Annex 2 附录2
Points to consider when including Health-Based Exposure Limits (HBELs) in cleaning validation 清洁验证中包括基于健康的暴露限（HBEL）时的考虑要点
1. Introduction and background 介绍与背景
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).
WHO已在2014年WHO 第986号技术报告附录2发布了题为《药品GMP：主要原则》的指南.
The WHO Supplementary guidelines on good manufacturing practice: validation were published in 2006 and were supported by seven appendices. The main text (2) and its appendixes (3, 4, 6, 7, 8, 9) were revised between 2006 and 2019. Appendix 3, relating to cleaning validation (5), 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 prepa red 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.
WHO《GMP补充指南：验证》于2006年发布，有7个支持性附录。主要正文及其附录（3、4、6、7、8、9）在2006-2019年间进行了修订。与清洁验证（5）有关的附录3当时未有更新。但在2019年7月瑞士日内瓦的正式咨询会议中有对其进行讨论，讨论结果被提交至2019年10月的ECSPP会议。ECSPP了解统一清洁验证方法方面的监管要求的重要性，因此专家委员会建议起草一份“考虑要点”文件，描述目前清洁验证中所用的方法，着重强调其中复杂性，从而达成共识。在此后专家委员会考虑了对相关附录进行修订。
Some of the main principles of good manufacturing practices (GMP) include the prevention of
validation verificationmix-ups and the prevention of contamination and cross-contamination. Multi-product facilities in particular, have a potential risk of cross-contamination. It is therefore important that manufacturers identify all risks relating to contamination and cross-contamination and identify and implement the appropriate controls to mitigate these risks.
GMP的一些主则包括防止混淆和防止污染与交叉污染。尤其是多产品设施会具有潜在的交叉污染风险。因此，生产商要识别出与污染和交叉污染有关的风险，识别并实施恰当的控制措施缓解这些风险就显得特别重要。
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组织措施，使用专用设施、密闭系统、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.
我们强烈建议生产商对其现有技术和组织措施、清洁程序的适用性以及现有清洁验证研究的恰当性进行审核。
Technical controls, such as the design of the premises and utilities (e.g. 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.
技术控制手段如设施与公用系统的设计（例如HVAC系统、水系统和用气）均应适合于所生产的药品范
围（例如，药学分级、活性和特性）。如果HVAC系统有再循环空气，应实施有效的控制措施防止交叉污染。
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.
如果认为可采用组织控制措施作为降低交叉污染风险的手段，应考虑如专用区域和公用系统、专用设备、程序控制和周期生产。
Measures to prevent cross-contamination and their effectiveness should be reviewed periodically in accordance with authorized procedures.
应根据批准的程序对防止交叉污染的措施及其有效性进行定期回顾。
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.
应注意上述例子在其它文件中有更为详细的描述。本文重点在于清洁验证中的HBEL设定。
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.
本文提供了在清洁验证中根据药学和毒性数据考虑HBEL时基于风险的科学方法的考虑要点。
This document further provides points to consider when reviewing the current status and approaches to cleaning validation in multiproduct facilities.
本文还提供了审核多产品设施清洁验证的现行状态和方法审核时的考虑要点。
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.
本文中所列原则可用于API、IMP、疫苗、人药与兽药生产设施。医疗器械生产设施亦可考虑这些原则（适用时）。
This document should be read in conjunction with the main GMP text and supplementary texts on validation (1–9).
本文应与GMP主文件及验证方面的补充文件一起解读。
3. Glossary 术语
Adjustment factor (safety factors). Numerical factor used in a quantitative risk assessment to
represent or allow for the extrapolation, uncertainty, or variability of an observed exposure concentration and its associated health outcome in a particular laboratory species or exposed population to an exposure concentration for the target population (for example, from animals to human patients and short-term exposure to chronic exposure) that would be associated with the same delivered dose. Adjustment factors can also be used when dealing with clinical data, e.g. when a study population is not representative of the general population (10).
调整因子（安全因子）：定量风险评估中所用的数值因子，表现测得暴露浓度及其相关健康结果，尤其是实验室物种或暴露人相关健康结果的外推、不确定性或波动性至目标人使用相同给药剂量时的暴露浓度（例如，从动物到人类患者，从短期暴露到长期暴露）。调整因子亦可用于处理临床数据，例如，当研究人不代表一般人时。
Cleanability. The ability of a cleaning procedure to effectively remove material, cleaning agent residue and microbial contamination.
清洁能力：清洁程序有效清除物料、清洁剂残留和微生物污染的能力。
Cleaning validation. The collection and evaluation of data, from the cleaning process design stage through cleaning at commercial scale, which establishes scientific evidence that a cleaning process is capable of consistently delivering clean equipment, taking into consideration factors such as batch size, dosing, toxicology and equipment size.
清洁验证：从清洁工艺设计阶段到商业阶段清洁过程中所采集和评估数据，建立科学证据证明清洁工艺有能力持续交付清洁设备，同时考虑如批量、剂量、毒性和设备尺寸等因子的过程。
Contamination. The presence of undesired foreign entities of a chemical, microbiological or physical nature in or on equipment, a starting material, or an intermediate or pharmaceutical product during handling, production, sampling, packaging, repackaging, storage or transport.
污染：设备、起始物料或中间体或药品在处置、生产、取样、包装、重新包装、贮运期间出现非预期化学、微生物或物理属性异物的情况。
Cross-contamination. Contamination of a starting material, intermediate product or finished product with another starting material or product.
交叉污染：起始物料、中间体或成吕与另一起始物料或产品之间的污染。
Health Based Exposure Limits (HBELs). See definition of Permitted Daily Exposure (PDE)
基于健康的暴露限（HBEL）：参见允许日暴露值（PDE）的定义。
Margin of safety. The margin of safety is the ratio between the cleaning acceptance limit based on HBEL and the process residue data.
安全余量：安全余量是基于HBEL的清洁可接受限度与工艺残留数据的比例。
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）：工艺残留物（API、清洁剂、降解产物及类似物品）残留至下一产品，不会对患者造成明显健康风险的最大残留数量。
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 by dividing the Maximum Safe Carryover (MSC) by the total area of shared contact (MSC/Total Product Contact Surface Area).
最大安全表面残留（MSSR）：MSSR是可以留存于设备表面但对患者仍是安全的工艺残留物的最大数量。MSSR是半最大安全残留（MSC）除以共用接触面积（MSC/产品总接触表面积）计算而得的。
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.
允许日暴露值（PDE）：PDE代表的是个体终生每日暴露于低于等于该剂量时不可能导致不良反应的一个物质特有的剂量。
Point of departure (of the HBEL calculation). The dose-response point that marks the beginning of a low-dose extrapolation to derive an HBEL. This point can be a No Observed Adverse Effect Level (NOAEL) or No Observed Effect Level (NOEL), Lowest Observed Adverse Effect Level (LOAEL) or Lowest Observed Effect Level (LOEL), or Benchmark Dose Level (BMDL) for an observed effect [the highest dose at which no unwanted/adverse effect is observed (NOEL/NOAEL), or, if unavailable, the dose at which a significant adverse effect is first observed (LOEL/LOAEL)].
（HBEL计算的）起始点：标示从低剂量外推计算出HBEL的剂量响应点。该点可以是未观察到不良反应水平（NOAEL）或未观察到影响水平（NOEL）、观察到不良影响的最低水平（LOAEL）或观察到影响的最低水平（LOEL），或者是观察到影响【未观察到非预期/不良影响的最高水平
（NOEL/NOAEL），或者上述数据均没有时，使用首次观察到严重不良影响的剂量（LOEL/LOAEL）】的标准剂量水平（BMDL）。
Verification. Evidence that the equipment is clean (i.e. that residues are reduced from prior operations to levels no higher than those that are predetermined and specified as acceptable). Appropriate methods should be used and, depending upon the circumstances, may include visual inspection, analytical and microbial (as applicable) testing of swab and/or rinse samples.
确认：证明设备清洁的证据（即，残留被从之前的操作降低到不高于之前确定且认为可接受的水平）。应使用恰当的方法，根据具体情况可包括目视检查、擦拭和/或淋洗样品分析和微生物（适用时）检测。
4. Historical approach in cleaning validation 清洁验证历史方法
For details on the historical approaches in cleaning validation, see the WHO Technical Report Series, No. 1019, Annexure 3, Appendix 3, 2019 (5).
清洁验证的历史方法详细信息参见WHO 2019年第1019号TRS附录3的附录3。
The acceptance criteria for cleaning validation recommended in historical GMP texts did not account for HBELs. A cleaning limit based on HBELs should be calculated and compared against an existing cleaning limit.
在历史GMP文件中所建议的清洁验证可接受标准并未考虑HBEL。现在应计算基于HBEL的清洁限度，并与正在使用的清洁限度进行比较。
Historically established cleaning limits may be used when these are more stringent than HBELs. Any alert and action limits should not be based on historically established cleaning limits, but should be based on a statistical analysis if existing data (i.e. statistical process control).
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