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Finally:EMA’s Q&A on Health-Based Exposure Limits was published 终于等到你：EMA的HBEL问答终版发布 On 30 April 2018, the EMA published the final, revisedversion of the Q&A document with its focus on setting health-based exposurelimits for risk identification and the risk-based prevention ofcross-contamination. The Q&A covers 13 questions and answers relating tothe “Guideline on setting health based exposure limits for use in riskidentification in the manufacture of different medicinal products in sharedfacilities”, which has been in force sinceJune 2015. 2018年4月30日，EMA发布了其问答文件的修订最终版本，主要关注风险识别和基于风险防止交叉污染中基于健康的暴露限设定专题。该问题包括有13个与2015年6月实施的“共同设施中生产不同药品时风险识别所用基于健康的暴露限设定指南”有关的问题。 In January 2017, the EMA released a draft for publicconsultation (we reported). But this paper constituted a roll backwards! 2017年1月，EMA发布了草案公开征求意见，但该文件实际是一种退步。 It re-introduced the traditional criteria (such as 1/1000thof minimum therapeutic dose and 10 ppm) for establishing limits for cleaningvalidation. This contradicts the original scientific approach of establishinghealth based exposure limits. The need for a toxicological evaluation wasintroduced into the EU GMP Guide just because the traditional criteria are notscientifically based. 其中重新引入了传统的标准（例如，1/1000的最低治疗剂量和10ppm）用于建立清洁验证限度。这与原来建立基于健康暴露限度的科学方法是冲突的。毒理学评估被引入EU GMP指南就是因为传统的标准并不科学。 In July 2017, the EMA held a workshop with participants fromindustry and authorities. During the workshop it became clear that nobody ishappy with the newly introduced differentiation between highly hazardousproducts and others as well as with the re-introduction ofthe traditional criteria. The outcome was that the Q&Ahas to be finally revised. 2017年7月，EMA召开了研讨会，参与者有企业人员和药监人员。在研讨会期间，大家发现谁都不支持新引入的高危害产品和其它产品之间的区分，以及重新引入传统标准。结果就是问答得要进行修订。 What‘s in the new version?新版本里有什么？ Health-Based-Exposure Limits (HBELs = PDEs) should beestablished for all medicinal products. The toxicological orpharmacological data, on which the HBEL calculation relies, requires periodicalre-assessment throughout a product’s lifecycle. 所有药品均应建立基于健康的暴露限度（HBEL=PDE）。HBEL计算所依赖的毒性或药学数据需要在产品生命周期内定期进行重新评估。 A broad hypothetical model (Source: ISPE Baseline®Pharmaceutical Engineering Guide, Volume 7) could be considered to show theincreasing level of hazard presented by products and there should be acommensurate increase in the level of control to prevent potential crosscontamination in a shared facility. PDE values <10µg ay="" represent="" thehighes="" risk="" and="" pde="" values="">10000µg/day the lowest. Actual PDE values shouldbe used in QRM studies to determine the actual controls required. 可以考虑使用广义的假定模型（来源：ISPE基准药物工程指南，卷7）来展示产品所呈现的危害水平增长，相对应在共用设施中防止潜在交叉污染的控制水平也应增加。PDE值<10µg>代表了高风险，PDE值>10000µg/天为最低。在QRM研究中应使用实际PDE值来确定实际所需控制。 Once the health-based assessment has been completed and thePDE confirmed, these data should be used via aQuality Risk Managementprocess to determine what controls need to be put in place and to assess ifexisting organisational and technical control measures are adequate or if theyneed to be supplemented. 在基于健康的评估完成并确认了PDE之后，这些数据应通过质量风险管理流程（QRMP）使用这些数据来确定需要制订哪些控制，并评估现有组织和技术控制措施是否已足够，还是需要增补措施。 PDE reports should be determined by a person who has adequateexpertise and experience in toxicology/pharmacology, familiarity withpharmaceuticals as well as experience in the determination of health-basedexposure limits such as Occupational Exposure Levels (OEL) or PDE. Whereexperts are contracted to provide the HBEL, contractual agreements incompliance with Chapter 7 requirements should be in place prior to work beingconducted. PDE报告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。如果使用合同专家来提供HBEL，则应在开始工作前依第7章的要求订立合同。 What responsibility do contract givers have to contractmanufacturers in relation to data to support a HBEL assessment? Contractgivers should either provide a full HBEL assessment to contract manufacturersor provide the data to allow the contract manufacturer to conduct the HBELassessment. In either case the HBEL assessment, including data references andrelevant experts should be available on request during inspection of themanufacturer. 委托生产方在支持HBEL评估的数据方面有什么职责？委托方应该要么将全面的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。无论哪种情形，HBEL评估，包括数据引用和相关专家均应在生产商受检时可以应检查要求提供。 Limits for cleaning purposes can be established based on the PDE value, but should notbe identical with it. For existing products, manufacturer’s historically usedcleaning limits should be retained and can be considered alert limits providedthat when taking cleaning process capability into account, they providesufficient assurance that excursions above the PDE will be prevented. 可以基于PDE值建立清洁目的限度，但不应与PDE值完全相同。对于现有产品，生产商历史上所用清洁限度应保留，可以考虑依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。 Analytical testing isexpected at each changeover unless justified otherwise via a robust, documentedQuality Risk Management (QRM) process. 每次更换产品时均应进行分析检测，通过稳健的书面质量风险管理（QRM）流程进行论证者除外。 Visual inspection: Manufacturersshould establish the threshold at which the product is readily visible as aresidue. This should also take into account the ability to visually inspect theequipment, for example, under the lighting conditions and distances observed inthe field. Visual inspection should include all product contact surfaces wherecontamination may be held. Non-product contact surfaces that may retain productthat could be dislodged or transferred into future batches should be includedin the visual inspection. 目视检查：生产商应建立产品易于目视残留的阈值。这时也可以考虑目视检查设备的能力，例如，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。目视检查中应包括可能残留产品的非产品接触表面，而残留可能在未来掉落或转移至后续批次中的情况。 Manufacturers cannot just segregate common products fromother product types as a means of dealing with the risk to patient and animalsafety. Although this may prevent contamination of other product classes itdoes not address the possibility for cross contamination within productclasses. 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。 The LD50 is not an adequate point of departure todetermine a HBEL for drug products. LD50不足以用作确定药品的HBEL。 If a PDE cannot be determined or data cannot supportmanufacture in shared facilities then the Ectoparasiticidesshould bemanufactured in dedicated facilities. 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。 Veterinary Medicinal Products: The guideline on setting health-based exposure limitsindicates that the carry over limit should generally be derived using the humanPDE. However, in cases where there is concern relating to known susceptibilityof a particular species (e.g. monensin in horses) the HBEL approach should takeinto account knowledge of specific animal toxicity when evaluating productsmanufactured in shared facilities/equipment. 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。 PDE values should be established based on all availabledata, and particularly as the knowledge base forInvestigational MedicinalProducts (IMPs) is continually evolving the basis for establishing the PDE,should be regularly reviewed taking account of any new relevant data. 应基于所有可以获得的数据建立PDE值，特别是由于临床药品（IMP）的知识基础持续改变PDE建立的基础，因此应考虑所有的新近相关数据定期进行审核。 |
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