EMA共用设施中暴露限设定问答-中英文

小皮球

andyouandme

beiwei5du 发表于 2018-5-13 12:29
不能用了，至少不能直接用了！指南还是有一定的后路：Deviation from the main approach highlighted in  ...

Q6前面部分，不是说，可以继续使用吗？

罗伊鲱

2018-05-02

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&#174harmaceutical 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 <10&#181;g/day represent thehighes risk and PDE values >10000&#181;g/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<10&#181;g/代表了高风险，PDE值>10000&#181;g/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 a Quality 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 Ectoparasiticides should 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 for Investigational 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。

转自微信公众号：Julia法规翻译                                                         

cl1612002

谢谢分享，好好学习

罗伊鲱

06.06.2018

EMA publishesfinal Q&A Document on the use of PDE (HBEL) Values / EMA发布关于使用PDE（HBEL）值的最终问答文件

In April 2018, the EMA published the final version ofthe Q&A document on the use of Health-Based Exposure Limits (HBELs) withoutspecial notice. The draft version had become necessary in 2016 because the EMAhad generated uncertainty within the pharmaceutical industry with theirGuideline on setting these limits (PDE values as well). The Permitted DailyExposure (PDE) values had been defined by the EMA in a new guideline in orderto mathematically decide upon the dedicated or multi-purpose use of plants. Thenew health-based values influence the cleaning validation threshold values aswell. In short, it can be determined how much cross contamination may betolerated from a health risk point of view by using the PDE values. Foridentifying and using these values, the EMA had to provide a Q&A documentwhich has now been published in its final version.

2018年4月，EMA发布了关于使用基于健康的暴露限值（HBELs）问答文件的最终版本，没有另行通知。该草案版本在2016年已成为必要，因为EMA关于设定这些限值（也称PDE值）的指南在制药行业中产生了不确定性。EMA在新指南中定义了允许的每日暴露（PDE）值，以便在数学上决定车间的专用或多用途。新的基于健康值也会影响清洁验证阈值。简而言之，通过使用PDE值，可以从健康风险的角度确定可以容忍多少交叉污染。 为了识别和使用这些值，EMA必须提供问答文件，现在已经出版了它的最终版本。

The document currently available mostly talks of HBELsand the term PDE is used only very occasionally. HBEL seems to be used as ageneral term and PDE as a part of HBEL. The threshold values described as ADE(Acceptable Daily Exposures) in ISPE Risk-MaPP would also be a sort of HBEL.When calculating the cleaning threshold values, the terms of PDE, ADE and HBELare used interchangeably.

目前可用的文件主要谈论HBEL，术语PDE只是偶尔使用。HBEL似乎被用作一般术语，PDE作为HBEL的一部分。在ISPE Risk-MaPP文件中描述为ADE（可接受的每日暴露）的阈值也将是一种HBEL。在计算清洁限值时，PDE、ADE和HBEL的术语可互换使用。

The differences between the draft and the finalversion of the Q&A document in brief:

问答文件草案与最终版本之间的差异简述如下：

The number of questions listed has been reduced from14 to 13. The order and to some extent the content of the questions were alsochanged.

列出的问题数量已从14个减少到13个。问题的顺序和在某种程度上的内容也发生了变化。

The statement that Health-Based Exposure Limits(HBELs) are required for all products is basically the same (question 1). Inaddition, these must be checked repeatedly during the product life cycle.

所有产品都需要基于健康的暴露限值（HBELs）的声明基本相同（问题1）。此外，必须在产品生命周期中反复检查这些限值。

The question of what constitutes a highly hazardoussubstance (question 2) is no longer included in the document. Instead, question2 states that every substance is to be classified in a band somewhere between alow up to a very high hazard potential. This means that classifying thesubstances as "highly hazardous" and "non-highly hazardous"is not considered reasonable.

关于什么构成高度危险物质的问题（问题2）不再包括在文件中。相反，问题2指出，每种物质都应归入一个介于低至潜在极高危险之间的范围内。这意味着将物质分类为“高度危险”和“非高度危险”并不合理。

There is a new question about how a producer shouldhandle HBELs (question 3). Here as well, they refer to risk managementprocesses. In case that these indicate that the specified control measures donot sufficiently protect from contamination, dedicating the production shouldbe considered.

有一个关于生产者应如何处理HBEL的新问题（问题3）。这里他们也提到风险管理过程。假设这些（风险管理）表明指定的控制措施不能充分防止污染，则应考虑专线生产。

Another new question deals with who should developresp. define the HBEL values (question 4). According to the current paper, thiscan be a person with the appropriate toxicological/pharmacological expertisewho is familiar with medicinal products and with determining exposure limits(apart from occupational exposure limit, PDE limits are mentioned here aswell). This is somewhat confusing, since PDE values are a subset of HBELs.

另一个新问题涉及谁应该开发、分别定义HBEL值（问题4）。根据目前的文件，这可能是具有适当的毒理学/药理学专业知识的人，他们熟悉药品并确定暴露限值（除了职业接触限值，这里也提及PDE限值）。这有点令人困惑，因为PDE值是HBEL的子集。

Question no. 5 is also new: in which way are clientsresponsible towards contract manufacturers? It is clearly stated that theclient is obliged to provide a complete HBEL assessment to the contractmanufacturer or else the required data so that the contract manufacturerhimself can prepare a HBEL document (or have it prepared).

问题5也是新的：客户对合同制造商负责的方式是什么？它明确指出，客户有义务向合同制造商提供完整的HBEL评估，或所需数据以便合同制造商自己准备HBEL文件（或使其被准备好）。

Question no. 6 remains unchanged: How can thresholdvalues for cleaning be established? While in the draft, the traditionalcalculations according to the 1/1000 dose or 10 ppm criterion for 'non-highlyhazardous' are named as an option, the new document has a different passage.For existing products, the existing limit values for cleaning shall bemaintained and regarded as alert values, provided that they are significantlyhigher than the corresponding HBEL values. So the content stays the same: lessstrict HBEL values should not lead to a less well-executed cleaning.

问题6保持不变：如何确定清洁阈值？在草案中，根据1/1000剂量或10 ppm标准对“非高度危险”的传统计算被指定为一个选项，新文件有不同的段落。对于现有产品，现有的清洁限值应保持并视为警报值，前提是它们明显高于相应的HBEL值。所以内容保持不变：不太严格的HBEL值不应该导致执行不太好的清洁。

The 8th question, which is also new, is interesting aswell. It deals with the "visually clean" criterion. It is possible touse this as a criterion for success in cleaning, provided that numerouspreconditions are fulfilled. For instance, surface-specific threshold studiesare required, all relevant surfaces must be visible (if necessary, bydismantling), light and distance must be defined and the examiners need aspecific training etc.

第8个问题（也是新问题）也很有趣。它涉及“目视清洁”标准。只要满足许多前提条件，就可以将其作为清洁成功的标准。例如，需要表面特定的阈值研究，所有相关表面必须是可见的（如有必要，通过拆除），必须定义光线和距离以及检查员需要特定的培训等。

Question 9 is the former question 13. Separating aproduct class into a dedicated section without further measures to preventcross contamination within this class is still not allowed.

问题9是以前的问题13。将产品分类在一个专用区域而不采取进一步措施防止此类产品间的交叉污染仍是不允许的。

Question 10 is the former question 5: it is still notpossible to use an LD50 value to obtain an HBEL.

问题10是以前的问题5：仍然不可能使用LD50值来获得HBEL。

Question 11 is the former question 7 (antiparasitictreatment); question 12 is the former question 8 (veterinary medicine),question 13 covers development products. However, it no longer addresseswhether HBELs are required for them; the answer to question 1 clearly indicatesthat these are also required for development products. In fact, it is evenpointed out that HBELs have to be reviewed periodically, if the associated datachange within the product life cycle - which applies mainly to developmentproducts after all.

问题11是以前的问题7（抗寄生虫治疗）；问题12是以前的问题8（兽药），问题13涉及开发产品。但是，它不再说明它们是否需要HBELs；问题1的答案清楚地表明这些也是开发产品所必需的。实际上，它甚至指出，如果相关数据在产品生命周期内发生变化，则必须定期审查HBELs——毕竟这主要适用于开发产品。

For more information please see the the new Q&A paper on the use of HBEL resp. PDE values.

更多信息请参阅有关HBEL/PDE值使用的新问答文件。

kc1711422001

Thanks for sharing

leelsy

Good job.

lsy3794

多谢分享。谢谢

keakea211

谢谢分享，谢谢。

jeanee

多谢分享                                         

小金库

感谢分享。

葱花芋头

谢谢分享，谢谢

落叶归根12

谢谢分享