Appendix 2 附录 2
Validation of water systems for pharmaceutical use
制药用水系统的验证
83 General 概要
84 Start-up and commissioning of water systems 水系统的启用和试运行 85 Quali?cation 确认 86 Reference 参考文献
1. General 概要
1.1 All water-treatment systems should be subject to planned mainte-nance, validation and monitoring.
应针对所有水处理系统，计划其维护、验证和监控。
1.2 Validation of water systems should consist of at least three phases: Phase 1: investigational phase; Phase 2: short-term control; and Phase 3: long-term control. 水系统的验证至少分三个阶段：1.调查阶段；2.短期控制；3.长期控制。 1.3 During the period following phase 3 (typically running for one year) the objective should be to demonstrate that the system is under control over a long period of time. Sampling may be reduced from, e.g. daily to weekly.
第三阶段（通常为一年）完成之后，接下来的任务是证明该系统能在相当长的时期内处于受控状态，这时，取样频率可减少为一日一次至每周一次。 1.4 The validation performed and revalidation requirements should be included in the ―Water quality manual‖.
应在―水质量手册‖中说明已执行的验证和再验证的要求。 2. Start-up and commissioning of water systems 水系统的启用和试运行
2.1 Planned, well-de?ned, successful and well-documented commission-ing is an essential precursor to successful validation of water systems. The commissioning work should include setting to work, system set-up, controls, loop tuning and
recording of all system performance parameters. If it is in-tended to use or refer to commissioning data within the validation work then the quality of the commissioning work and associated data and documenta-tion must be commensurate with the validation plan requirements.
计划良好、定义完整、成功并拥有优秀的文件的试运行是成功的水系统验证的先决条件，它的工作内容包括运行设置、系统安装、控制、回路调整和记录所有的系统性能参数。如某项试运行或试运行的数据为验证活动所囊括，那么该试运行工作的质量和相关数据及文件必须符合验证计划的要求。 3 Qualification
确认
3.1 Water for pharmaceutical use (WPU), puri?ed water (PW), highly puri?ed water (HPW) and water for injections (WFI) systems are all con-sidered to be direct impact, quality critical systems that should be quali? ed. The quali?cation should follow the validation convention of design review or design quali?cation (DQ), installation quali?cation (IQ), operational quali?cation (OQ) and performance quali? cation (PQ).
制药用水（WPU）、纯化水（PW）、高度纯化水（HPW）和注射用水（WFI）系统都是能对产品质量产生直接影响的关键质量系统，因此需要对它们全部开展确认活动。确认活动的开展应遵循的验证规定有设计审核或设计确认（DQ）、安装确认（IQ）、运行确认（OQ）和性能确认（PQ）。 3.2 This guidance does not de?ne the standard requirements for the con-ventional validation stages DQ, IQ and OQ, but concentrates on the par-ticular PQ approach that should be used for WPU systems to demonstrate their consistent and reliable performance. A three-phase approach should be used to satisfy the objective of proving the reliability and robustness of the system in service over an extended period.
本指南并未详细说明DQ、IQ和OQ的常规验证阶段，而将重点放在说明用以证明WPU系统性能的连续性和可靠性的PQ方法上；为证明该系统在相当长的时期内的可靠性和耐用性，可将该过程分为三个阶段。
Phase 1. A test period of 2–4 weeks should be spent monitoring the sys-tem intensively. During this period the system should operate continuously without failure or performance deviation. The following procedures should be included in the testing approach.
第一阶段 应在2-4周的测试期内对该系统进行密集监控。在这段时间里，运行未间断的水系统应不出现故障，也不会有性能偏差。下面列出的是测试方法应囊括的步骤：
87 Undertake chemical and microbiological testing in accordance with a de? ned plan.
根据既定计划，采用化学和微生物试验。
88 Sample the incoming feed-water to verify its quality. 为确认水质，对进水采样。
89 Sample after each step in the puri?cation process daily. 每天都对纯化工艺的每一步骤的水进行采样。
90 Sample at each point of use and at other de?ned sampling points daily. 每天对每个使用点及指定的取样点采样。 91 Develop appropriate operating ranges. 研究制订适当的运行范围。
92 Develop and ?nalize operating, cleaning, sanitizing and maintenance procedures.
研究并完成操作、清洁、卫生和维护规程。
93 Demonstrate production and delivery of product water of the required quality and quantity.
证明产水的生产和输送符合质量和数量的要求。
94 Use and re?ne the standard operating procedures (SOPs) for operation, maintenance, sanitization and troubleshooting.
在执行系统操作、维护、卫生和解决故障时，使用且不断完善标准操作规程（SOP）。
95 Verify provisional alert and action levels. 确认临时的警戒线的行动限
96 Develop and re?ne the test-failure procedure. 研究并不断完善失败试验的处理规程。
Phase 2. A further test period of 2–4 weeks should be spent carrying out further intensive monitoring while deploying all the re?ned SOPs after the satisfactory completion of phase 1. The sampling scheme should be gener-ally the same as in phase 1. Water can be used for manufacturing purposes during this phase. The approach should also:
第二阶段 圆满完成第一阶段后，接下来的2-4星期，应在使用所有完善后的SOP的同时，实施进一步的密集监控，取样计划也应当与第一阶段大致相同。这个阶段生产得到的水可用于生产。就目的而言，该阶段应：
97 — demonstrate consistent operation within established ranges; and 证明系统的持续运行不超出既定范围；
98 — demonstrate consistent production and delivery of water of the required quan-tity and quality when the system is operated in accordance with the SOPs. 在按照SOP操作的同时，证明水的持续生产和运输符合质量和数量的要求。
Phase 3. Phase 3 typically runs for one year after the satisfactory comple-tion of phase 2. Water can be used for manufacturing purposes during this phase which has the following objectives and features:
第三阶段 完成第二阶段后，通常需要再花一年来实施第三阶段。第三阶段生产得到的水可供生产使用。这个阶段的活动应当： 99 Demonstrate extended reliable performance.
证明在延长的时期内，系统性能仍然可靠。 100 Ensure that seasonal variations are evaluated.
确保已经评估了季节性差异。
101 The sample locations, sampling frequencies and tests should be reduced to
the normal routine pattern based on established procedures proven during phases 1 and 2.
在第一和第二阶段里证实的既定规程的基础上，取样点、取样频率和试验都应减少至正常的日常模式。
Reference 参考文献
1. WHO good manufacturing practices: water for pharmaceutical use. Geneva,
World Health Organization 2005 (WHO Technical Report Series, No. 929), Annex 3.
Appendix 3 附录 3
Cleaning validation
清洁验证
102 Principle 基本原则 103 Scope 范围 104 General 概要
4. Cleaning validation protocols and reports 清洁验证的方案和报告
4.1 Cleaning validation protocols 清洁验证方案
4.2 Cleaning validation reports 清洁验证报告 5 Personnel 人员
6 Equipment 设备
7 Detergents 清洁剂
8 Microbiology 微生物 9. Sampling 取样
9.1 General 概要
9.2 Direct surface sampling (direct method) 表面直接取样（直接法） 9.3 Rinse samples (indirect method) 淋洗取样（间接法） 9.4 Batch placebo method 模拟批生产法 10 Analytical methods 分析方法
11 Establishing acceptable limits 建立合格限度
1. Principle 基本原则
1.1 The objectives of good manufacturing practices (GMP) include the prevention of
possible contamination and cross-contamination of pharma-ceutical starting materials and products.
药品生产管理规范针对的对象还包括预防制药生产的起始物料和产品潜在的污染和交叉污染。 1.2 Pharmaceutical products can be contaminated by a variety of substances such as
contaminants associated with microbes, previous products (both active pharmaceutical ingredients (API) and excipient residues), residues of cleaning agents, airborne materials, such as dust and particulate matter, lubricants and ancillary material, such as disinfectants, and decomposition residues from:
药品可能会受到微生物、前批产品（活性药物成分（API）和辅料残留）、清洁剂的残留、空气中的物质如尘埃和颗粒物质等、润滑剂和辅助物料如消毒剂残留和分解后的残余物质，这些污染可能源自： — product residue breakdown occasioned by, e.g. the use of strong acids and
alkalis during the cleaning process; and
偶然的残留产品的分解，如因为清洁过程使用的强酸和强碱而造成的物质的分解；
— breakdown products of the detergents, acids and alkalis that may be used as
part of the cleaning process.
清洁过程中可能使用的清洁剂、酸和碱的分解。
1.3 Adequate cleaning procedures play an important role in preventing contamination
and cross-contamination. Validation of cleaning methods provides documented evidence that an approved cleaning procedure will provide clean equipment, suitable for its intended use.
良好的清洁方法能有效预防污染和交叉污染。清洁方法的验证的文件资料可证明获准的清洁方法能够在清洁设备上获得令人满意的效果。 1.4 The objective of cleaning validation is to prove that the equipment is consistently
cleaned of product, detergent and microbial residues to an ac-ceptable level, to prevent possible contamination and cross-contamination.
清洁验证的目的在于证明所使用的清洁方法能持续有效地去除产品、清洁剂和微生物残留，产生令人满意的清洁效果，从而实现对潜在的污染和交换污染的预防。 1.5 Cleaning validation is not necessarily required for non-critical clean-ing such as
that which takes place between batches of the same product (or different lots of the same intermediate in a bulk process), or of ? oors, walls, the outside of vessels, and following some intermediate steps.
非关键对象的清洁，如同一产品不同批次（或同一工艺中的同一种简体的不同小批）的生产之间的清洁、地面、墙、容器外表面和针对中间产品的某些后续步骤是不一定要求验证的。 1.6 Cleaning validation should be considered important in multiproduct facilities and
should be performed among others, for equipment, sanitiza-tion procedures and garment laundering.
对于有多种产品的工厂，清洁验证尤为重要。除了厂房设施的清洁以外，设备、卫生规程和洗衣程序也需要验证。