2018年4月30日，EMA发布了《Questions and answers on implementation of risk-based prevention of cross-contamination in production and ‘Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities’ (EMA/CHMP/CVMP/SWP/169430/2012)基于风险防止药品生产中交叉污染以及“共用设施中不同药品生产风险识别所用基于健康的暴露限设定指南”实施问答》文件。该文件为的最终版。
有关该问答文件的解读如下：
删除了使用1/1000最低治疗剂量和10ppm法来建立清洁验证限度。
删除了高危害产品和其它产品之间的区分
所有药品均应建立基于健康的暴露限度（HBEL=PDE），并定期重新评估。
该文件提供了一个不同PDE值对应的风险水平的模型，以帮助企业针对不同水平的PDE值建立相应的风险控制措施
PDE值<10µg 表了高风险，pde值="">10000µg/天为最低。
PDE应由具备足够专业知识并具有毒理学/药学经验、熟悉药物并具备基于健康暴露限确定经验如职业暴露水平（OEL）或PDE的人员来确定。
如果使用第三方来确定HBEL（PDE），则应在开始工作前签订合同。
委托生产时，要么将全面的HBEL评估给受托方，要么提供数据使得受托方可以实施HBEL评估。
可以考虑根据清洁工艺能力设置警戒限。
每次更换产品时均应对残留进行检验，除非通过稳健的书面质量风险管理（QRM）流程进行论证。论证时考虑以下几点：清洁过程的可重复性、产品构成的危害、是否可以依靠目视检查来确定设备的清洁程度能否符合 HBEL 规定的残留限度
人工清洗通常不如自动清洗重复性好
生产商应建立可见残留的限度水平
对清洁残留进行目视检查时，应考虑现场的照明条件和观察距离。
目视检查应包括所有可能留有污染的产品接触表面，包括拆卸设备进入检查/或使用工具（例如镜子，光源，内窥镜）检查不可见区域的表面
对于非产品接触表面，但可能在未来掉落或转移至后续批次的，也应进行检查。
生产商不能只是将一般产品与其它类型产品分隔作为处理患者风险和动物安全的手段。尽管此方法可以防止其它级别产品的污染，但它并未解决同一级别产品中交叉污染的可能性。
LD50不足以用作确定药品的HBEL。
如果无法确定一个PDE值，或者是数据不能支持生产商使用共用设备，则杀外寄生虫剂应在专用设备中生产。
兽药：基于健康的暴露限设定指南认为残留限度一般应使用人类PDE来计算。但是，如果已知某个特殊物种有感受性关切（例如，马对莫能菌素特别敏感，不能使用），则在使用HBEL方法评估共用设施/设备中生产的产品时应考虑特定动物毒性知识。
该问答原文翻译如下（点击文章底部'阅读原文'获取全文）：
Q1. Are Health-Based Exposure Limits (HBELs) required for all medicinal products?
是否所有药品都需要基于健康的暴露限度（HBEL）？
A: Yes, HBELs should be established for all medicinal products. The toxicological or pharmacological data, on which the HBEL calculation relies, requires periodical reassessment throughout a product’s lifecycle.
是的，所有药品都需要建立HBEL。用于计算HBEL的毒理或药理数据需要在药品生命周期中定期评估。
Q2. Is there a framework that could be used to define the significance of the Health-Based Exposure Limit (HBEL) such that there can be broad guidance on the extent of Quality Risk Management (QRM) and control measures required?
是否有一个框架定义基于健康的暴露限度（HBEL）的重要性，例如一个关于质量风险管理（QRM）和相应控制措施的程度的指导？
A: Firstly, it should be recognised that hazard varies on a continuum scale and that there are no firm cut off points, risk should be controlled on a proportionate basis. However, as a broad hypothetical model the following figure could be considered to show the increasing level of hazard (red being highest hazard) presented by products and there should be a commensurate increase in the level of control to prevent potential cross contamination in a shared facility. Actual HBEL values should be used in QRM studies to determine the actual controls required.
首先，应该认识到危害在连续规模上有所不同，并且没有确切的切点，风险应该按比例控制。 但是，作为一个广泛适用的假设模型，可以考虑下图来展示产品所呈现的危险程度的增加（红色为最高危险），并且控制级别应该相应增加以防止共享设施中潜在的交叉污染。 在QRM研究中应使用实际的HBEL值来确定所需的实际控制。
Q3. How should manufacturers use the HBELs?
生产商如何使用HBEL?
A: The role of HBELs in determining cleaning limits is explained in Q&A 6. However, the purpose of generating HBELs goes beyond justification of cleaning limits.
Q&A6中已解释了HBEL在确定清洁限度中的作用。然而，产生HBEL的目的远不止计算清洁限度。
Once the health-based assessment has been completed and the HBEL confirmed, these data should be used via a Quality Risk Management process to determine what controls need to be put in place and to assess if existing organisational and technical control measures are adequate or if they need to be supplemented. This Quality Risk Management process should be carried out prospectively in the case of new equipment/facility to determine what control measures are required.
一旦完成基于健康的评估并确认HBEL，应通过质量风险管理流程使用这些数据，以确定需要实施哪些控制措施，并评估现有的组织和技术控制措施是否足够或者是否需要补充。在新设备/设施的情况下，应前瞻性地开展质量风险管理程序，以确定需要采取哪些控制措施。
It is expected that for products which present a higher potential harm to patients/animals, more elaborate organisational and technical control measures will be required. Using a structured Quality Risk Management process, manufacturers should consider the risks of cross contamination down to the established level from the HBEL. During the QRM study manufacturers should consider how easily such a quantity of contamination could occur, without detection, at batch and unit dose level.
预计对于对患者/动物具有较高潜在危害的产品，将需要更详尽的组织和技术控制措施。使用结构化的质量风险管理流程，制造商应将交叉污染的风险降至HBEL的既定水平。在QRM研究期间，制造商应该考虑在批量和单位剂量水平下如何容易地发生这样的量的污染。
The level of detail in the QRM process should be commensurate with the potential harm as indicated by the HBEL and the suitability of control measures supported by practical and science-based evidence.
QRM过程的详细程度应与HBEL指出的潜在危害以及由实际和科学证据支持的控制措施的适用性相匹配。
Manufacturers should be mindful that cross contamination controls implemented previously may not adequately assure control of the cross-contamination risk in the context of the HBEL approach.
制造商应该注意，原来实施的交叉污染控制措施可能无法充分保证控制HBEL方法中的交叉污染风险。
Additional observation of working practices, investigation and analysis may be required to provide full practical confidence in the effectiveness of controls.
可能需要对工作实践进行更多的观察，调查和分析，以对控制措施的有效性提供充分的实际信心。
Where control measures cannot adequately assure that the potential contamination is consistently controlled to a level below that of the HBEL then the products concerned should be manufactured in dedicated facilities.
如果控制措施不能充分确保潜在污染一直控制在低于HBEL的水平，那么相关产品应在专用设施中生产。
Q4. What competencies are required for the person developing the Health-Based Exposure Limits (HBEL)?
开发基于健康的暴露限度（HBEL）的人员需要哪些能力？
A: Health-Based Exposure Limits should be determined by a person who has adequate expertise and experience in toxicology/pharmacology, familiarity with pharmaceuticals as well as experience in the determination of health-based exposure limits such as Occupational Exposure Levels (OEL) or Permitted Daily Exposure (PDE).
基于健康的暴露限值应由在毒理学/药理学方面具有足够专业知识和经验，熟悉药物以及确定基于健康的暴露限值（如职业暴露水平（OEL）或允许的经验）的人员确定日常暴露（PDE）？
Where experts are contracted to provide the HBEL, contractual agreements in compliance with Chapter 7 requirements should be in place prior to work being conducted. It is not considered acceptable for manufacturers to ‘purchase’ HBEL assessments without recording an assessment of the suitability of the provider (including the specific technical expert) as a qualified contractor.
在专家签约提供HBEL的情况下，应在工作开始前制定符合第7章要求的合同协议。 制造商在购买HBEL评估时未考虑供应商（包括特定技术专家）作为合格承包商的适用性评估是不被接受的。
Q5. What responsibility do contract givers have to contract manufacturers in relation to data to support a HBEL assessment?
合同授予者在支持合同制造商评估HBEL方面有什么责任？
A: Contract givers should either provide a full HBEL assessment to contract manufacturers or provide the data to allow the contract manufacturer to conduct the HBEL assessment. In either case the HBEL assessment, including data references and relevant experts should be available on request during inspection of the manufacturer.
合同授予人应该向合同制造商提供完整的HBEL评估，或提供数据以允许合同制造商进行HBEL评估。 在任何一种情况下，HBEL评估（包括数据参考和相关专家）应在制造商检查期间根据要求提供。
Q6. How can limits for cleaning purposes be established?
如何建立清洁限度？
A: Although the EMA guideline (EMA/CHMP/CVMP/SWP/169430/2012) may be used to justify cleaning limits (as per Introduction paragraph 3), it is not intended to be used to set cleaning limits at the level of the calculated HBEL.
尽管EMA指导原则（EMA / CHMP / CVMP / SWP / 169430/2012）可用于证明清洁限度（按照引言第3段），但并不打算用于设置清洁限度计算HBEL。
For existing products, manufacturer’s historically used cleaning limits should be retained and can be considered alert limits provided that when taking cleaning process capability into account, they provide sufficient assurance that excursions above the HBEL will be prevented. A similar process should be adopted when establishing cleaning alert levels for products introduced into a facility for the first-time.
对于现有产品，制造商的历史使用清洁限值应予保留，并考虑根据清洁工艺能力所提供的警戒限，这样可以提供足够的保障防止超出PDE值。在为首次引入设施的产品建立清洁警戒级别时，应采用类似的流程。
Results above the alert cleaning limit should trigger an investigation and, where appropriate, corrective action to bring the cleaning process performance within the alert cleaning limits. Repeated excursions above the alert cleaning limit will not be considered acceptable where these indicate that the cleaning method is not in control. Recognised appropriate statistical methods may be used to determine whether the cleaning process is in control or not.
超出清洁限度警戒限的结果应予以调查，并在适当情况下采取纠正措施，以使清洁过程性能处于清洁限度警戒限内。重复超出清洁警戒限将不被视为可接受，因为这提示清洁方法不受控。可以使用公认的适当的统计方法来确定清洁过程是否在控制之中。
Q7. Is analytical testing required at product changeover, on equipment in shared facilities, following completion of cleaning validation?
在完成清洁验证后，共用设施中的设备在产品换线时是否需要进行分析测试？
A: Analytical testing is expected at each changeover unless justified otherwise via a robust, documented Quality Risk Management (QRM) process. The QRM process should consider, at a minimum, each of the following:
除非有正当理由，否则预计每次换线都会进行分析测试，记录质量风险管理（QRM）流程。 QRM过程应该至少考虑以下各项：
· the repeatability of the cleaning process (manual cleaning is generally less repeatable than
automated cleaning);
清洁过程的可重复性（人工清洗通常不如自动清洗重复性好）;
· the hazard posed by the product;
产品构成的危害;
· whether visual inspection can be relied upon to determine the cleanliness of the equipment at the residue limit justified by the HBEL.
是否可以依靠目视检查来确定设备的清洁程度能否符合HBEL规定的残留限度
Q8. What are the requirements for conducting visual inspection as per Q&A 7?
按照Q＆A 7进行目视检查有什么要求？
A. When applying visual inspection to determine cleanliness of equipment, manufacturers should stablish the threshold at which the product is readily visible as a residue. This should also take into account the ability to visually inspect the equipment, for example, under the lighting conditions and istances observed in the field.
在进行目视检查确定设备的清洁程度时，制造商应该建立产品残留可以被看到的界限。这也应该考虑对设备进行目视检查的可行性，如，现场照明条件和观察距离。
Visual inspection should include all product contact surfaces where contamination may be held, including those that require dismantling of equipment to gain access for inspection and/or by use of tools (for example mirror, light source, boroscope) to access areas not otherwise visible. Non-product contact surfaces that may retain product that could be dislodged or transferred into future batches should be included in the visual inspection.
目视检查应包括可能存在污染物的所有产品接触表面，包括拆卸设备进入检查和/或使用工具（例如镜子，光源，内窥镜）检查不可见区域的表面。对于那些存在残留产品且可能被引入下一批次的非产品接触表面，也应包含在目视检查中。
Written instructions specifying all areas requiring visual inspection should be in place and records should clearly confirm that all inspections are completed.
应有书面规程规定所有需要目视检查的区域，且记录应清楚地确认所有检查都已完成。
Operators performing visual inspection require specific training in the process including periodic eye sight testing. Their competency should be proven through a practical assessment.
执行目视检查的操作人员需要进行特定的培训，包括定期视力检查。应通过实践评估来证明他们的资质。
Q9. Is it acceptable to simply segregate products of a common therapeutic classification in a dedicated area as a means of controlling risk of cross contamination?
简单地将常见治疗分类的产品隔离在专用区域作为控制交叉污染风险的手段是否可接受？
A: Manufacturers cannot just segregate common products from other product types as a means of dealing with the risk to patient and animal safety. Although this may prevent contamination of other product classes it does not address the possibility for cross contamination within product classes. The approach taken to control cross contamination between individual products within a class produced in the same dedicated area should follow the principles in Q&A 3. This should include implementation of appropriate organisational and technical control measures to prevent contamination between such products within product specific HBELs.
制造商不能仅从其他产品类型中分离出通用产品作为处理患者和动物安全风险的手段。 虽然这可能会阻止其他产品类别的污染，但它并不能解决产品类别内产生交叉污染的可能性。 为控制同一专用区域内生产的一类产品之间的交叉污染所采取的方法应遵循问答3中的原则。这应包括实施适当的组织和技术控制措施，以防止产品特定HBEL中此类产品之间发生污染。
Q10. Is the use of LD50 to determine Health-Based Exposure Limits for drug products acceptable?
是否可以使用LD50来确定基于健康的限度？
A: No, LD50 is not an adequate point of departure to determine a HBEL for drug products.
不可以，LD50用于确定HBEL是不充分的。
Q11. Can Ectoparasiticides be manufactured or primary packed in common equipment with other categories of medicinal products for human or veterinary use?
杀外寄生虫药是否可以在通用设备中与其它类别人药或兽药一起生产或内包装？
A: If a HBEL cannot be determined or data cannot support manufacture in shared facilities then the Ectoparasiticides should be manufactured in dedicated facilities.
如果HBEL无法确定或HBEL数据不能支持在共用设施中生产，则杀外寄生虫药应在专用设施中生产。
Q12. What needs to be taken into account when manufacturing Veterinary Medicinal Products for different species in the same facility?
在同一设施内为不同物种生产兽用药品时需要考虑哪些因素？
A: The guideline on setting health-based exposure limits indicates that the carry over limit should generally be derived using the human HBEL.
关于设置基于健康的暴露限制的指导原则表明，应该使用人类HBEL来推导残留限度。
However, in cases where there is concern relating to known susceptibility of a particular species (e.g. monensin in horses) the HBEL approach should take into account knowledge of specific animal toxicity when evaluating products manufactured in shared facilities/equipment.
然而，在对特定物种的已知易感性（例如马中的莫能菌素）有关注的情况下，HBEL方法在评估在共用设施/设备中制造的产品时应考虑到对特定动物毒性的知识。
Q13. Should the HBEL be re-assessed throughout the phases of development of Investigational Medicinal Products (IMPs)?
在试验用药品（IMPs）的整个开发阶段，是否需要重新评估HBEL？
A: Health-Based Exposure Limits should be established based on all available data, and particularly as the knowledge base for IMPs is continually evolving the basis for establishing the HBEL, should be regularly reviewed taking account of any new relevant data.
应基于所有可用数据建立基于健康的暴露限制，特别是因为IMP的知识库不断发展建立HBEL的基础，应定期审查任何新的相关数据。
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