EMA防止交叉污染问答 20161215

julia朱玉姣

15 December2016

EMA/CHMP/CVMP/SWP/463311/2016

Committee forMedicinal Products for Veterinary Use (CVMP)

Committee forMedicinal Products for Human Use (CHMP)

Questionsand answers on implementation of risk based prevention of cross contaminationin production and ‘Guideline on setting health based exposure limits for use inrisk identification in the manufacture of different medicinal products inshared facilities’

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”

实施问题

(EMA/CHMP/CVMP/SWP/169430/2012)

Draft  agreed by SWP, vSWP and GMP/GDP Inspectors WG	September 2016
SWP，vSWP和GMP/GDP检查员WG通过草案	2016年9月
Adopted  by CVMP for release for consultation	8 November 2016
CVMP通过并发布征求公众意见	2016年11月8日
Adopted  by CHMP for release for consultation	15 December 2016
CHMP通过并发布征求公众意见	2016年12月15日
Start  of public consultation	January 2017
开始征求公众意见	2017年1月
End  of consultation (deadline for comments)	30 April 2017
征求意见截止	2017年3月30日

Comments should be provided using this template.The completed comments form should be sent to adm-gmdp@ema.europa.eu

意见应使用上述链接的模板填写并提交至上述邮箱。

Q1. Do companies haveto establish Health Based Exposure Limits (HBELs) for all products?

公司是否必须为所有产品建立基于健康的暴露限（HBEL）？

A: Yes, HBELs should be established forall products. HBELs for highly hazardous products are expected to be completedin full as per the EMA guide (EMA/CHMP/CVMP/SWP/169430/2012) or equivalent. SeeQ2 for products/active substances considered to be highly hazardous. Productsthat do not fall into the highly hazardous category may be addressed as per Q4.

是的，所有产品都应建立HBEL。高有害产品的HBEL应按EMA指南（EMA/CHMP/CVMP/SWP/169430/2012）或等同的要求制订。参见问答2中应作为高有害产品考虑的产品/活性物，不在高有害类别的产品可以按问答4的内容处理。

Q2. Whatproducts/active substances are considered to be highly hazardous?

什么样的药品/活性物质应作为高有害物质考虑？

A: Highly hazardous products are thosethat can cause serious adverse effects at low doses and that therefore wouldbenefit from a full toxicological assessment in order to derive a safe HBEL.

高有害物质是指低剂量即可能导致严重不良反应，因而需要进行全面毒性评估以制订安全的HBEL的物质。

Highly hazardous products areidentified based on their inherent toxicological and pharmacologicalcharacteristics and include the groups below (this list is not an exhaustivelist and if evidence is available indicating that the product may cause adverseeffects at low doses by other mechanisms it should be considered as highlyhazardous).

高有害物质应根据其内在毒性和药学特性进行识别，并分为以下几类（此清单并不是穷尽清单，如果有证据显示该产品可能因其它机制由低剂量即导致不良反应，则也应作为高有害物质考虑）。

Manufacturers should consider, via asafety assessment against the guidance below, if products/active substancesshould be considered highly hazardous. Evidence indicating a product or activesubstance falls within any of the categories below should result in a productbeing considered highly hazardous. If in doubt, manufacturers should considerthe product potentially highly hazardous and apply the EMA guide(EMA/CHMP/CVMP/SWP/169430/2012) in full to derive a safe HBEL.

如果药品/活性物质应作为高有害物质，则生产商应根据以下指南进行安全评估。显示一种药品或活性物质属于以下某个类别的证据应能证明一种药品作为高有害物质来考虑。如果有疑问，则生产商应将该物质作为潜在高有害物质考虑，并全面应用EMA指南（EMA/CHMP/CVMP/SWP/169430/2012）来建立安全HBEL。

1.     Genotoxic (specifically mutagenic) compoundsthat are known to be, or highly likely to be, carcinogenic to humans. Compoundsof this group are easily identifiable, since genotoxicity would be related tothe pharmacology, e.g. as DNA alkylating cytostatics, and their use is usuallyrestricted to oncology indications with respective warning statements in theSummary of Product Characteristics.

基因毒性（尤其是基因诱变）化合物一般是，或者非常可能是，对人类致癌的。此类化合物一般易于识别，因为基因毒性一般与药学相关，例如，是DNA烷基化细胞抑制剂，它们的使用一般局限于肿瘤症状，在产品特性摘要上有相关的警示声明。

2.     Compounds that can produce reproductiveand/or developmental effects at low dosages, for example where evidence existsof such effects being caused by a clinical dose of <10 mg/day (veterinarydose equivalent 0.2 mg/kg/day) or dosages in animal studies of ≤1 mg/kg/day.

低剂量即可以产生生殖反应和/或发育反应的化合物，例如，有证据证明此类反应是由临床剂量<10mg/天（兽药剂量等于0.2mg/kg/天）或兽用研究≤1 mg/kg/天剂量引发。

3.     Compounds that can produce serious targetorgan toxicity or other significant adverse effects at low doses, for examplewhere evidence exists of such effects being caused by a clinical dose of <10mg/day (veterinary dose equivalent 0.2 mg/kg/day) or dosages in animal studiesof ≤1 mg/kg/day.

低剂量即可能会导致目标器官严重毒性，或其它重大不良反应的化合物，例如，有证据证明此类反应是由临床剂量<10mg/天（兽药剂量等于0.2mg/kg/天）或兽用研究≤1 mg/kg/天剂量引发。

4.     Compounds with a high pharmacological potencyi.e. recommended daily dose of <1 mg (veterinary dose equivalent 0.02 mg/kg).

具有高药效的化合物，即，建议日剂量<1mg (兽药剂量等于0.02mg/kg)。

5.     Compounds with a high sensitising potential.

具有高致敏可能性的化合物。

冷血无情

朱版主，那个Q4是什么意思？通常情况下，千分之一日最低治疗量可以被默认为最低日暴露量？Q6是通常来说，千分之一和10ppm依然能够满足大多数限度计算？

homelee

学习学习，谢谢分享

静水蓝心

谢谢分享

胜利者

顶起

scslk0045

谢谢楼主分享！

chemstar

请问楼主，基于健康的暴露限（HBEL）是否可以认为是PDE或ADE？

yscaiyl

谢谢分享

有毒的雪上

感谢分享，学习学习

云扬风轻

谢谢分享，学习学习！

罗伊鲱

Q5. Is the use of LD50 to determine health based limits acceptable?
A: No, LD50 is not an adequate point of departure to determine an HBEL.

xqliu

学习一下啦，谢谢提供分享。

julia朱玉姣

chemstar 发表于 2017-3-13 08:32
请问楼主，基于健康的暴露限（HBEL）是否可以认为是PDE或ADE？

不是

chemstar

冷血无情 发表于 2017-3-13 09:07
朱版主，那个Q4是什么意思？通常情况下，千分之一日最低治疗量可以被默认为最低日暴露量？Q6是通常来说，千 ...

个人认为它的意思是对于普通药品的限度计算不用考虑毒理数据。我的理解是否对，朱版主@julia朱玉姣

云卷云舒0415

谢谢分享

云卷云舒0415

谢谢分享

chemstar

julia朱玉姣 发表于 2017-3-15 07:42
不是

@julia朱玉姣 哪是啥呢？与PDE、ADE有什么关系呢？

千寻bj

如何建立HBEL？好困惑啊

tz0004

学习学习，谢谢分享

小麦新

谢谢分享！