2. Scope 范围
2.1 These guidelines describe the general aspects of cleaning validation,
excluding specialized cleaning or inactivation that may be required, e.g. for removal of viral or mycoplasmal contaminants in the biological manufac-turing industry.
这里给出的指南对清洁验证进行了大致说明，但某些可能需要实施的特别的清洁或钝化程序（如生物制品生产车间内，对滤过性病毒或支原体污染的去除）的验证则不在此列。
2.2 Normally cleaning validation would be applicable for critical clean-ing such
as cleaning between manufacturing of one product and another, of surfaces that come into contact with products, drug products and API.
往往只有关键对象的清洁需要验证，如在更换生产的产品之间对生产区域的清洁，或与产品、制剂和API直接接触的表面的清洁。 3. General 概要
3.1 There should be written SOPs detailing the cleaning process for equipment
and apparatus. The cleaning procedures should be validated.
应当有详细说明设备和仪器的清洁方法的书面SOP，并验证这些清洁程序。 3.2 The manufacturer should have a cleaning policy and an appropriate procedure
for cleaning validation, covering: 生产商应当制定有清洁方针，并为清洁验证制定合适的程序，其内容应包括： 105 surfaces that come into contact with the product;
与产品直接接触的表面；
106 cleaning after product changeover (when one pharmaceutical formula-tion is
being changed for another, completely different formulation);
更换生产的产品之间的清洁（用一种药品配方替代另一种完全不同的配方）；
107 between batches in campaigns (when the same formula is being
manufac-tured over a period of time, and on different days);
开始不同批次的产品生产之前的清洁（当某种配方的产品已持续生产了一段时间时，每天重新开始生产之前，都要求对现场进行清洁）； 108 bracketing products for cleaning validation. (This often arises where
products contain substances with similar properties (such as solubili-ty) or the same substance in different strengths. An acceptable strategy is to ?rst manufacture the more dilute form (not necessarily the lowest dose) and then the most concentrated form. There are sometimes ―fam-ilies‖ of products which differ slightly as to actives or excipients.); and
生产相似的产品所需的清洁验证（当产品的成分性质相似（如溶解度）或含有不同含量的同种物质时，往往需要。出现这种情况时，可先生产稀释倍数较大（不一定是最低剂量）的产品形式，再生产浓度较大的产品。有时，可能会出现同一―家族‖的产品，它们的差别不大，仅在活性成分或辅料上有微小的区别）；
109 periodic evaluation and revalidation of the number of batches manufac-tured
between cleaning validations.
对两次清洁验证之间生产的产品批次进行定期评估和开展再验证。
3.3. At least three consecutive applications of the cleaning procedure should be
performed and shown to be successful to prove that the method is validated. 至少应对三个连续生产的批次实施清洁程序，当且仅当这三次清洁程序的实施都取得了满意的效果时，方可证明该清洁方法的效力。 110 Cleaning validation protocols and reports 清洁验证的方案和报告
4.1 Cleaning validation protocols 清洁验证的方案
4.1.1 Cleaning validation should be described in cleaning validation protocols, which should be formally approved, e.g. by the quality control or quality assurance unit.
在清洁验证方案中，必须描述清洁验证。这份清洁验证方案应得到如质量控制或质量保证部门的批准。
4.1.2 In preparing the cleaning validation protocol, the following should be considered:
准备清洁验证方案时，需要考虑的问题如下：
111 — disassembly of system; 系统的拆卸； 112 — precleaning; 预清洗；
113 — cleaning agent, concentration, solution volume, water quality; 清洁剂、清洁溶液的浓度、数量、水质等； 114 — time and temperature; 时间和温度；
115 — ?ow rate, pressure and rinsing; 流速、压强和淋洗；
116 — complexity and design of the equipment; 设备的复杂程度和设计； 117 — training of operators; and 操作者的培训； 118 — size of the system. 系统的大小。
4.1.3 The cleaning validation protocol should include: 清洁验证方案的内容有：
119 the objectives of the validation process;
验证的目的；
120 the people responsible for performing and approving the validation study;
负责实施和批准验证研究的责任人；
121 the description of the equipment to be used, including a list of the
equip-ment, make, model, serial number or other unique code;
将用到的设备的说明，包括设备清单、制造商、型号、序列号或其它独有的代码；
122 the interval between the end of production and the commencement of the
cleaning procedure (interval may be part of the validation challenge study itself)
生产结束至开始清洁之间的时间间隔（该时间间隔本身可能就是挑战性验证研究的组成部分）
the maximum period that equipment may be left dirty before being cleaned as well as the establishment of the time that should elapse after cleaning and before use;
生产结束至开始清洁之间的最长时间，以及清洁过后至开始生产之前的时间间隔的确定；
123 the levels of microorganisms (bioburden);
微生物数量（生物负载）；
124 the cleaning procedures (documented in an existing SOP, including de?
-nition of any automated process) to be used for each product, each manu-facturing system or each piece of equipment;
每种产品、生产系统和设备的清洁程序（可在现有的SOP中查阅到这些清洁程序，其中所有自动化程序也要清楚说明）；
125 all the equipment used for routine monitoring, e.g. conductivity meters, pH
meters and total organic carbon analysers;
用于日常监控的所有设备，如电导率仪、pH计和总有机碳测定仪等； 126 the number of cleaning cycles to be performed consecutively;
需要连续运转的清洁周期的数量；
127 the sampling procedures to be used (direct sampling, rinse sampling,
in-process monitoring and sampling locations) and the rationale for their use; 将用到的取样规程（说明取样方法、淋洗取样法、过程监控和取样点）和取样方法的原理；
128 the data on recovery studies (ef?ciency of the recovery of the sampling
technique should be established);
回收试验的数据（应确定取样技术的回收率的效力）
129 the analytical methods (speci? city and sensitivity) including the limit of
detection and the limit of quanti? cation;
说明分析方法（专属性和灵敏度），包括检测限和定量限； 130 the acceptance criteria (with rationale for setting the speci?c limits)
in-cluding a margin for error and for sampling ef? ciency;
合格标准（说明专属限度的设置原理），包括误差和取样效率的安全因子；
131 the choice of the cleaning agent should be documented and approved by the
quality unit and should be scienti? cally justi?ed on the basis of, e.g.
应记录清洁剂的选择并由质量部门审批。针对该选择过程，应能在以下几个方面给出科学合理的证据：
132 — the solubility of the materials to be removed; 待去除的物质的溶解度；
— the design and construction of the equipment and surface materials to
be cleaned;
设备的设计和构造，以及待清洁的表面物质；
133 — the safety of the cleaning agent; 清洁剂的安全性； 134 — the ease of removal and detection;
其本身被清除和检测的难易程度； 135 — the product attributes; 产品的性质； 136 — the minimum temperature and volume of cleaning agent and rinse solution; and
清洁剂和淋洗溶液的温度和体积的最小值； 137 — the manufacturer's recommendations; 生产商的建议； 138revalidation requirements. 关于再验证的要求。
4.1.4 Cleaning procedures for products and processes which are very simi-lar do not need to be individually validated. A validation study of the ―worst case‖ may be considered acceptable. There should be a justi?ed validation programme for this approach referred to as ―bracketing‖, addressing critical issues relating to the selected product, equipment or process.
如产品和工艺的清洁程序很相似，那么无需分别对它们验证。验证时，需注意―最差状况‖也可能属于可接受的范畴。对这些相似的产品（同一―家族‖）和工艺的清洁方法，应有合理的验证项目阐明被选为验证对象的产品、设备或工艺的关键问题。
4.1.5 Where ―bracketing‖ of products is done, consideration should be given to type of products and equipment.
但确定了哪些产品属于同一―家族‖之后，接下来就应考虑产品和设备的类型。
4.1.6 Bracketing by product should be done only when the products con-cerned are similar in nature or property and will be processed using the same equipment. Identical cleaning procedures should then be used for these products. 仅对性质或属性相似、且生产时用到的设备也相同的产品才可被视为属于同一―家族‖。同一―家族‖的产品，可使用同样的清洁方法。
4.1.7 When a representative product is chosen, this should be the one that is most dif?cult to clean.
挑选典型产品时，应选择最难清洁的产品。
4.1.8 Bracketing by equipment should be done only when it is similar equipment, or the same equipment in different sizes (e.g. 300-l, 500-l and 1000-l tanks). An alternative approach may be to validate the smallest and the largest sizes separately.
仅相似的设备、或仅在大小上有差别的同种设备（如300-1、500-1和1000-1水槽）方可视为属于同一―家族‖。验证最小和最大的设备时，可分别选用不
同的方法。
4.2 Cleaning validation reports 清洁验证报告
4.2.1 The relevant cleaning records (signed by the operator, checked by
production and reviewed by quality assurance) and source data (original results) should be kept. The results of the cleaning validation should be pre-sented in cleaning validation reports stating the outcome and conclusion.
应保存相关的清洁记录（上有操作员的签名，由生产部门复查，并由质量保证部门的复核）和数据（原始数据）。清洁验证的报告中，应说明验证的结果，并阐明验证的成果和结论。 5. Personnel 人员
5.1 Personnel or operators who perform cleaning routinely should be trained and should be effectively supervised.
应培训执行日常清洁的人员或操作员，并监督其清洁过程。 6. Equipment 设备
6.1 Normally only procedures for the cleaning of surfaces of the equip-ment that
come into contact with the product need to be validated. Consid-eration should be given to ―non-contact‖ parts of the equipment into which product or any process material may migrate. Critical areas should be identi-?ed (independently from method of cleaning), particularly in large systems employing semi-automatic or fully automatic clean-in-place systems.
就设备清洁而言，通常只需要验证直接接触产品的设备表面的清洁方法，但也不能就此忽略不与产品直接接触的设备表面，这是因为在生产过程中，这些表面也有沾染到产品和中间物料的可能。应确定哪些区域属于关键区域（该过程不隶属清洁方法），一般来说，使用了半自动或全自动在线清洁设备的大型系统属于关键区域。
6.2 Dedicated equipment should be used for products which are dif? cult to clean,
equipment which is dif?cult to clean, or for products with a high safety risk where it is not possible to achieve the required cleaning accep-tance limits using a validated cleaning procedure.
应有专门的设备和验证过的清洁程序供清洁难以清洁的产品和设备，以及清洁效果难以达到合格标准的、具有高度安全风险的产品。
6.3 Ideally, there should be one process for cleaning a piece of equipment or
system. This will depend on the products being produced, whether the cleaning occurs between batches of the same product (as in a large campaign) or whether the cleaning occurs between batches of different products.
最好为每件设备和每个系统分别制订清洁程序；具体生产的产品决定程序的制订，不论是同种产品不同批次的生产（一次大的生产），还是不同产品的生产，都应分别制订清洁规程。
6.4 The design of equipment may in?uence the effectiveness of the cleaning
process. Consideration should therefore be given to the design of the equipment