EMA发布《交叉污染和共用设施清洁限度指南问答》

1、EMA发布交叉污染和共用设施清洁限度指南问答-2018 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 ide nti ficati on in the manu facture of di幵 ere nt medicinal products in sha

2、red facilities 69430/2012）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。删除了咼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二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10pg/代表了高风险，PDE值10000pg/天为最低。PDE应由具备足够专业知识并具有毒理

3、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

4、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

5、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 medic inal products. The toxicologica

6、l or pharmacological data, on which the HBEL calculati on relies, requires periodical reassessme nt throughout a products lif ecycle.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

7、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XS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 shoul

8、d be con trolled on a proporti on ate basis. However, as a broad hypothetical model the followi ng figure could be considered to show the increasing level of hazard (red being highest hazard) presented by products and there should be a comme nsurate in crease in the level of con trol to preve nt pot

9、ential cross contamination in a shared facility. Actual HBEL values should be used in QRM studies to determine the actual con trols 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。Increasing

10、 hazardHealthExposure Limit HBEL PDE10000100CC pg/day 1000 pg/day 10010 pg/ch*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 expla ined in Q&A 6. However, the purpose of gen erat ing HBELs goes beyond justification of cleaning limits.Q&A

11、6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 assessme nt has bee n completed and the HBEL con firmed, these data should be used via a Quality Risk Man ageme nt process to determi ne what con trols n eed to be put in place and to assess if existing organisational and technical

12、con trol measures are adequate or if they n eed to be suppleme nted. This Quality Risk Man ageme nt process should be carried out prospectively in the case of new equipme nt/facility to determ ine what con trol 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

13、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 pote ntial harm to patie nts/a nimals,more elaborateorganisational and technical control measures will be required. Usi ng a structured Quality Risk Man ageme nt process, manufacturers s

14、hould consider the risks of cross contamination down to the established level from the HBEL. During the QRM study manu facturers should con sider how easily such a qua ntity 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

15、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 con trol measures supported by practical and scie nce-based evide nee.QRM过程的详细程度应与HBEL指出的潜在

16、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 con trol of the cross-c on tami natio n risk in the con text 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 wo

17、rking practices, investigation and an alysis may be required to provide full practical con fide nce in the efectiveness 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 pote ntial con tami natio n is con siste ntly con trolled to a leve

18、l below that of the HBEL then the products concerned should be manu factured 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

19、 Limits should be determined by a pers on who has adequate expertise and experie nce in toxicology/pharmacology, familiarity with pharmaceuticals as well as experie nce in the determi nati on of health-based exposure limits such as Occupational Exposure Levels (OEL) or Permitted Daily Exposure (PDE)

20、.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 con tracted to provide the HBEL, con tractualagreeme ntsin complia nee withChapter 7requireme nts should be in place prior to work being con ducted. It is not considered acceptable for manufact

21、urers to z purchase HBEL assessments without recording an assessment of the suitability of the provider （in cludi ng the specific tech ni cal expert） as a qualified con tractor.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

22、 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: Con tract givers should either provide a full HBEL assessme nt to con tract manu facturers or provide the data to allow the con tract manu facturer to con duct the HBEL assessme nt.

23、 In either case the HBEL assessme nt, i nclud ing data refere nces and releva nt experts should be available on request dur ing in specti on of the manu facturer.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 e

24、stablished?如何建立清洁限度？A:AlthoughtheEMAguideli ne(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

25、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 usedcleaning limits should be retained and can be considered alert limits provided that when taking cleaning process capability into acco unt, they provide sufficie nt assura nee that excursi ons above the HBEL will be

26、preve nted. 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 inv

27、estigation and, where appropriate, corrective action to bring the clea ning process performa nce with in the alert clea ning 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 approp

28、riate statistical methods may be used to determ ine whether the clea ning process is in con trol 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 fa

29、cilities, 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, docume nted Quality RiskMan ageme nt (QRM) process. The QRM process should con sider,at a min imum, each of the follo

30、w ing: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 clea ning process (ma nual clea ning is gen erally less repeatable tha nautomated clea nin g);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 in specti on can be relied upon t

31、o determ ine 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. Whe n apply ing visual in specti on to determ ine clea nli ness of equipment,

32、manufacturers should stablish the threshold atwhich the product is readily visible as a residue. This should alsotake into acco unt the ability to visually in spect the equipme nt, 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

33、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 in specti on should in clude all product con tact surfaces where contamination may be held, including those that require disma ntli ng of equipme nt to gain access for in specti on an d/or by use of tools (for example mirror, light source, boroscope) to access

34、 areas not otherwise visible. Non-product con tact surfaces that may retain product that could be dislodged or transferred into future batches should be in cluded in the visual in specti on.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。Wr

35、itten instructions specifying all areas requiring visual in specti on should be in place and records should clearly con firm that all in specti ons 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 performi ng visual in specti on require spec ific tra ining in the process in clud ing per

36、iodic eye sight testi ng. Their compete ncy should be prove n through a practical assessme nt.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 ameans of controlling risk of cross contaminatio

37、n?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: Manu facturers cannot just segregate comm on products from other product types as a means of deali ng with the risk to patie nt and an imal safety. Although this may preve nt contamination of other product classes it does not address the possibility for cro

38、ss contamination within product classes. The approach take n to con trol cross con tam in ati on betwee nin dividual products with in 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 con

39、trol measures to preve nt con tam in ati onbetwee n such products within product spec ific 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 Hea

40、lth-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 determ ine 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 cann