评价失败是某位点上的（如：某个特定的独立的端口）还是整个系统的，并确定怎样处理不同类型的失败。10.3.2 Phase 210.3.2 阶段2The second phase is intended to demonstrate that the system consistently operates within predetermined operating ranges and delivers water of the required quality when operated in accordance with the SOPs. The FDA Guide suggests that the sampling scheme and duration should be the same as for phase one. During phases 1 and 2, multiple samples should be taken from each point of use. Sampling methodology should be representative of the way water will be used. For example, sampling should not involve a lengthy preliminary purge if water usage will be direct and immediate. If water is used through an attached hose/then the sample should be taken from the hose.第二阶段的目的是证明系统可在预设的操作范围内可连续的操作，并且当依照SOP操作时能传送处满足质量要求的水。FDA指南建议取样计划和持续时间和第一阶段一样。在阶段1和阶段2，应对各个用点重复取样。取样方式应和用水时去水方式一样。例如，如果是直接并立即使用的水，取样时应不涉及一个漫长的预清洁过程。如果用水是由一个连着的胶皮管出来的，那么样品也应经胶皮管取出。It is recommended that each point be sampled at least once per week as a minimum. In this manner, localized contamination may be discovered. (Note that too frequent sampling of little used points may mask incipient localized microbial growth by artificial purging.) Phase 2 allows the gathering of sufficient data to establish microbial alert and action limits (see Section 10.4).建议每个取样点至少每星期取样一次。这样，就可以发现污染的位置。（注意：对不常用的用点过于频繁的取样，会因人为的放水掩盖了其初始的微生物生长。）在阶段2应收集充分的数据以建立微生物警报界限和行动界限（见10.4部分）。10.3.3 Phase 310.3.3 阶段3The third phase is intended to demonstrate that, when operated for an extended time period (typically one year), the system produces and delivers water of the required quality, despite possible seasonal variations of the feed water. Sample locations, frequencies, and test requirements are based on the established procedures. For WFI systems, the FDA Guide recommends sampling daily from a minimum of one point of use, with all points of use tested weekly. At the end of this phase (i.e., after a full year of testing), the validation is considered completed. In most cases, ongoing monitoring will establish a continuing record of water quality.第三阶段目的是证明，在延长操作期（通常是一年），尽管存在可能因季节变化而引起的给水变化，系统仍能生产并输送出满足质量要求的水。取样位点、频率和检测规格是以已建立的规程为基础的。对于注射用水系统，FDA指南建议至少每天要从一个用点取样，在一周之内将所有的用点都取到。在该阶段的结束时（如，检测一年以后），就认为验证已经完成了。多数情况下，进行的监控将建立一份水质的持续记录。10.4 ACCEPTANCE CRITERIA10.4 验收标准Acceptance criteria for water are dependent upon its use. For both Purified Water and WFI, the chemical acceptance criteria are clearly described in the US Pharmacopoeia (USP). It is expected that a well designed water system, operating within specified design parameters will consistently be able to meet these criteria. Therefore, failures in chemical analysis during phases 1 and 2 must be investigated, the reason for failure corrected, and (except where errors in sampling or laboratory error are clearly indicated) the sampling phase extended to re-establish consistency of performance.对水的验收标准取决于它的使用。对于纯化水和注射用水来说，美国药典（USP）中明确的描述了化学验收标准。一般认为在特定设计参数内操作的一个设计良好的水系统是可以一直满足这些标准的。因此，必须调查在阶段1和阶段2中出现的化学分析失败以及经校正的失败的原因，以及（清晰表明的取样错误和实验室错误除外）必须延长取样阶段以重新建立性能的一致性。Microbial quality is not specified by the USP, but is established by the user based upon water use. The USP does recommend action limits for the different waters in its General Information chapter. These are 10 CFU/100ml for WFI and 100 CFU/ml for Purified Water. These may be employed as initial acceptance criteria for system qualification, although some flexibility is allowable, depending upon system design and use. It is permissible that a single excursion, followed by acceptable re-sampling would not constitute a failure. In addition, because of the inherently bacteriostatic nature of WFI production and distribution systems, it should be expected that the large majority of samples should be well below the initial acceptance criterion. Therefore, for WFI it is prudent to establish a sample average acceptance criterion, which will be below the limit for a single sample. Failure investigation would be handled similarly to chemical analysis failure.USP没有规定微生物质量，但用户可根据水的应用来建立。USP在其总论章节介绍了对于不同的水的行动限度。注射用水的限度是10 CFU/100ml，纯化水的限度是100 CFU/ml。这可作为系统确认的初始验收