when preparing the cleaning validation protocol, e.g. V-blenders, transfer pumps or ? lling lines.
设备的设计可能会影响清洁工艺的效果。因此起草清洁验证方案时，要考虑设备的设计因素，如V-搅拌机、传送泵和灌装生产线等。 7. Detergents 清洁剂
7.1 Detergents should facilitate the cleaning process and be easily re-movable.
Detergents that have persistent residues such as cationic deter-gents which adhere very strongly to glass and are dif?cult to remove, should be avoided where possible.
清洁剂应适合清洁工艺的要求，并且本身易被清除。阳离子清洁剂对玻璃有很强的吸附作用，且难以去除，因此，应尽可能避免使用这类能导致难以去除的残留出现的清洁剂。
7.2 The composition of the detergent should be known to the manufac-turer and
its removal during rinsing, demonstrated.
药品生产商应清楚清洁剂的组成，且淋洗工艺对于清洁剂的清除效果也应得到证实。
7.3 Acceptable limits for detergent residues after cleaning should be de-?ned. The
possibility of detergent breakdown should also be considered when validating cleaning procedures.
应规定清洁后，清洁剂的残留限度。验证清洁程序时，应考虑到可能发生的清洁剂的降解。
7.4 Detergents should be released by quality control and, where pos-sible, should
meet local food standards or regulations.
选用的清洁剂应当得到质量控制部门的认可，有时还可能需要符合当地的食品标准或管理条例的要求。 8. Microbiology 微生物
8.1 The need to include measures to prevent microbial growth and re-move
contamination where it has occurred should be considered.
应考虑对预防微生物生长以及污染发生后如何去除污染的方法的需求。 8.2 There should be documented evidence to indicate that routine clean-ing and
storage of equipment does not allow microbial proliferation.
应有说明日常清洁和设备的贮存不利于微生物生长的文件证明。
8.3 The period and conditions for storage of unclean equipment before cleaning,
and the time between cleaning and equipment reuse, should form part of the validation of cleaning procedures.
验证清洁程序时，还应验证未清洁设备的贮存时间和贮存条件，清洁后至再次使用设备之间的时间间隔。
8.4 Equipment should be stored in a dry condition after cleaning. Stagnant water
should not be allowed to remain in equipment after cleaning. 清洁后，设备上不得有积水，且应贮存在干燥环境中。
8.5 Control of the bioburden through adequate cleaning and appropriate storage of
equipment is important to ensure that subsequent sterilization or sanitization
procedures achieve the necessary assurance of sterility, and the control of pyrogens in sterile processing. Equipment sterilization processes may not be adequate to achieve signi?cant inactivation or removal of pyrogens.
为确保后续的灭菌或卫生规程可实现无菌工艺要求的无菌保证水平和热原控制，应重视良好的清洁和适当的贮存对设备上的生物负载所起的控制作用；单凭设备灭菌工艺，可能不足以满足灭活和去除热原的要求。 9 Sampling 取样 9.1 General 概要
9.1.1 Equipment should normally be cleaned as soon as possible after use. This may be especially important for operations with topical products, sus-pensions and bulk drug or where the drying of residues will directly affect the ef?ciency of a cleaning procedure.
通常，使用设备后，应尽快清洁；尤其是用来生产那些残留物干燥后能直接影响清洁程序的产品、混悬液和散装药品的设备。
9.1.2 Two methods of sampling are considered to be acceptable. These are direct surface sampling and rinse samples. A combination of the two methods is generally the most desirable.
可使用的取样方法有两种：表面直接取样和淋洗水取样。一般来说，最好同时使用这两种方法。
9.1.3 The practice of resampling should not be used before or during cleaning and operations and is acceptable only in rare cases. Constant retesting and resampling can show that the cleaning process is not validated because these retests actually document the presence of unacceptable residue and contaminants resulting from an ineffective cleaning process.
在清洁和使用设备之前，或在清洁和使用过程中，都不应重新取样；在这些时期，只有极少数的情况，方可重新取样。不断的重新检验和取样得到的结果可能显示该清洁工艺无效，这是因为，只有导致残留限度超标和污染物出现的无效的清洁工艺才需要重新检验。 9.2 Direct surface sampling (direct method) 表面直接取样（直接法）
Note: This method of sampling is the most commonly used and involves taking an inert material (e.g. cotton wool) on the end of a probe (referred to as a ―swab‖) and rubbing it methodically across a surface. The type of sampling material used and its potential impact on the test data is important as the sampling material may interfere with the test. (For example, the adhesive used in swabs has been found to interfere with the analysis of samples.)
注：这种方法是最常用的。通常使用一端缠绕有不掉纤维的材料（如棉花）的棒（通常称为药签）擦拭取样表面，从而达到取样的目的。要注意的是，药签头的材料对检测可能会产生干扰，因而对实验结果可能有显著影响。（例如，已证实药签上使用的粘合剂会感染样品分析。）
9.2.1 Factors that should be considered include the supplier of the swab, area swabbed, number of swabs used, whether they are wet or dry swabs, swab handling and swabbing technique. 需要考虑的与药签有关的因素有：药签的供应商、擦拭面积、药签的使用量、药签的状态是润湿还是干燥、药签的贮存和擦拭方法等。
9.2.2 The location from which the sample is taken should take into consideration the composition of the equipment (e.g. glass or steel) and the location (e.g. blades, tank walls or ?ttings). Worst case locations should be considered. The protocol should identify the sampling locations.
选择取样点时，应考虑到设备的构造（如玻璃材料或钢铁材料）、安装位置（如锟刀、贮槽壁和其它装置等）。应当考虑最差状况的安装位置，并在方案中阐明取样点的选择。
9.2.3 Critical areas, i.e. those hardest to clean, should be identi? ed, par-ticularly in large systems that employ semi-automatic or fully automatic clean-in-place systems.
应确定哪些区域属于关键区域（如最难清洁的区域），尤其是那些使用了半自动或全自动在线清洁设备的大型系统的区域。
9.2.4 The sampling medium and solvent used should be appropriate to the task. 采用的取样方法和溶剂应当能满足检验的需要。 9.3 Rinse samples (indirect method) 淋洗水取样（间接取样）
Note: This method allows sampling of a large surface, of areas that are in-accessible or that cannot be routinely disassembled and provides an overall picture. Rinse samples may give suf?cient evidence of adequate cleaning where accessibility of equipment parts can preclude direct surface sam-pling, and may be useful for checking for residues of cleaning agents, e.g. detergents.
注：该方法为大面积取样方法，对不易接触到的表面和不便经常拆卸的设备也能取样。淋洗水取样不仅可证明不易直接取样的设备表面的清洁效果，而且在检查清洁剂残留时也十分有用。
9.3.1 Rinse samples should be used in combination with other sampling methods such as surface sampling.
淋洗水取样可与表面直接取样等取样方法一同使用。
9.3.2. There should be evidence that samples are accurately recovered. For example, a recovery of > 80% is considered good, > 50% reasonable and < 50% questionable.
应证明样品的回收率。例如，大于80%的回收率可视为良好；大于50%也属于合理，可以接受；若小于50%，则该样品的质量很可疑。 9.4 Batch placebo method 模拟批生产法
Note: This method relies on the manufacture of a placebo batch which is then
checked for carry-over of the previous product. It is an expensive and laborious process. It is dif?cult to provide assurance that the contaminants will be dislodged from the equipment surface uniformly. Additionally, if the particles of the contaminant or residue are large enough, they may not be uniformly dispersed in the placebo batch.
注：该法要求模拟一个批次的生产，然后检查前批生产的残留污染，也因为这样，这种方法耗资且耗时。要想给出已经清除全部设备表面的污染的证明，是很不轻松的工作。此外，若污染物或残留物的颗粒太大，它们也可能不会全部转移到模拟生产的批次中去。
9.4.1 The batch placebo method should be used in conjunction with rinse and/or surface sampling method(s).
模拟批生产法应与淋洗取样和/或表面直接取样法联合使用。
9.4.2 Samples should be taken throughout the process of manufacture. Traces of the preceding products should be sought in these samples. (Note that the sensitivity of the assay may be greatly reduced by dilution of the contaminant.) 生产过程也应取样。应通过这些样品，追踪生产的前批产品的痕迹。（注意：因为污染物的稀释，分析实验的灵敏度也会大大降低。）
10. Analytical methods 分析方法
10.1 The analytical methods should be validated before the cleaning vali-dation is performed.
执行清洁验证前，应验证分析方法。
10.2 The methods chosen should detect residuals or contaminants speci?c for the substance(s) being assayed at an appropriate level of cleanliness (sensitivity). 选用的方法应能检测待分析物中特定的残留物或污染物的含量（灵敏度）。 10.3 Validation of the analytical method should include as appropriate: 分析方法验证应包括以下内容：
— precision, linearity and selectivity (the latter if speci?c analytes are targeted); 精确度、线性和选择性（选择性仅针对特定的分析物而言）； — limit of detection (LOD); 检测限（LOD）；
— limit of quantitation (LOQ); 定量限（LOQ）；
— recovery, by spiking with the analyte; and 添加了标准样的分析物的回收率； — reproducibility. 再现性。
10.4 The detection limit for each analytical method should be suf? ciently sensitive to detect the established acceptable level of the residue or contaminants. 每种分析方法的检测限的灵敏程度应足以检测残留物或污染物的合格限度的量。
10.5 Suitable methods that are sensitive and speci?c should be used where possible and may include chromatographic methods (e.g. high pres-sure liquid
chromotography (HPLC), gas chromotography (GC), and high pressure thin-layer chromatography (HPTLC)). Other methods may include (alone or in combination) measurement of total organic carbon (TOC), pH, or conductivity; ultraviolet (UV) spectroscopy; and enzyme-linked immu-nosorbent assay (ELISA). 分析方法应当具备专属性和一定的灵敏度，如色谱（如高效液相色谱（HPLC）、气相色谱（GC）、高效波层色谱（HPTLC））。其它可能用到的方法还有（单独使用或联合使用）总有机碳（TOC）、pH和电导率测定法、紫外（UV）吸收光谱和酶联免疫吸附分析法（ELISA）。 139 Establishing acceptable limits 建立合格限度
Note: uniform distribution of contaminants is not guaranteed. 注 ：不能保证污染物的分布是均匀的。
11.1 The acceptance criteria established for contaminant levels in the sample should be practical, achievable and veri?able. The rationale for the residue limits established should be logical, and based on the knowledge of the materials involved.
要根据物料的性质和残留限度的确定原理，建立污染物残留的合格标准；建立的限度应是现实的、可行的和可以证明的。
11.2 Each situation should be assessed individually. The manner in which limits are established should be carefully considered. In establishing re-sidual limits it may not be adequate to focus only on the principal reactant, because other chemical variations may be more dif?cult to remove.
应当分别评估每种情况，仔细选择建立限度的方式。确定限度时，仅仅考虑主要反应物是不够的，因为其它的化学反应的产物可能更难以去除。 11.3 Where necessary, screening using thin-layer chromatography should be performed in addition to chemical analyses.
需要时，可用薄层色谱法作为化学分析方法的补充。
11.4 There should be no residue from the previous product, from reaction by-products and degradants, or from the cleaning process itself (e.g. deter-gents or solvents).
不应检测出前批产品、副产物、降解物和清洁工艺本身造成的物质（如清洁剂和溶剂）的残留。
11.5 The limit-setting approach can: 限度设置方法可以是：
140 be product-speci? c; 产品专一的；
141 group products into families and choose a worst case product; 先将产品归入家族，然后再选择最差状况的产品；
142 group products into groups according to risk, e.g. very soluble products, products with similar potency, highly toxic, or dif?cult to detect products;
根据风险将产品归类，如极易溶产品、效能相似的产品、剧毒产品和难检测产品等；