WHO：清洁验证新指南（中英文对照版）！

Points to consider when including Health-Based Exposure Limits(HBELs) in cleaning validation清洁验证使用基于健康的暴露限（HBEL）的考量1. Introduction andbackground介绍和背景2. Scope范围3. Glossary术语4. Historical approach传统方法5. New approaches新的方法5.1Documentation文件5.2 Equipment设备5.3 Cleaningagents清洁剂5.4 Sampling取样5.5Cleanability studies清洁能力研究5.6 Riskmanagement风险评估5.7 Guidancefor Health-BasedExposure Limits (HBELs) setting基于健康的暴露限设定的指南5.8Acceptance criteria接受标准5.9Analytical procedures分析方法5.10 Dataintegrity数据完整性5.11 Cleaningvalidation andcleaning verification清洁验证和清洁确认5.12 Visuallyclean目视干净5.13 Cleaningprocess capability清洁工艺能力5.14Personnel人员5.15 Qualitymetrics andperformance indicators质量量度和性能指标5.16 Lifecycle生命周期References参考文献Furtherreading扩展阅读Annex 1附录11.      Introductionand background介绍及背景The World HealthOrganization (WHO) has published the guideline entitled Good manufacturing practicesfor pharmaceutical products: main principles in the WHO Technical ReportSeries, No. 986, Annex 2, 2014 (1).WHO 于 2014 年 TRS 986 附录2 发布了题为“药品 GMP：主则”的指南。The WHOSupplementary guidelines on good manufacturing practice: validation werepublished in 2006andwere supported by seven appendices. The main text (2) and its appendixes (3, 4, 6, 7, 8, 9) were revised between 2006and 2019. Appendix 3, relating to cleaning validation(5), was not updated at that time. Its revision, however, was discussed duringan informal consultation held in Geneva, Switzerland, in July 2019. The outcomeof the discussion was presented to the WHO Expert Committee on Specificationsfor Pharmaceutical Products (ECSPP) meeting in October 2019. The ECSPPacknowledged the importance of harmonization in regulatory expectations withregards to cleaning validation approaches. The Expert Committee recommended a“Points to consider” document be prepared in order to describe the currentapproaches used in cleaning validation and highlighting the complexitiesinvolved in order to establish a common understanding. A revision of therelevant appendix would then be considered by the Expert Committee thereafter.WHO 于 2014 年 TRS 986 附录 2 发布了题为“药品 GMP：主则”的指南。WHO 的“GMP 补充指南：验证”于 2006 年发布，有 7 个附录作为支持文件。该主文件及其附录于2006到2019年之间进行了修订。与清洁验证有关的附录 3 当时未更新。但在 2019 年 7 月瑞士日内瓦的非正式沟通期间对其修订进行了讨论，讨论结果于2019 年 10 月提交给了ECSPP 会议。ECSPP 了解清洁验证方法的监管要求保持一致的重要性，因此专家委员会建立起草一份“考量要点”文件，以阐述当前清洁验证中所用方法，强调其所涉及的复杂性，以求对此达成共识。鉴于此，专家委员会随后考虑要对相关附录进行修订。Many manufacturersproduce products in multi-product facilities where there is a risk ofcontamination and cross-contamination. Some of the main principles of goodmanufacturing practices (GMP) include the prevention of mix-ups and theprevention of contamination and cross-contamination. It is therefore importantthat manufacturers identify all risks for contamination and cross-contamination and identify and implement the appropriate controls to mitigate theserisks.许多生产商会在多产品设施中生产多个产品， 这时就会存在污染和交叉污染的风险。优良生产规范（GMP）的一些重要原则包括有防止混淆和防止污染与交叉污染，因此生产商识别所有污染与交叉污染，识别实施适当控制措施以降低这些风险就非常重要。These controls mayinclude, for example, technical and organizational measures, dedicatedfacilities, closed systems, cleaning and cleaning validation.这些控制措施可以包括例如技术和组织措施、使用专用设施、封闭系统、清洁和清洁验证It is stronglyrecommended that manufacturers review their existing technical andorganizational measures, suitability of cleaning procedures and appropriatenessof existing cleaning validation studies.强烈建议制造商审查其现有的技术和组织措施、清洁程序的适用性以及现有清洁验证试验的适当性。Technical controls,such as the design of the premises and utilities (e.g. heating, ventilation and air-conditioning {heating, ventilation and airconditioning (HVAC)}, water and gas), should be appropriatefor the range of products manufactured (e.g.pharmacological classification, activities and properties). Effective controls should be implemented to prevent cross-contaminationwhen air is re-circulated through the HVAC system.技术控制，如厂房和公用设施的设计（如暖通空调[HVAC）系统，应适用于所制造的产品范围（如药理类别、活性和特性）。当空气通过 HVAC 系统重新循环时，应实施有效的控制以防止交叉污染。Organizational controls, such as dedicated areas and utilities,dedicated equipment, procedural control, and campaign production, should beconsidered where appropriate as a means to reduce the risk ofcross-contamination.组织控制，如专用区域和公用设施、专用设备、程序性控制和错峰生产，应酌情考虑作为减少交叉污染风险的一种手段。It should be noted that the above examples are described in more detailin other documents. The focus of this document is on Health-Based ExposureLimits (HBELs) setting in cleaning validation应当指出，上述事例已在其他文件进行了更为详细的描述。本文的重点是在清洁验证中基于健康的暴露限（HBEL）的设置2.      Scope范围Thisdocument provides points to consider for a risk and science-based approach when considering HBELs, based on pharmacological andtoxicological data,in cleaning validation.本文件提供了在清洁验证中考虑基于药理学和毒理学数据的 HBEL 时需要考虑的风险和科学方法。This documentfurther provides points to consider when reviewing the current status andapproaches to cleaning validation in multiproduct facilities.本文件进一步提供了在审查多产品设施清洁验证的现行状态和方法时要考虑的点。Theprinciples describedin this document may be applied in facilities where activepharmaceutical ingredients (APIs), investigational medical products (IMP), vaccines, human and veterinary medicalproducts are manufactured. The principles may also be considered, whereappropriate, in facilities where medical devices are manufactured.本文件所描述的原则适用于活性药物成分（API）、临床试验用药物产品（IMP）、疫苗、人用和兽用药品的生产设施。医疗器械的生产设施，也可酌情考虑这些原则。This documentshould be read in conjunction with the main GMP text and supplementary texts onvalidation (1-9).本文件应与GMP主文本和验证补充指南(1-9)一起阅读。3.      Glossary术语adjustment factor (safety factors). A series of modifying or safetyfactors are applied to take into account the fact that data from toxicological studiesof differing types and durations in differing species have been used.调整系数（安全系数）。一系列调整或安全系数，用以考虑来自其他物种不同类型和持续时间的毒理学研究数据。cleanability. The ability of a cleaning procedure to effectively removematerial, cleaning agent residue and microbial contamination清洁能力。清洁程序有效去除物料、清洁剂残留物和微生物污染的能力。cleaningvalidation. Documented evidence to establish that cleaning procedures areremoving residues to predetermined levels of acceptability, taking intoconsideration factors such as batch size, dosing, toxicology and equipmentsize.清洁验证：证明清洁方法可将残留清除至预定的可接受水平的文件化证据，同时考虑的因素有如批量、给药剂量、毒性和设备尺寸。contamination. Theundesired introduction of impurities of a chemical or microbiological nature,or of foreign matter, into or on to a starting material or an intermediate orpharmaceutical product during handling, production, sampling, packaging,repackaging, storage or transport.污染：起始物料或中间体或药品在处理、生产、取样、包装、重新包装、存贮或运输期间引入的不希望存在的化学或微生物杂质，或异物。cross-contamination.Contamination of a starting material, intermediate product or finished productwith another starting material or product during production.交叉污染：起始物料、中间体或成品与另一起始物料或产品在生产期间相互污染。Health Based Exposure Limits (HBELs)基于健康的暴露限（HBEL）See definition of Permitted Daily Exposure (PDE)见日允许接触量（PDE）的定义。margin of safety.The margin of safety is the difference between the cleaning acceptance limit based on HBEL andthe process residue data.安全空间。安全空间是基于 HBEL 的清洁接受限值与工艺残留数据之间的差值。maximum safe carryover(MSC). The maximum amount of carryover of a residual process residue (API, cleaningagent, degradant, and so forth) into the next product manufacturedwithout presenting an appreciable health risk to patients..最大安全残留（MSC）。残留下一个产品但不会给患者带来明显的健康风险的（API、清洁剂、降解物等）的工艺残留的最大量。maximum safesurface residue (MSSR). The MSSR is the maximum amount of process residue that can remain on equipment surfaces and still besafe to patients. The MSSR is mathematically calculateddividing the Maximum Safe Carryover (MSC) bythe total area of contact (MSC/Total).最大安全表面残留（MSSR）。MSSR 是残留在设备表面但对患者仍是安全的工艺残留的最大量， MSSR以最大安全残留（MSC）除以总接触面积（MSC/Total）算得。permitted daily exposure (PDE). PDE represents a substance-specific dosethat is unlikely to cause an adverse effect if an individual is exposed at orbelow this dose every day for a lifetime.日允许接触量（PDE）。PDE 代表一种物质的特定剂量，即如一个人在一生中每天以或低于该剂量接触该物质，不太可能造成不良影响。point of departure. The dose at which a significant adverse effect isfirst observed, or the lowest-observed-adverse-effect level (LOAEL).参考点。首次观察到严重不良反应的剂量，或最低可见不良反应水平（LOAEL）。verification. Theapplication of procedures to provide evidence through chemicalanalysis (e.g. after a batch or campaign) to show that the residues of theprevious product and cleaning agents, where applicable, have been reduced belowthe scientifically set maximum allowable or maximum safe carryover level.确认。应用程序通过化学分析（例如在批次或运动之后）提供证据，以表明以前产品和清洁剂的残留物（如适用）已降低到科学设定的最大允许或最大安全结转水平以下。4.    Historical approach旧的方法For details on the historical approaches incleaning validation, see the WHO Technical Report Series, No. 1019, Annexure 3,Appendix 3, 2019 (5).有关清洁验证的传统方法的详细信息，请参阅 WHO 技术报告，第 1019 号，附录 3，附录 3,2019(5)。The acceptance criteria for cleaning validationrecommended in historical GMP texts did not account for HBELs.传统GMP 正文中建议的清洁验证的接受标准不包括HBEL。A limit based on HBELs should still beestablished. Historically established limits may be used as alert limits whenthese are more stringent than HBELs .应建立基于HBEL 的限度。当使用传统方法确立的限度比HBEL更严时，可用作警戒限。Where the historical approach cannot besatisfactorily justified, and in view of the risks of contamination andcross-contamination, the new approaches, as described below, should beprioritized and implemented.如传统方法不能令人满意地证明合理，并且鉴于污染和交叉污染的风险，应毫不拖延地实施下文所述的新方法。5.       New approaches新的方法Historical cleaning validation approaches often merely showed that usinga defined cleaning procedure achieved an objective of meeting historicallimits. In many instances, no development work or cleanability studies weredone nor was consideration given to toxicological data for establishing limitsfor cleaning residues.传统清洁验证方法通常只是表明，使用既定的清洁程序实现了满足传统限度的目标。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以确定清洁残留的限度。Manufacturers should ensure that their cleaningprocedures are appropriately developed and that their cleaning validationprovides scientific evidence that residues of identified products that can bemanufactured in shared facilities are removed to safe levels, providinga high margin of safety to patients. Control measures should be implemented tomitigate the risks of contamination and cross-contamination.制造商应确保其清洁程序得到适当开发，并确保其清洁验证提供科学证据，证明在共用设施中生产的相关产品的残留可以被清除到安全水平，为患者提供高度安全空间。应实施控制措施，以减轻污染和交叉污染的风险。This approach should include at least thefollowing points (which are further described in the text below):这种方法至少应包括以下几点（下文将进一步说明）：risk assessmentto identify hazards, analyse risks, and to identify risk controls;风险评估，以识别风险、分析风险并制定风险控制措施;cleaningprocedure 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）（例如新的产品或新的清洁程序）;determinationof technical and organizational controls;确定技术性和组织性控制措施;HBELs setting;HBEL设置selection ofappropriate analytical procedures; and选择适当的分析方法；以及cleaningprocess control strategy.清洁工艺控制策略Manufacturers should describe and implement theirpolicy and approaches, including the points mentioned above, in a document suchas a master plan.制造商应在总计划等文件中描述和实施其政策和方法，包括上述要点。Genotoxic and carcinogenic substances,degradants and other contaminants should be identified and their risksevaluated. Appropriate action should be taken where required (11).应识别基因毒性和致癌物质、降解物和其他污染物，并评估其风险。必要时应采取适当措施（11）。5.1       Documentation文件Risk management principles, as described by WHOand other guidelines on quality risk management (10), should be applied toassist in identifying and assessing risks. The appropriate controls should beidentified and implemented to mitigate contamination and cross-contamination.应使用风险管理原则，如WHO和其他质量风险管理指南（10）所述，以帮助确定和评估风险。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 andcleaning validation require that good scientific practices should be applied(including the use of appropriate equipment and methods). This should bedescribed in a cleaning validation master plan. Development studies, cleaningand cleaning validation should be performed in accordance with predefined,authorized standard operating procedures, protocols and reports, asappropriate. Records should be kept.清洁和清洁验证的政策和方法要求使用良好的科学实践（包括使用适当的设备和方法）。应在清洁验证总计划中对此进行说明。开发研究、清洁和清洁验证应按照既定的、经批准的标准操作程序、方案和报告进行。记录应保存。The design and layout of documents, and thereporting of data and information, should be in compliance with the principlesof good documentation practices (12) and should also meet data integrityrequirements (12).文件的设计和布局以及数据和信息的报告应符合良好的文件规范原则（12），还应符合数据完整性要求（12）。5.2       Equipment设备Cleaning validation should cover direct productcontact surfaces. Non-contact surfaces should be included in cleaning validationwhere these have been identified as areas of risk.清洁验证应覆盖产品直接接触的表面。非接触表面如被确定为风险区域也应包含在清洁验证中。Authorized drawings of equipment should becurrent, accurate and available. Equipment surface area calculations should bedocumented and justified. The source data for these calculations should beavailable. The calculated values should be used in the calculations in cleaningvalidation.已批准的设备图纸应是最新的、准确的和可用的。应记录并论证设备表面积的计算。应有这些计算的源数据。算出的值应在清洁验证的计算中使用。All equipment and components, including thosethat are difficult to clean (for example, sieves, screens, filters and bags(such as centrifuge bags) should be considered in cleaning validation andcalculations. Where the need is identified, dedicated equipment and orcomponents should be used.在清洁验证和计算时，应考虑所有设备和部件，包括难以清洁的设备（例如筛子、筛网、过滤器、过滤器和袋子（如离心袋）。必要时，应使用专用设备和/或部件。5.3       Cleaning agents清洁剂Cleaning agents (including solvents anddetergents used in cleaning processes) should be selected with care. Theyshould be appropriate for their intended use. The selection of the relevantcleaning agent should be scientifically justified.清洁剂（包括清洗过程中使用的溶剂和洗涤剂）应谨慎选择。它们应适合其预期用途。有关清洁剂的选择应具有科学依据。There should beproof of effectiveness and appropriateness of the selected cleaning agent.应证明所选清洁剂的有效性和适当性。Other points to consider include theconcentration in which these are used, their composition and removal of theirresidues to an acceptable level.需要考虑的其他事项包括使用这些物质的浓度、组成及其残留的清除。When cleaning agents are used in cleaningprocesses, these should be included in cleaning process development studies andcleaning validation.当清洁过程使用清洁剂时，应包含在清洁工艺开发研究和清洁验证中。5.4       Sampling取样Historically, cleaning validation includeddifferent methods being applied to determine whether or not there was anyresidue remaining on surface areas after cleaning. The focus was mainly onproduct contact surface areas.传统上，清洁验证包括采用不同的方法来确定清洁后表面是否有残留。重点主要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 preferredother method to be used. Rinse samples should be taken for areas which areinaccessible for swab sampling.通常应使用至少两种或三种方法的组合。包括，例如，擦拭样品，冲洗样品和目视检查。应始终执行目视检查。其他方法首选擦拭取样。对于无法进行擦拭取样的区域，应采集冲洗样品。Appropriate sampling procedures, swab materialand sampling techniques should be selected and used to collect swab and rinsesamples. The detail should be clearly described in procedures and protocols.The number of swabs, location of swabbing, swab area, rinse sample volume andthe manner in which the samples are collected should be scientificallyjustified.应选择适当的取样程序、棉签材料和取样技术，并用于收集擦拭和冲洗样品。应在程序和方案中明确详细描述。擦拭的数量、位置、面积、冲洗取样的体积以及采集样品的方式应科学论证。Swab and rinse sample methods should be validated.Recovery studies for swab and rinse sampling should be performed.擦拭和冲洗取样的方法应验证。应执行擦拭和冲洗取样的回收率研究。Wheremicrobiological sampling is carried out, the microbiological method should alsobe validated.如进行微生物取样，应验证微生物方法。The manner in which collected samples are stored (if required) andprepared for analysis should be appropriate, described in detail and includedin the cleaning validation.样品的存储（如需要）和分析前的处理方式应适当，详细描述并包含在清洁验证中。5.5       Cleanability studies清洁能力研究Before a new cleaning procedure is validated andadopted for routine use, a cleanability study should be performed in order todetermine the appropriateness of the procedure for removing for example productresidue, cleaning agents and microorganisms. For cleaning procedures that havealready been validated where the data show that the cleaning procedure iseffective and consistent, or where risk assessment indicated that cleanabilitystudies may not be required, this may be considered acceptable.在新的清洁程序经验证和并供日常使用之前，应进行清洁能力研究，以确定去除产品残留物、清洁剂和微生物等程序是否适当。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进行清洁能力研究，可能被认为可以接受。5.6       Risk management风险管理Risk management should be implemented with afocus on the identification, evaluation, assessment and control of risks tomitigate the risk of contamination and cross-contamination.风险管理应注重风险的识别、评价、评估和控制，以减少污染和交叉污染的风险。These controls should include technical andorganization controls in order to deliver a validated cleaning process (10).这些控制应包括技术性和组织性控制，以便提供有效的清洁工艺（10）。5.7       Guidance for Health-Based Exposure Limits (HBELs) setting基于健康的暴露限（HBEL）设置指南Manufacturers should establish, document andimplement a company-wide policy on HBELs setting for shared facilities.制造商应建立、记录和实施关于共用设施的HBEL 设置的公司层面的策略。The appropriateness of the production and control of various APIs orvarious products in shared facilities should be evaluated on the basis ofscientific data and information.应根据科学数据和信息评估共用设施中不同 API 或不同产品的生产和控制是否适当。This is applicable to legacy products as well aswhen new products are planned to be introduced into a facility, for example,through a change control procedure.这适用于现有产品以及计划将新产品引入设施时，例如通过变更控制程序。Procedures should be established and implementeddescribing how the scientific and toxicological data and information areobtained and considered and how HBELs are established.应建立和实施用以说明如何获取和考虑科学和毒理学数据和信息，以及如何建立HBEL的程序。Data and information should be gathered by aperson with appropriate qualifications and experience in the field oftoxicology and/or pharmacology. The data and information should be presented ina 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收集。数据和信息应在一份报告中呈现。提供的数据和信息应无偏颇。Where this service is outsourced by themanufacturer, appropriate measures should be put in place in order to ensurethat the data obtained are reliable. GMP requirements, such as vendorqualification, agreements and other related aspects, should be considered.如果此服务由制造商外包，应采取适当措施，以确保获得的数据是可靠的。应考虑GMP 要求，如供应商确认、协议和其他相关方面。Note: The HBEL value for the same substancesometimes differs when it is determined by different individuals. The reasonfor the difference between the values should be clarified and investigated.注：同一物质的HBEL值有时因不同个体而不同。这种差异的原因予以说明和调查。The report foreach 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：substanceidentification物质名称chemicalstructure化学结构clinicalindication临床指征mode of action作用方式route ofadministration (Note: Where more than one route of administration is available,it may be necessary to calculate separate HBELs)给药途径（注：当有超过一种给药途径时，应分别计算HBEL）preclinical/nonclinicaldata, for example, of acute and repetitive dose studies临床前/非临床数据，例如急性和重复给药研究genotoxicitydata遗传毒性数据reproductivetoxicity data生殖毒性数据carcinogenicitydata致癌性数据data relatingto highly sensitizing potential与高致敏性相关的数据clinical data临床数据pharmacodynamicsand pharmacokinetics药理学和药代动力学identificationof the critical effect(s)确定关键反应point of departurefor the HBEL calculation(s)用于HBEL计算的开始点adjustmentfactors调整因子justificationof the selected lead rationale (if calculations with different points ofdeparture were made).所选引线理由的理由（如果进行了不同出发点的计算）。The report should be reviewed for its completeness and appropriatenessby the manufacturer’s designated internal personnel or by an appointed externalpersons. The person should have in-depth knowledge, appropriate qualificationsand experience in the field of toxicology. A summary document may be preparedfor each relevant substance and should contain information on the PDE value,and toxicity (13).该报告应由制造商指定的内部人员或外部人员审查其完整性和适当性。该审查人员应具有深入的知识、适当的资质和毒理学领域的经验。可为每种相关物质编写一份总结文件，并应包括关于PDE值和毒性的信息（13）。The scientific report and calculated PDE valueshould be used when defining the cleaning validation control measures.在制定清洁验证控制措施时，应使用科学的报告和所计算的PDE值。Note: If no NOAEL is obtained, thelowest-observed-adverse-effect level (LOAEL) may be used. Alternativeapproaches to the NOAEL, such as the benchmark dose, may also be used. The useof other approaches to determine HBELs could be considered acceptable if adequatelyand scientifically justified (13).注意：如果未获得NOAEL，则可以使用最低可见不良反应水平（LOAEL）。也可以使用NOAEL的替代方法，如基准剂量。如充分并经科学论证，使用其他方法确定HBEL可被视为可以接受（13）。Manufacturers should periodically consider newdata and information on HBELs. Appropriate action, such as the updating of PDEreports, should be taken where required.制造商应定期考虑有关HBEL 的新数据和信息。必要时，应采取适当行动，例如更新PDE报告。5.8       Acceptance criteria接受标准The limitsestablished in cleaning validation should be justified.制定的清洁验证限度应进行论证。Some manufacturers have specified acceptancecriteria based on carryover limits or limits reflected in some GMP guidelines.These limits may no longer be acceptable as HBELs and related toxicity datawere not included in the determination of such acceptance criteria.一些制造商根据某些GMP 指南中反映的残留限度来制定接受标准。这些限度可能不再被接受，因为此接受标准的制定未包含HBEL和相关毒理数据。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 availableand comply with data integrity principles. The calculation should includevalues of PDE, maximum daily dose, batch size and total shared equipmentsurface areas.应计算最大安全残留（MSC）/最大允许残留（MACO）和最大安全表面残留（MSSR）值等标准。计算和数据应可用，并符合数据完整性原则。计算应包括PDE 值、最大日剂量、批量大小和总设备共用表面积。MSSR should be calculated and presented, for example, in table formlisting preceding and following product values. The cleanability value obtainedshould be considered in determining the acceptability of the procedure(s) andwhether other controls including separate, dedicated facilities are required.(See Annex 1 as an example.)应计算和呈现MSSR，例如，在表格中列出清洁前后产品的值。在确定程序的可接受性以及是否需要其他控制措施（包括独立的专用设施）时，应考虑所获得的清洁能力的值。（见附件1）。The margin of safety (the distance between theanalytical data and the HBEL base limit) should be identified.应确定安全空间（分析数据与HBEL 基准限度之间的距离）。5.9       Analytical procedures分析程序Samples obtained in cleaning validation shouldbe analyzed by using procedures that are validated for their intended use. Theprocedures should be developed in accordance with the principles of AnalyticalQuality by Design.清洁验证中获得的样品应使用经过验证适合其预期用途程序进行分析。应基于分析质量源于设计的原则来开发程序。Specific methods, such as High-performance Liquid Chromatography (HPLC),should be used where appropriate. Non-specific methods including UVspectrophotometry should only be used where specific methods cannot be employedand their use can be justified, for example, based on the outcome of riskassessment.应酌情使用专属性方法，如高效液相色谱（HPLC）法。非专属性方法（包括紫外分光度法）应仅在无法使用专属性方法，并经论证的情况下方使用，例如，根据风险评估结果。Testing for total organic carbon (TOC) may be used where indicated andwhere justified.如经说明并论证的情况下，可以使用总有机碳（TOC）测试。Where analytical procedures were developed andvalidated off-site, the scope and extent of validation when these aretransferred to the site, should be defined and justified. This includesprocedures that are transferred from research and development laboratories tosite laboratories. Analytical procedures should be able to quantify or detectresidue levels at the maximum safe surface residue level. (For analyticalprocedure validation, see reference 6.)如果分析程序不是在工厂开发和验证的，则应界定和说明其转移至工厂时需要验证的范围和程度。这包括从研发实验室转移到工厂实验室的程序。分析程序应能够定量或检测最大安全表面残留水平的残留水平。（有关分析方法验证，见参考文献6）Manufacturersshould ensure that the procedures remain in a validated state.生产商应确保该保持已验证状态。5.10 Dataintegrity数据完整性Data, information and results pertaining to, forexample, HBELs, PDE reports, results obtained from cleaning validation and calculations,should be scientific and should be in compliance with the principles ascontained in data integrity guidelines (12).与HBEL、PDE报告、清洁验证和计算所得结果相关的数据、信息和结果应科学，并应当符合数据完整性指南（12）所载的原则。5.11 Cleaningvalidation and cleaning verification清洁验证和清洁确认Cleaningvalidation清洁验证The cleaningprocedure should be validated (5).清洁程序应被验证。Cleaning validation should include proof of, forexample, the applicability of the procedure to clean equipment that:清洁验证应包括证明清洁方法对以下设备状态的适用性：had been keptin an unclean state for a period of time (dirty equipment hold time);待清洁状态的保持时间（脏的保持时间） ;are used after a product is planned (e.g. change from one product toanother product);一个产品生产后，例如，从一个产品更换为另一个产品;are used in acampaign, where multiple batches of a product are produced one after the other;and/or连续生产的设备，一个产品的多个批次连续生产;及/或are stored in aclean state for defined periods of time (clean equipment hold time).洁净状态下存放一定时长（干净的保持时间）HBEL should be considered when establishing carryover limits in cleaningvalidation.确定清洁验证中残留限度时，应考虑 HBEL。Cleaningverification清洁确认The companyshould describe the policy and approach to cleaning verification. Cleaningverification is where the effectiveness of the validated cleaning procedure isroutinely verified. The approach mayinclude swab orrinse samples. The results obtained from testing on a routine basis should bereviewed and subjected to statistical trending.公司应说明清洁确认的政策和方法。清洁确认用于定期确认已验证清洁程序的有效性。该方法可能包括擦拭或淋洗取样。应审查日常测试的结果，并进行趋势分析。5.12 Visuallyclean目视洁净Visually clean is an important criterion incleaning validation. It should be one of the acceptance criteria used on aroutine basis. Personnel responsible for visual inspection should beappropriately trained. Training records should be kept.目视干净是清洁验证的一个重要标准。它应该是日常使用的接受标准之一。负责目视检查的人员应接受适当培训。应保存培训记录。Where visual inspection is used as aquantitative method, then Visible Residue Limits (VRLs) should be determined.The process to determine the limit should be appropriately described inprocedures and protocols covering, for example, concentrations, method ofspiking, surface areas, material of construction and other conditions such aslight (LUX level) and angles.目视检查用作定量方法时，应确定可见残留的限度（VLL）。确定限度的过程应在程序和方案中适当描述，包括浓度、涂布方法、表面积、载体材料和其他条件，如光线（LUX水平）和角度。5.13 Cleaningprocess capability清洁工艺能力The cleaning procedure should remain in avalidated state. It is recommended that cleaning verification results andcalculated process capability data be used to support this. For example, theresults from cleaning verification sample analysis could be statisticallytrended. The capability of the cleaning process is then calculated by using anappropriate statistical process.清洁程序应保持已验证状态。建议使用清洁确认结果和所计算的工艺能力数据来支持此要求。例如，清洁确认样品分析的结果可以统计趋势。然后使用适当的统计过程计算清洁工艺的能力。Data should be presented, for example, in graphform, and the capability of the process in relation to control limits and themargin of safety should be presented and discussed as part of continuousimprovement over the life cycle.例如，数据应以图表形式呈现，并给出过程与控制限度和安全边际的能力，并讨论作为生命周期持续改进的一部分。5.14 Personnel人员Personnel should be trained on the proceduresand principles of cleaning and cleaning validation, including contamination andcross-contamination control, HBELs setting, equipment disassembly, visualinspection, sampling, testing and statistical calculations, as appropriate andbased on their responsibilities.应酌情根据职责，对人员进行清洁和清洁验证的程序和原则的培训，包括污染和交叉污染控制、HBEL设置、设备拆解、目视检查、取样、检验和统计计算。5.15 Qualitymetrics and performance indicators质量量度和性能指标Aspects ofcleaning validation and cleaning verification should be considered in qualitymetrics, with performance indicators identified and monitored.应在质量量度中考虑清洁验证和清洁确认的各个方面，并确定和监测性能指标。5.16 Life cycle生命周期Cleaningprocedures, cleaning validation and cleaning verification should be included inthe life cycle approach described by the company.清洁程序、清洁验证和清洁确认应包含在公司描述的生命周期方法中。Annex 1. Using Health-Based Exposure Limit(HBEL) to assess risk in cleaning validation*附录1 在清洁验证中使用基于健康的暴露限（HBEL）评估风险Permitted DailyExposure (PDE)日允许暴露限（PDE）The Permitted Daily Exposure (PDE) can becalculated based on the data and information obtained. For example:日允许暴露量（PDE）可以根据获得的数据和信息进行计算。例如：

Where NOAEL isno-observed adverse effect level, andNOAEL为无可见不良反应水平F representsvarious adjustment factors. The value selected for each factor should bejustified.F为不同调整因子。每个因子选择的值应论证。The PDE is derived by dividing the NOAEL for thecritical effect by various adjustment factors (also referred to as safety-,uncertainty-, assessment- or modifying factors) to account for variousuncertainties and to allow extrapolation to a reliable and robust no-effectlevel in the human or target animal population. F1 to F5 are addressing thefollowing sources of uncertainty:PDE通过将关键反应的NOAEL除以各种调整因子(也称为安全性、不确定性、评估或修改因子)得出，以考虑各种不确定性，并允许外推到一个可靠的、稳健的人类或目标动物种群的无反应水平。F1到F5用以解决以下不确定性来源：F1: A factor(values between 2 and 12) to account for extrapolation between species;F1：一个因子（值介于 2 和 12 之间），用于考虑物种之间的推断;F2: A factor of10 to account for variability between individuals;F2：取10，用于解释个体差异;F3: A factor 10to account for repeat-dose toxicity studies of short duration, i.e., less than 4-weeks;F3：重复给药毒性研究为短期，取10，即少于4周;F4: A factor(1-10) that may be applied in cases of severe toxicity, e.g. non-genotoxiccarcinogenicity, neurotoxicity or teratogenicity;F4：用于严重毒性情况的因子（1-10），例如非基因毒性致癌性、神经毒性或致畸性;F5: A variable factor that may be applied if theno-effect level was not established. When only an LOEL is available, a factorof up to 10 could be used depending on the severity of the toxicity.F5：如未建立无反应水平，可应用该因子。当只有LOEL 可用时，根据毒性的严重程度，可以使用高达10 的因子。The use of additional modifying factors to address residualuncertainties not covered by the above factors may be accepted provided theyare well supported with literature data and an adequate discussion is providedto support their use (Ref: EMA document).如有充分的文献数据支持并充分讨论了其使用支持，也可以使用其它调整因子来解决上述未涵盖的其他不确定性（参考：EMA文件）。If no NOAEL is obtained, the lowest-observed-adverse-effect level(LOAEL) may be used.如未获得NOAEL，可以使用最低可见不良反应水平（LOAEL）。Calculating MSCand MSSR计算MSC（最大安全残留）和MSSR（最大表面安全残留）MSC and MSSRcan be calculated by using HBELs, to determine the risks associated withcleaning validation.MSC和MSSR可通过使用HBEL算得，以确定与清洁验证相关的风险。It can alsogive an indication of the acceptability, or not, of manufacturing specifiedproducts in shared facilities. For example:它还可以提供在共用设施中制造特定产品的可接受性或不可接受性的指标。例如:Step 1.Calculate MSC步骤1：计算MSC（最大安全残留）

Wherea = product aa=产品ab = product b or subsequent productb=产品b或后续产品Step 2.Tabulate the data步骤2：汇总数据

Step 3.Calculate MSSR (mg/m2)步骤3：计算MSSR（最大表面安全残留）

Step 4. Tabulate the data for MSSR and identifywhere there is a risk, based on the MSSR that are not met when considering thecleanability of the procedure.在考虑程序的清洁能力时，根据未满足的MSSR（最大表面安全残留）将MSSR（最大表面安全残留）数据制成表格，并确定哪里存在风险。MSSR最大表面安全残留Following product b后续产品b123456PreCedingProducta先前产品a123456*  Barle, E.L. Using Health-Based Exposure Limitsto assess risk in cleaning validation. Pharmaceutical Technology.*  使用基于健康的暴露限来评估清洁验证风险。制药技术。

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