WHO 最新清洁验证指南中英文

WHO 在上个月发布新指南 WHO TRS 1019-53，英文全文303页，本文节选其中 清洁验证部分，进行了翻译，供参考。

Appendix3

Cleaningvalidation

清洁验证

Thetext of this appendix was previously published as:

本附录的文本以前以下列形式发表:

■■ Appendix 3: Cleaning validation. In: WHO Expert Committee on

Specificationsfor Pharmaceutical Preparations, fortieth report. Geneva: World HealthOrganization; 2006: Annex 4 (WHO Technical Report

Series,No. 937;

附录3:清洁验证。在:世界卫生组织药物制剂规范专家委员会第四十次报告。日内瓦,世界卫生组织;2006:附件4(世卫组织技术报告系列，第937号;

https://www./medicines/areas/quality_safety/quality_assurance/SupplementaryGMPValidationTRS937Annex4.pdf?ua=1).

1.Principle 原则138

2.Scope 范围138

3.General 概述139

4.Cleaning validation protocols and reports 清洁验证方案和报告139

5.Personnel 人员142

6.Equipment 设备142

7.Detergents 清洗剂142

8.Microbiology 微生物143

9.Sampling 取样143

10.Analytical methods 分析方法145

11.Establishing acceptable limits 确定可接受标准146

1.Principle原则

1.1The objectives of good manufacturing practices (GMP) include the prevention of possiblecontamination and cross-contamination of pharmaceutical starting materials andproducts.

药品生产质量管理规范(GMP)的目标包括防止可能的污染和药物原料和产品的交叉污染。

1.2Pharmaceutical products can be contaminated by a variety of substances such ascontaminants associated with microbes, previous products (both activepharmaceutical ingredients [APIs] and excipient residues), residues of cleaningagents, airborne materials, such as dust and particulate matter,lubricants andancillary material, such as disinfectants, and decomposition residues from:

药品可以被各种物质污染,如污染物与微生物有关,以前的产品(包括原料药(api)和赋形剂残留),残留的清洁剂,空气传播的物料,如灰尘和颗粒物。润滑剂和辅助材料,如消毒剂、和残留降解产物:

■■ product residue breakdown occasioned by, for example, the use of strongacids and alkalis during the cleaning process;

例如，在清洗过程中使用强酸和强碱会导致产品残渣分解

■■ breakdown products of the detergents, acids and alkalis that may beused as part of the cleaning process.

洗涤剂、酸和碱的分解产物，可作为清洗工艺的一部分。

1.3Adequate cleaning procedures play an important role in preventing contaminationand cross-contamination. Validation of cleaning methods provides documentedevidence that an approved cleaning procedure will provide clean equipment,suitable for its intended use.

适当的清洗程序对防止污染和交叉污染具有重要作用。清洗方法的验证提供文件证明，经批准的清洗程序将提供与其预期用途相适应的清洁设备。

1.4The objective of cleaning validation is to prove that the equipment is consistentlycleaned of product, detergent and microbial residues to an acceptable level, toprevent possible contamination and cross-contamination.

清洁验证的目的是证明设备对产品、洗涤剂和微生物残留物的清洗一致并达到可接受的水平，以防止可能的污染和交叉污染。

1.5Cleaning validation is not necessarily required for non-critical cleaning suchas that which takes place between batches of the same product (or differentlots of the same intermediate in a bulk process), or of floors, walls, theoutside of vessels, and following some intermediate steps.

清洁验证对于非关键性的清洗并不一定是必需的，例如批次相同的产品(或散装过程中相同中间体的不同批次)、地板、墙壁、容器外部以及以下一些中间步骤之间的清洗。

1.6Cleaning validation should be considered important in multiproduct facilitiesand should be performed, among others, for equipment, sanitization proceduresand garment laundering.

清洁验证应被认为在多产品设施中很重要，并应在设备、消毒程序和服装洗涤等方面进行验证。

2.Scope 范围

2.1These guidelines describe the general aspects of cleaning validation, excludingspecialized cleaning or inactivation that may be required, for example, forremoval of viral or mycoplasmal contaminants in the biological manufacturingindustry.

这些指南描述了清洁验证的一般方面，不包括可能需要的特殊清洗或灭活，例如，在生物制造业中去除病毒或支原体污染物。

2.2Normally, cleaning validation would be applicable for critical cleaning such ascleaning between manufacturing of one product and another, of surfaces thatcome into contact with products, drug products and APIs.

一般情况下，清洁验证适用于关键的清洗，例如在生产一种产品与另一种产品，与产品、药品和原料药接触的表面之间的清洗。

3.General 概述

3.1There should be written standard operating procedures (SOPs) detailing thecleaning process for equipment and apparatus. The cleaning procedures should bevalidated.

应该有书面的标准操作规程(sop)，详细说明设备和仪器的清洗过程。清洗程序应经过验证。

3.2The manufacturer should have a cleaning policy and an appropriate procedure forcleaning validation, covering:

制造商应制定清洗策略和适当的清洁验证程序，包括:

■■ surfaces that come into contact with the product;

与产品接触的表面;

■■ cleaning after product changeover (when one pharmaceutical formulationis being changed for another, completely different, formulation);

产品转换后的清洗(当一种药物配方被另一种完全不同的配方替换时);

■■ between batches in campaigns (when the same formula is being manufacturedover a period of time, and on different days);

在批次之间的活动(当同一配方是在一段时间内，在不同的日期生产);

■■ bracketing products for cleaning validation. (This often arises whereproducts contain substances with similar properties [such as solubility] or thesame substance in different strengths. An acceptable strategy is to firstmanufacture the more dilute form [not necessarily the lowest dose] and then themost concentrated form.

用于清洁验证的产品组。(这种情况经常发生在产品中含有具有类似性质(如溶解度)或具有不同强度的相同物质的地方。一种可接受的策略是首先制造含量较低的剂型(不一定是最低剂量)，然后是含量较高的形式。

Thereare sometimes “families” of products which differ slightlyas to actives or excipients.);

有时产品的“组”在活性物质或赋形剂方面略有不同。

■■ periodic evaluation and revalidation of the number of batches manufacturedbetween cleaning validations.

定期评估和清洁再验证之间生产的批次数量。

3.3.At least three consecutive applications of the cleaning procedure should be performedand shown to be successful, to prove that the method is validated.

至少连续三次应用清洗程序，并证明是成功的，以证明该方法是有效的。

4.Cleaning validation protocols and reports Cleaning validation protocols

清洁验证方案和清洁验证报告。

4.1Cleaning validation should be described in cleaning validation protocols, whichshould be formally approved, for example, by the quality control or qualityassurance unit.

清洁验证应在清洁验证方案中进行描述，该方案应得到正式批准，例如由质量控制或质量保证部门批准。

4.2In preparing the cleaning validation protocol, the following should be considered:

在制定清洁验证方案时，应考虑以下事项:

■■ disassembly of the system;系统拆卸

■■ precleaning; 预清洗

■■ the cleaning agent, concentration, solution volume, water quality; 清洗剂、浓度、溶液体积、水的质量;

■■ the time and temperature;时间和温度

■■ the flow rate, pressure and rinsing; 流速、压力和冲洗

■■ the complexity and design of the equipment;设备复杂性及设备设计

■■ training of operators; 操作员培训

■■ the size of the system. 系统尺寸

4.3The cleaning validation protocol should include: 清洁验证方案应该包括：

■■ the objectives of the validation process; 验证过程的目标；

■■ the people responsible for performing and approving the validation study;

负责实施和批准验证研究的人员;

■■ the deion of the equipment to be used, including a list ofthe equipment, make, model, serial number or other unique code;

所使用设备的说明，包括设备清单、制造、型号、序列号或其他唯一代码；

■■ the interval between the end of production and the commencement ofthe cleaning procedure (the interval may be part of the validation challengestudy itself) – the maximum period that equipment may beleft dirty before being cleaned, as well as the establishment of the time thatshould elapse after cleaning and before use;

之间的时间间隔的生产和清洁过程的开始(间隔可能验证挑战研究本身的一部分),设备的最大时期可能离开脏在清洗之前,以及之后建立的时间应该消逝的清洁和使用前;

■■ the levels of microorganisms (bioburden);微生物（生物负载）的水平

■■ the cleaning procedures (documented in an existing SOP, including definitionof any automated process) to be used for each product, each manufacturingsystem or each piece of equipment;

为每一产品、每一制造系统或每一设备所采用的清洗程序(已编制在现行SOP中，包括任何自动化过程的定义);

■■ all the equipment used for routine monitoring, for example, conductivitymeters, pH meters and total organic carbon analysers;

用于日常监测的电导率仪、pH仪、总有机碳分析仪等设备;

■■ the number of cleaning cycles to be performed consecutively;

连续进行清洗的次数;

■■ the sampling procedures to be used (direct sampling, rinse sampling,in-process monitoring and sampling locations) and the rationale for their use;

所采用的取样程序(直接取样、冲洗取样、过程中监测和取样位置)及其使用理由;

■■ the data on recovery studies (efficiency of the recovery of the samplingtechnique should be established);

回收率研究的数据(应确定取样技术的回收效率);

■■ the analytical methods (specificity and sensitivity). including thelimit of detection and the limit of quantification;

分析方法(特异性和敏感性)。包括检测限和定量限;

■■ the acceptance criteria (with rationale for setting the specificlimits) including a margin for error and for sampling efficiency;

可接受标准(包括设定具体限制的理由)，包括误差范围和取样效率;

■■ Documentation of the choice of cleaning agent and approval by the qualityunit, which should be scientifically justified on the basis of, for example:

选择清洗剂的文件和质量部门的批准，这些文件应科学地证明是合理的，例如:

–– the solubility of the materials to be removed; 被除去的材料的溶解度

–– the design and construction of the equipment and surface materialsto be cleaned;

–– the safety of the cleaning agent;清洗剂的安全性；

–– the ease of removal and detection; 清除的简便性和检测；

–– the product attributes;产品属性

–– the minimum temperature and volume of cleaning agent and rinsesolution; 清洗剂和洗涤液的最低温度和体积;

–– the manufacturer’s recommendations; 制造商的建议

■■ revalidation requirements. 再验证需求

4.4Cleaning procedures for products and processes that are very similar do not needto be individually validated. A validation study of the “worst case” may be considered acceptable. There should be a justifiedvalidation programme for this approach, referred to as “bracketing”, addressing critical issues relatingto the selected product, equipment or process.

非常相似的产品和工艺的清洗程序不需要单独验证。对“最坏情况”的验证研究可能被认为是可以接受的。这种方法应该有一个合理的验证方案，称为“括号法”，处理与所选产品、设备或工艺有关的关键问题。

4.5Where “bracketing” of products is done, consideration should be given to the type ofproducts and equipment.

产品的“包装”应考虑产品和设备的类型。

4.6Bracketing by product should be done only when the products concerned aresimilar in nature or property and will be processed using the same equipment.Identical cleaning procedures should then be used for these products.

只有当有关产品性质或性质相似，并将使用相同的设备加工时，才应按产品进行分组。然后应该对这些产品使用相同的清洗程序。

4.7When a representative product is chosen, this should be the one that is most difficultto clean.

当选择有代表性的产品时，这个应该是最难清洗的。

4.8Bracketing by equipment should be done only when it is similar equipment, orthe same equipment in different sizes (e.g. 300 L, 500 L and 1000 L tanks).

只有当设备是类似的设备，或者相同的设备有不同尺寸时(例如300l、500l和1000l的储罐)，才可以用设备组。

Analternative approach may be to validate the smallest and the largest sizesseparately.

另一种方法可能是分别验证最小和最大的尺寸。

Cleaningvalidation reports 清洁验证报告

4.9The relevant cleaning records (signed by the operator, checked by productionand reviewed by quality assurance) and source data (original results) should bekept. The results of the cleaning validation should be presented in cleaningvalidation reports stating the outcome and conclusion.

应保存相关的清洗记录(由操作员签字，由生产部门检查，由质量保证部门评审)和原始数据(原始结果)。清洁验证的结果应在清洁验证报告中说明结果和结论。

5.Personnel 人员

5.1Personnel or operators who perform cleaning routinely should be trained andeffectively supervised.

对日常清洁人员或操作人员应进行培训并进行有效监督。

6.Equipment 设备

6.1Normally, only procedures for the cleaning of surfaces of the equipment thatcome into contact with the product need to be validated. Consideration shouldbe given to “non-contact” parts of the equipment intowhich product or any process material may migrate. Critical areas should beidentified (independently from the method of cleaning), particularly in largesystems employing semi-automatic or fully automatic clean-in-place systems.

通常，只需要验证与产品接触的设备表面清洗程序。应该考虑设备的“非接触”部件，产品或任何工艺材料可能会迁移到这些部件中。关键区域应该被识别(独立于清洗方法)，特别是在使用半自动或全自动就地清洗系统的大型系统中。

6.2Dedicated equipment should be used for products that are difficult to clean, equipmentthat is difficult to clean, or products with a high safety risk where it is notpossible to achieve the required cleaning acceptance limits using a validatedcleaning procedure.

专用设备应用于难以清洗的产品、难以清洗的设备或具有较高安全风险的产品，这些产品使用经过验证的清洗程序不可能达到所需的清洗接受限度。

6.3Ideally, there should be one process for cleaning a piece of equipment or system.This will depend on the products being manufactured, whether the cleaningoccurs between batches of the same product (as in a large campaign), or whetherthe cleaning occurs between batches of different products.

理想情况下，应该有一个清洗设备或系统的过程。这将取决于所生产的产品，清洗是否发生在同一产品的批次之间(如在大型活动中)，或者清洗是否发生在不同产品的批次之间。

6.4The design of equipment may influence the effectiveness of the cleaning process.Consideration should therefore be given to the design of the equipment whenpreparing the cleaning validation protocol, for example, V-blenders, transferpumps or filling lines.

设备的设计可能会影响清洗过程的效率。因此，在编制清洁验证规程时，应考虑设备的设计，例如v型搅拌机、输送泵或灌装管路。

7.Detergents 清洁剂

7.1Detergents should facilitate the cleaning process and be easily removable. Detergentsthat have persistent residues, such as cationic detergents, which adhere verystrongly to glass and are difficult to remove, should be avoided wherepossible.

洗涤剂应便于清洗过程，并易于拆卸。应尽可能避免使用具有持久性残留物的洗涤剂，例如阳离子洗涤剂，它们对玻璃的附着力非常强，难以去除。

7.2The composition of the detergent should be known to the manufacturer and itsremoval during rinsing demonstrated.

清洁剂的成分应告知生产商，并在清洗过程中演示其去除方法。

7.3Acceptable limits for detergent residues after cleaning should be defined. Thepossibility of detergent breakdown should also be considered when validatingcleaning procedures.

清洗后洗涤剂残留的可接受限度应加以规定。在验证清洗程序时，还应考虑洗涤剂损坏的可能性。

7.4Detergents should be released by quality control and, where possible, should meetlocal food standards or regulations.

洗涤剂应通过质量控制放行，并在可能的情况下，应符合当地食品标准或法规。

8.Microbiology 微生物

8.1The need to include measures to prevent microbial growth and remove

contaminationwhere it has occurred should be considered.

应考虑采取措施防止微生物生长和清除已发生的污染。

8.2There should be documented evidence to indicate that routine cleaning andstorage of equipment does not allow microbial proliferation.

应该有书面证据表明，设备的常规清洗和储存不允许微生物增殖。

8.3The period and conditions for storage of unclean equipment before cleaning, andthe time between cleaning and equipment reuse, should form part of thevalidation of cleaning procedures.

清洗前不洁净设备的储存期限和条件，以及清洗和设备重复使用之间的时间，应构成清洗方法验证的一部分。

8.4Equipment should be stored in a dry condition after cleaning. Stagnant watershould not be allowed to remain in equipment after cleaning.

设备清洗后应存放在干燥的环境中。清洗后，不应让积水留在设备内。

8.5Control of the bioburden through adequate cleaning and appropriate storage ofequipment is important to ensure that subsequent sterilization or sanitizationprocedures achieve the necessary assurance of sterility, and the control ofpyrogens in sterile processing. Equipment sterilization processes may not beadequate to achieve significant inactivation or removal of pyrogens.

通过适当的清洁和适当的设备储存来控制生物群落，对于确保后续的灭菌或消毒程序实现必要的无菌保证，以及在无菌处理过程中对热源的控制非常重要。设备灭菌过程可能不足以实现显著的失活或去除热源。