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WHO清洁验证指南草案修订稿(中英文对照)
发布时间: 2020-09-03     来源: 蒲公英

近日,WHO发布清洁验证指南草案修订稿,名为:在清洁验证中,使用基于健康的暴露限(HBEL)时应考虑的要点。

该指南初稿于今年5月发布,之后基于收集到的反馈意见形成了本版本。WHO表示,将在9月21日前再次收集反馈意见,之后的修订稿将在今年10月份召开的第55届WHO 药物制剂专家委员会(ECSPP)会议上进行报告。

本指南主要涵盖了:

在清洁验证中,基于药理和毒理学数据的HBEL时应考虑的要点,即如何基于风险和科学的方法。
就审查多产品设施中和清洁验证的当前状态和方法时,需要考虑的要点。
该指南正文分为五个部分,分别是:(1)介绍和背景、(2)范围、(3)术语、(4)传统方法和(5)新方法。

PharmLink指南组将对全文主要内容进行翻译和连载,供大家参考。

1.Introduction and background 介绍和背景

The World Health Organization (WHO) has published the guideline entitled Good manufacturing practices for pharmaceutical products: main principles in the WHO Technical Report Series, No. 986,Annex 2, 2014 (1).

世界卫生组织(WHO)已发布指南,标题为“药品的GMP:WHO技术报告丛书的主要原则”,第986号,附件2,2014(1)。

The WHO Supplementary guidelines on good manufacturing practice: validation were published in 2006 and were supported by seven appendices. The main text and its appendixes were revised between 2006 and 2019. Appendix 3, relating to cleaning validation , was not updated at that time. Its revision, however, was discussed during an informal consultation held in Geneva, Switzerland, in July 2019. The outcome of the discussion was presented to the WHO Expert Committee on Specifications for Pharmaceutical Products (ECSPP) meeting in October 2019. The ECSPP acknowledged the importance of harmonization in regulatory expectations with regards to cleaning validation approaches. The Expert Committee recommended a “Points to consider” document be prepared in order to describe the current approaches used in cleaning validation and highlighting the complexities involved in order to establish a common understanding. A revision of the relevant appendix would then be considered by the Expert Committee thereafter.

世界卫生组织“GMP补充指南:验证”于2006年发布,并有七个附录作为支持。正文及其附录在2006年至2019年之间进行了修订。关于清洁验证的附录3当时尚未更新。但是,在2019年7月在瑞士日内瓦举行的非正式磋商中讨论了其修订版。讨论的结果已提交给2019年10月的WHO 的ECSPP会议。ECSPP认识到就清洁验证方法而言,协调在监管预期中的重要性。专家委员会建议编写一份“考虑要点”文件,以描述清洁验证中使用的当前方法,并强调其中涉及的复杂性,以建立共识。此后,专家委员会将考虑对相关附录进行修订。

Many manufacturers produce products in multi-product facilities where there is a risk of contamination and cross-contamination. Some of the main principles of good manufacturing practices (GMP) include the prevention of mix-ups and the prevention of contamination and cross-contamination. It is therefore important that manufacturers identify all risks for contamination and cross-contamination and identify and implement the appropriate controls to mitigate these risks.

许多生产商会在多产品设施中生产多个产品,存在污染和交叉污染的风险。GMP的一些主要原则包括防止混淆,防止污染和交叉污染。因此,重要的是,生产商必须确定所有污染和交叉污染的风险,并确定并实施适当的控制措施,以减轻这些风险。

These controls may include, for example, technical and organizational measures, dedicated facilities, closed systems, cleaning and cleaning validation.

这些控制措施可能包括,例如,技术和管理措施、专用设施、封闭系统,清洁和清洁验证。

It is strongly recommended that manufacturers review their existing technical and organizational measures, suitability of cleaning procedures and appropriateness of existing cleaning validation studies.

强烈建议生产商审查其现有的技术和管理措施、清洁程序的适用性,以及现有清洁验证研究的适当性。

Technical controls, such as the design of the premises and utilities (e.g. heating, ventilation and air-conditioning {heating, ventilation and air conditioning (HVAC)}, water and gas), should be appropriate for the range of products manufactured (e.g. pharmacological classification, activities and properties). Effective controls should be implemented to prevent cross-contamination when air is re-circulated through the HVAC system.

技术控制,例如场所和公用系统的设计(例如,HVAC、水和气),应适合所生产产品的范围(例如,药理学分类、活动和属性)。当空气通过HVAC系统再循环时,应执行有效的控制措施,以防止交叉污染。

Organizational controls, such as dedicated areas and utilities, dedicated equipment, procedural control, and campaign production, should be considered where appropriate as a means to reduce the risk of cross-contamination.

应酌情考虑管理控制措施,例如专用的区域和公用系统、专用设备、程序控制和周期生产,以减少交叉污染的风险。

It should be noted that the above examples are described in more detail in other documents. The focus of this document is on Health-Based Exposure Limits (HBELs) setting in cleaning validation

应当注意,上述示例在其他文档中有更详细的描述。本文档的重点是清洁验证中基于健康的暴露限(HBEL)设置。

2.Scope范围

This document provides points to consider for a risk and science-based approach when considering HBELs, based on pharmacological and toxicological data, in cleaning validation.

本文档提供了:在清洁验证中,基于药理和毒理学数据的HBEL时应考虑的要点,即基于风险和科学的方法。

This document further provides points to consider when reviewing the current status and approaches to cleaning validation in multiproduct facilities.

本文档还提供了:就审查多产品设施中和清洁验证的当前状态和方法时,需要考虑的要点。

The principles described in this document may be applied in facilities where active pharmaceutical ingredients (APIs), investigational medical products (IMP), vaccines, human and veterinary medical products are manufactured. The principles may also be considered, where appropriate, in facilities where medical devices are manufactured.

本文档中描述的原理可能适用于:生产活性药物成分(API)、研究医疗产品(IMP),疫苗、人和兽用医疗产品的设施。在适当的情况下,也可以在生产医疗器械的设施中,考虑这些原则。

This document should be read in conjunction with the main GMP text and supplementary texts on validation.

该文档应与GMP主要文本和验证补充性文本一起阅读。

3.Glossary 术语

adjustment factor (safety factors). A series of modifying or safety factors are applied to take into account the fact that data from toxicological studies of differing types and durations in differing species have been used.

调整系数(安全系数):对于来自不同物种的、不同类型和持续时间的毒理学研究数据,应用了一系列修正或安全因子。

cleanability. The ability of a cleaning procedure to effectively remove material, cleaning agent residue and microbial contamination

清洁性:清洁程序能够有效去除物料、清洁剂残留和微生物污染的能力。

cleaning validation. Documented evidence to establish that cleaning procedures are removing residues to predetermined levels of acceptability, taking into consideration factors such as batch size, dosing, toxicology and equipment size.

清洁验证:证明清洁程序可将残留清除至预定可接受水平的书面证据,同时考虑到诸如批量、剂量、毒理学和设备规格等因素。

contamination. The undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter, into or on to a starting material or an intermediate or pharmaceutical product during handling, production, sampling, packaging, repackaging, storage or transport.

污染:在处理、生产、取样、包装、分包装、存储或运输工艺中,化学或微生物杂质或异物非希望地引入到起始物料、中间体或药品之中或之上。

cross-contamination. Contamination of a starting material, intermediate product or finished product with another starting material or product during production.

交叉污染:在生产工艺中,起始原料、中间体或成品与另一种起始原料或产品的相互污染。

Health Based Exposure Limits (HBELs)

See definition of Permitted Daily Exposure (PDE)

基于健康的暴露限(HBEL):参阅允许的每日暴露量(PDE)的定义

margin of safety. The margin of safety is the difference between the cleaning acceptance limit based on HBEL and the process residue data.

安全边际:基于HBEL的清洁可接受极限与工艺残留数据之间的差异。

maximum safe carryover (MSC). The maximum amount of carryover of a residual process residue (API, cleaning agent, degradant, and so forth) into the next product manufactured without presenting an appreciable health risk to patients..

最大安全残留(MSC):残留物(API、清洁剂、降解剂等)的最大残留量,其进入所生产的下一个产品,而不会给患者带来明显的健康风险。

maximum safe surface residue (MSSR). The MSSR is the maximum amount of process residue that can remain on equipment surfaces and still be safe to patients. The MSSR is mathematically calculated dividing the Maximum Safe Carryover (MSC) by the total area of contact (MSC/Total).

最大安全表面残留(MSSR):MSSR是最大工艺残留量,其可以保留在设备表面上、且对患者仍是安全的。MSSR是通过数学计算得出的,将最大安全残留(MSC)除以接触的总面积(MSC / Total)。

permitted daily exposure (PDE). PDE represents a substance-specific dose that is unlikely to cause an adverse effect if an individual is exposed at or below this dose every day for a lifetime.

允许的每日暴露量(PDE):PDE代表一种特定于物质的剂量。个体一生中,每天以该剂量或低于该剂量的剂量接触,不太可能造成不利影响。

point of departure. The dose at which a significant adverse effect is first observed, or the lowest- observed-adverse-effect level (LOAEL).

出发点:在该剂量下,首次观察到明显不良反应,或可观察到的最低不良反应水平(LOAEL)。

verification. The application of procedures to provide evidence through chemical analysis (e.g. after a batch or campaign) to show that the residues of the previous product and cleaning agents, where applicable, have been reduced below the scientifically set maximum allowable or maximum safe carryover level.

确认:对程序的应用,通过化学分析提供证据(例如在批或周期生产后),以表明先前产品和清洁剂的残留(如适用)已减少至最大允许或最大安全残留水平以下,这些限度是基于科学而设定的。

4. Historical approach传统方法

For details on the historical approaches in cleaning validation, see the WHO Technical Report Series, No. 1019, Annexure 3, Appendix 3, 2019.

有关清洁验证的传统方法的详细信息,请参阅WHO技术报告系列,第1019号,附件3,2019年附录3。

The acceptance criteria for cleaning validation recommended in historical GMP texts did not account for HBELs.

传统上,在GMP文本中建议的清洁验证可接受标准中,未考虑HBEL。

A limit based on HBELs should still be established. Historically established limits may be used as alert limits when these are more stringent than HBELs.

应建立基于HBEL的限度。当传统限度比HBEL更为严格时,可以将其用作警戒线。

Where the historical approach cannot be satisfactorily justified, and in view of the risks of contamination and cross-contamination, the new approaches, as described below, should be prioritized and implemented.

如果不能令人满意地证明传统方法是正确的,考虑到污染和交叉污染的风险,则应优先考虑和实施如下所述的新方法。

5.New approaches 新方法

Historical cleaning validation approaches often merely showed that using a defined cleaning procedure achieved an objective of meeting historical limits. In many instances, no development work or cleanability studies were done nor was consideration given to toxicological data for establishing limits for cleaning residues.

传统上,清洁验证方法通常仅表明使用定义的清洁程序,可以达到满足传统限度的目的。在许多情况下,没有进行开发工作或清洁能力研究,也没有考虑毒理学数据,来确定清洁残留物的极限。

Manufacturers should ensure that their cleaning procedures are appropriately developed and that their cleaning validation provides scientific evidence that residues of identified products that can be manufactured in shared facilities are removed to safe levels, providing a high margin of safety to patients. Control measures should be implemented to mitigate the risks of contamination and cross- contamination.

生产商应确保正确制定其清洁程序,并进行清洁验证,以提供科学证据,针对在共享设施中生产的特定产品,证明其残留被清除到安全水平,为患者提供了很高的安全系数。应采取控制措施,以减轻污染和交叉污染的风险。

This approach should include at least the following points (which are further described in the text below):

该方法至少应包括以下几点(下文将进一步描述):

• risk assessment to identify hazards, analyse risks, and to identify risk controls;

•风险评估,以识别危害、分析风险,并确定风险控制措施;

• cleaning procedure development studies including cleanability studies, where applicable (e.g. new products or cleaning procedures);

•清洁程序开发研究,包括清洁能力研究(如适用)(例如新产品或清洁程序);

• determination of technical and organizational controls;

确定技术和管理控制;

• HBELs setting;

HBEL设置;

• selection of appropriate analytical procedures; and

选择适当的分析程序;

• cleaning process control strategy.

清洁工艺控制策略。

Manufacturers should describe and implement their policy and approaches, including the points mentioned above, in a document such as a master plan.

在诸如主计划之类的文件中,生产商应描述并实施其政策和方法,包括上述要点。

Genotoxic and carcinogenic substances, degradants and other contaminants should be identified and their risks evaluated. Appropriate action should be taken where required .

应当确定遗传毒性和致癌物质、降解物和其他污染物,并评估其风险。需要时,应采取适当的措施。

5.1 Documentation 文件化

Risk management principles, as described by WHO and other guidelines on quality risk management (10), should be applied to assist in identifying and assessing risks. The appropriate controls should be identified and implemented to mitigate contamination and cross-contamination.

应采用世卫组织和其他质量风险管理指南所述的风险管理原则,以帮助识别和评估风险。应确定并实施适当的控制措施,以减轻污染和交叉污染。

The policy and approaches in cleaning and cleaning validation require that good scientific practices should be applied (including the use of appropriate equipment and methods). This should be described in a cleaning validation master plan. Development studies, cleaning and cleaning validation should be performed in accordance with predefined, authorized standard operating procedures, protocols and reports, as appropriate. Records should be kept.

清洁和清洁验证的政策和方法要求应采用良好的科学实践,包括使用适当的设备和方法。这应该在清洁验证主计划中进行描述。应根据预定义和批准的标准操作程序、草案和报告,进行开发研究、清洁和清洁验证。记录应保存。

The design and layout of documents, and the reporting of data and information, should be in compliance with the principles of good documentation practices and should also meet data integrity requirements .

文档的设计规划、以及数据和信息的报告,应符合良好文档规范的原则,并且还应满足数据完整性要求。

5.2 Equipment 设备

Cleaning validation should cover direct product contact surfaces. Non-contact surfaces should be included in cleaning validation where these have been identified as areas of risk.

清洁验证应覆盖产品的直接接触表面。如果非接触表面已被确定为风险区域,则应将其包括在清洁验证中。

Authorized drawings of equipment should be current, accurate and available. Equipment surface area calculations should be documented and justified. The source data for these calculations should be available. The calculated values should be used in the calculations in cleaning validation.

设备的已批准图纸应是最新、准确且可用的。对于设备表面积的计算,应形成文件并证明其合理性。这些计算的源数据应该可用。计算值应用于清洁验证的计算中。

All equipment and components, including those that are difficult to clean (for example, sieves, screens, filters and bags (such as centrifuge bags) should be considered in cleaning validation and calculations. Where the need is identified, dedicated equipment and or components should be used.

所有设备和组件,包括那些难以清洁的设备和组件(例如,筛子、筛网、过滤器和袋子(例如离心袋)都应在清洁验证和计算中予以考虑。需要时,应使用专用设备和/或组件。

5.3 Cleaning agents 清洁剂

Cleaning agents (including solvents and detergents used in cleaning processes) should be selected with care. They should be appropriate for their intended use. The selection of the relevant cleaning agent should be scientifically justified.

应当谨慎选择清洁剂(包括清洁工艺中使用的溶剂和清洁剂)。它们应适合其预期用途。有关清洁剂的选择应有科学依据。

There should be proof of effectiveness and appropriateness of the selected cleaning agent.

应当有所选清洁剂的有效性和适当性的证明。

Other points to consider include the concentration in which these are used, their composition and removal of their residues to an acceptable level.

其他要考虑的因素包括这些物质的使用浓度,其组成以及将残留物清除至可接受水平。

When cleaning agents are used in cleaning processes, these should be included in cleaning process development studies and cleaning validation.

在清洁工艺中使用清洁剂时,应将其纳入清洁工艺开发研究和清洁验证中。

5.4 Sampling 取样

Historically, cleaning validation included different methods being applied to determine whether or not there was any residue remaining on surface areas after cleaning. The focus was mainly on product contact surface areas.

从传统上看,清洁验证包括:采用不同的方法来确定清洁后表面上是否残留任何残留物。重点主要放在产品接触表面积上。

A combination of at least two or three methods should normally be used. These include, for example, swab samples, rinse samples and visual inspection. Visual inspection should always be performed. Swab sampling is the preferred other method to be used. Rinse samples should be taken for areas which are inaccessible for swab sampling.

通常应至少结合使用两种或三种方法。这些包括例如棉签样品、冲洗样品和目检。目检应始终进行。相当于其他使用方法,棉签取样是首选的。应在无法进行棉签取样的区域,进行冲洗样品的取样。

Appropriate sampling procedures, swab material and sampling techniques should be selected and used to collect swab and rinse samples. The detail should be clearly described in procedures and protocols. The number of swabs, location of swabbing, swab area, rinse sample volume and the manner in which the samples are collected should be scientifically justified.

应选择适当的取样程序,棉签材料和取样技术,并将其用于收集棉签和冲洗样品。应在程序和草案中清楚地描述细节。对于棉签的数量、棉签的位置、棉签的面积、冲洗样品的量以及收集样品的方式,应在科学上合理。

Swab and rinse sample methods should be validated. Recovery studies for swab and rinse sampling should be performed.

棉签和冲洗样品方法应经过验证。应进行棉签和冲洗样品的回收率研究。

Where microbiological sampling is carried out, the microbiological method should also be validated.

在进行微生物取样的地方,微生物方法也应得到验证。

The manner in which collected samples are stored (if required) and prepared for analysis should be appropriate, described in detail and included in the cleaning validation.

已收集样品的存储方式(如果需要)和分析准备方式应该适当,详细描述并包括在清洁验证中。

5.5 Cleanability studies 清洁能力研究

Before a new cleaning procedure is validated and adopted for routine use, a cleanability study should be performed in order to determine the appropriateness of the procedure for removing for example product residue, cleaning agents and microorganisms. For cleaning procedures that have already been validated where the data show that the cleaning procedure is effective and consistent, or where risk assessment indicated that cleanability studies may not be required, this may be considered acceptable.

在确认新的清洁程序并将其用于日常使用之前,应进行清洁能力研究,以确定清除产品残留物、清洁剂和微生物等程序的适当性。对于已验证的清洁程序,如果数据表明清洁程序有效且一致,或者风险评估表明可能不需要清洁能力研究,则可以认为这是可以接受的。

5.6 Risk management 风险管理

Risk management should be implemented with a focus on the identification, evaluation, assessment and control of risks to mitigate the risk of contamination and cross-contamination.

实施风险管理时应侧重于风险的识别、评价、评估和控制,以减轻污染和交叉污染的风险。

These controls should include technical and organization controls in order to deliver a validated cleaning process.

这些控制措施应包括技术和管理控制措施,以提供经过验证的清洁工艺。
5.7 Guidance for Health-Based Exposure Limits (HBELs) setting HBEL的设置HBEL的设置
HBEL的设置

Manufacturers should establish, document and implement a company-wide policy on HBELs setting for shared facilities.

生产商应建立、记录并实施公司范围内有关共享设施HBEL设置的政策。

The appropriateness of the production and control of various APIs or various products in shared facilities should be evaluated on the basis of scientific data and information.

应当在科学数据和信息的基础上,评估共享设施中各种API或产品生产和控制措施的适当性。

This is applicable to legacy products as well as when new products are planned to be introduced into a facility, for example, through a change control procedure.

这适用于老产品、以及计划将新产品引入设施的情况(如通过变更控制程序)。

Procedures should be established and implemented describing how the scientific and toxicological data and information are obtained and considered and how HBELs are established.

应建立并执行程序,描述如何获取和考虑科学和毒理学数据与信息,以及如何建立HBEL。

Data and information should be gathered by a person with appropriate qualifications and experience in the field of toxicology and/or pharmacology. The data and information should be presented in a report. The data and information presented should be free from bias.

数据和信息应由在毒理学和/或药理学领域具有适当资质和经验的人员收集。数据和信息应在报告中提供。所提供的数据和信息应没有偏见。

Where this service is outsourced by the manufacturer, appropriate measures should be put in place in order to ensure that the data obtained are reliable. GMP requirements, such as vendor qualification, agreements and other related aspects, should be considered.

如果该服务由生产商外包,则应采取适当措施以确保获得的数据是可靠的。应该考虑GMP要求,例如供应商资质、协议和其他相关方面。

Note: The HBEL value for the same substance sometimes differs when it is determined by different individuals. The reason for the difference between the values should be clarified and investigated.

注意:有时,同一物质的HBEL值由不同的人确定时会有所不同。值之间的差异的原因应予以澄清和调查。

The report for each substance should include scientific detail and information, as applicable, such as:

每种物质的报告应包括科学细节和信息(如适用),例如:

• substance identification

物质识别

• chemical structure

化学结构

• clinical indication

临床适应症

• mode of action

作用方式

• route of administration (Note: Where more than one route of administration is available, it may be necessary to calculate separate HBELs)

给药途径(注意:如果有多个给药途径,则可能有必要计算单独的HBEL)

• preclinical/nonclinical data, for example, of acute and repetitive dose studies

o genotoxicity data

o reproductive toxicity data

o carcinogenicity data

o data relating to highly sensitizing potential

临床前/非临床数据,例如急性和重复剂量研究

o遗传毒性数据

o生殖毒性数据

o致癌性数据

o与高敏感潜力有关的数据

• clinical data

临床资料

• pharmacodynamics and pharmacokinetics

药效学和药代动力学

• identification of the critical effect(s)

确定关键影响

• point of departure for the HBEL calculation(s)

HBEL计算的出发点

• adjustment factors

调整因子

• justification of the selected lead rationale (if calculations with different points of departure were made).

证明所选择的主要论证依据(如果进行了不同出发点的计算)。

The report should be reviewed for its completeness and appropriateness by the manufacturer’s designated internal personnel or by an appointed external persons. The person should have in-depth knowledge, appropriate qualifications and experience in the field of toxicology. A summary document may be prepared for each relevant substance and should contain information on the PDE value, and toxicity.

生产商指定的内部人员或指定的外部人员应检查报告的完整性和适当性。该人员应在毒理学领域具有深入的知识、适当的资质和经验。可能会为每种相关物质准备一份摘要文件,其中应包含有关PDE值和毒性的信息。

The scientific report and calculated PDE value should be used when defining the cleaning validation control measures.

定义清洁验证控制措施时,应使用科学报告和计算出的PDE值。

Note: If no NOAEL is obtained, the lowest-observed-adverse-effect level (LOAEL) may be used. Alternative approaches to the NOAEL, such as the benchmark dose, may also be used. The use of other approaches to determine HBELs could be considered acceptable if adequately and scientifically justified.

注意:如果未获得NOAEL,则可以使用观察到的最低不良反应水平(LOAEL)。也可以使用NOAEL的替代方法,例如基准剂量。如果有充分和科学的理由,使用其他方法确定HBEL是可以接受的。

Manufacturers should periodically consider new data and information on HBELs. Appropriate action, such as the updating of PDE reports, should be taken where required.

生产商应定期考虑有关HBEL的新数据和信息。在需要时,应采取适当的措施,例如更新PDE报告。

5.8 Acceptance criteria 可接受标准

The limits established in cleaning validation should be justified.

清洁验证中建立的限度应该是合理的。

Some manufacturers have specified acceptance criteria based on carryover limits or limits reflected in some GMP guidelines. These limits may no longer be acceptable as HBELs and related toxicity data were not included in the determination of such acceptance criteria.

一些生产商根据残留限度或某些GMP指南中反映的限度,规定了可接受标准。这些限度可能不再可接受,因为确定此类可接受标准时,未包含HBEL和相关毒性数据。

Criteria such as Maximum Safe Carryover (MSC)/Maximum Allowable Carryover (MACO) and Maximum Safe Surface Residue (MSSR) values should be calculated. Calculations and data should be available and comply with data integrity principles. The calculation should include values of PDE, maximum daily dose, batch size and total shared equipment surface areas.

应计算诸如最大安全残留(MSC)/最大允许残留(MACO)和最大安全表面残留(MSSR)值之类的标准。相关计算和数据应可查,并符合数据完整性原则。计算应包括PDE值、最大日剂量、批量和共用设备总表面积。

MSSR should be calculated and presented, for example, in table form listing preceding and following product values. The cleanability value obtained should be considered in determining the acceptability of the procedure(s) and whether other controls including separate, dedicated facilities are required. (See Annex 1 as an example.)

MSSR应该以表格形式进行计算和显示,例如列出前后产品的值。在确定程序的可接受性、以及是否需要其他控制措施(包括单独的专用设施)时,应考虑获得的清洁能力值。(请参见附件1。)

The margin of safety (the distance between the analytical data and the HBEL base limit) should be identified.

应确定安全边际(分析数据与HBEL限度之间的距离)。

5.9 Analytical procedures 分析程序

Samples obtained in cleaning validation should be analyzed by using procedures that are validated for their intended use. The procedures should be developed in accordance with the principles of Analytical Quality by Design.

在清洁验证中获得的样品应使用经验证可用于其预期用途的程序进行分析。应根据“质量源于分析设计”的原则制定程序。

Specific methods, such as High-performance Liquid Chromatography (HPLC), should be used where appropriate. Non-specific methods including UV spectrophotometry should only be used where specific methods cannot be employed and their use can be justified, for example, based on the outcome of risk assessment.

适当时应使用特定方法,例如高效液相色谱(HPLC)。仅在无法采用特定方法且可以合理使用它们的情况下,才应使用包括UV分光光度法在内的非特定方法,例如,基于风险评估的结果。

Testing for total organic carbon (TOC) may be used where indicated and where justified.

有说明和有论证时,可使用总有机碳(TOC)检验。

Where analytical procedures were developed and validated off-site, the scope and extent of validation when these are transferred to the site, should be defined and justified. This includes procedures that are transferred from research and development laboratories to site laboratories. Analytical procedures should be able to quantify or detect residue levels at the maximum safe surface residue level. (For analytical procedure validation, see reference 6.)

在制定分析程序并在场外进行验证时,应定义并证明将其转移到现场时的验证范围和程度。这包括从研发实验室转移到现场实验室的程序。分析程序应能够在最大安全表面残留水平下量化或检测残留水平。(有关分析程序的验证,请参见参考文献6。)

Manufacturers should ensure that the procedures remain in a validated state.

生产商应确保程序保持已验证的状态。

5.10 Data integrity 数据完整性

Data, information and results pertaining to, for example, HBELs, PDE reports, results obtained from cleaning validation and calculations, should be scientific and should be in compliance with the principles as contained in data integrity guidelines.

有关数据、信息和结果,例如HBEL、PDE报告、从清洁验证和计算中获得的结果,应是科学的,并且应符合数据完整性指南中包含的原则。

5.11 Cleaning validation and cleaning verification 清洁验证和清洁确认
Cleaning validation 清洁验证

The cleaning procedure should be validated.

清洁程序应已验证。

Cleaning validation should include proof of, for example, the applicability of the procedure to clean equipment that:

清洁验证应包括证明该程序是否适用于清洁设备的证明:

• had been kept in an unclean state for a period of time (dirty equipment hold time);

保持不清洁状态一段时间(设备清洁前放置时间);

• are used after a product is planned (e.g. change from one product to another product);

在计划产品之后使用(例如,从一种产品更改为另一种产品);

• are used in a campaign, where multiple batches of a product are produced one after the other; and/or

用于一个周期生产中,一个接一个地生产多批产品;和/或

• are stored in a clean state for defined periods of time (clean equipment hold time).

以清洁状态存储规定的时间(设备清洁后放置时间)。

HBEL should be considered when establishing carryover limits in cleaning validation.

在清洁验证中建立残留限度时,应考虑使用HBEL。

Cleaning verification 清洁确认

The company should describe the policy and approach to cleaning verification. Cleaning verification is where the effectiveness of the validated cleaning procedure is routinely verified. The approach may include swab or rinse samples. The results obtained from testing on a routine basis should be reviewed and subjected to statistical trending.

公司应说明清洁确认的政策和方法。清洁确认,是对已验证清洁程序的有效性进行例行的确认。该方法可能包括棉签或冲洗样品。常规检验获得的结果应进行审查,并进行统计趋势分析。

5.12 Visually clean 目检干净

Visually clean is an important criterion in cleaning validation. It should be one of the acceptance criteria used on a routine basis. Personnel responsible for visual inspection should be appropriately trained. Training records should be kept.

目检干净是清洁验证的重要标准。它应该是常规使用的验收标准之一。负责目检的人员应接受适当的培训。应保留培训记录。

Where visual inspection is used as a quantitative method, then Visible Residue Limits (VRLs) should be determined. The process to determine the limit should be appropriately described in procedures and protocols covering, for example, concentrations, method of spiking, surface areas, material of construction and other conditions such as light (LUX level) and angles.

如果使用目检作为定量方法,则应确定可见残留限量(VRL)。确定限度的过程应在程序和草案中适当描述,包括浓度、加标方法、表面积、结构材料和其他条件,例如,光(LUX水平)和角度。

5.13 Cleaning process capability 清洁工艺能力

The cleaning procedure should remain in a validated state. It is recommended that cleaning verification results and calculated process capability data be used to support this. For example, the results from cleaning verification sample analysis could be statistically trended. The capability of the cleaning process is then calculated by using an appropriate statistical process.

清洁程序应保持在已验证的状态。建议使用清洁验证结果和计算出的过程能力数据,来支持这一点。例如,清洁验证样品分析的结果可以统计趋势。然后通过使用适当的统计过程,来计算清洁工艺能力。

Data should be presented, for example, in graph form, and the capability of the process in relation to control limits and the margin of safety should be presented and discussed as part of continuous improvement over the life cycle.

数据应该以图表的形式呈现,并且过程控制能力和安全边际能力应作为生命周期内持续改进的一部分,进行呈现和讨论。

5.14 Personnel 人员

Personnel should be trained on the procedures and principles of cleaning and cleaning validation, including contamination and cross-contamination control, HBELs setting, equipment disassembly, visual inspection, sampling, testing and statistical calculations, as appropriate and based on their responsibilities.

应根据人员的职责,对人员进行清洁和清洁验证的程序和原则方面的培训,包括污染和交叉污染控制、HBEL设置、设备拆卸、目检、取样、检验和统计计算。

5.15 Quality metrics and performance indicators 质量指标和绩效指标

Aspects of cleaning validation and cleaning verification should be considered in quality metrics, with performance indicators identified and monitored.

应在质量指标中,考虑清洁验证和清洁确认的各个方面,并确定和监控性能指标。

5.16 Life cycle 生命周期

Cleaning procedures, cleaning validation and cleaning verification should be included in the life cycle approach described by the company.