13 December 2012 2012年12月13日 | |||
EMA/CHMP/ CVMP/ SWP/169430/2012 | |||
Committee for medicinal products for human u (CHMP) 人用药品委员会(CHMP) | |||
Committee for medicinal products for veterinary u (CVMP) 兽用药委员会(CVMP) | |||
Guideline on tting health bad exposure limits for u in risk identification in the manufacture of different medicinal products in shared facilities 在共享设施中生产不同药品用风险辨识建立健康暴露限度指南 | |||
Draft 草案 | |||
Draft Agreed by Safety Working Party 安全工作组同意草案 | December 2012 2012年12月 | ||
Adoption by CVMP for relea for consultation 兽用药委员会采用发放征求意见 | November 2012 2012年11月 | ||
Adoption by CHMP for relea for consultation 人用药委员会采用发放征求意见 | 13 December 2012 2012年12月13日 | ||
Start of consultation 开始征求意见 | 08 January 2013 2013年01月08日 | ||
End of consultation (deadline for comments) 结束征求意见(意见截止期) | 30 June 2013 2013年06月30日 | ||
Comments should be provided using this template. The completed comments form should be nt to SWP-H@ema.europa.eu 提交意见应使用本模板。完整的意见格式应发送到SWP-H@ema.europa.eu。 | |||
Keywords 关键词 | Shared facilities, risk identification, exposure limits 共享设施、风险辨识、暴露限度 | ||
Guideline on tting health bad exposure limits for u in risk identification in the manufacture of different medicinal products in shared facilities 在共享设施中生产不同药品用风险辨识建立健康暴露限度指南 | |||
Executive summary 概要 | |||
When different medicinal products are produced in shared facilities, the potential for cross-contamination becomes an issue for concern. Hence, residues of an active substance which remain after cleaning of production equipment and other product contact surfaces may contaminate other medicinal products produced in the same facility. Active substances provide a medicinal benefit to the intended patient or target animal; however as a cross over contaminant, they provide no benefit to the patient or target animal and may even po a risk. Hence, the prence of active substance contaminants should be restricted to a level that can be considered safe for all populations. The derivation of a threshold value (permitted daily exposure (PDE) or threshold of toxicological concern (TTC) should be the result of a structured scientific evaluation of all available pharmacological and toxicological data including both non-clinical and clinical data. In cas where scientific data does not support threshold values for safety (e.g., allergenic potential from highly nsitising materials) or where the risk cannot be adequately controlled by operational and/or technical measures, dedicated facilities are required for manufacturing of the high-risk medicinal products. 当在共享设施生产不同的药用产品时，潜在交叉污染将成为关注的一个问题。因此，在生产设备与其它产品接触表面清洁后的残留物，残留原料药，可能污染用相同设施生产的其它药品。原料药为患者或目标动物提供预期医疗好处；然而，作为交叉污染，其没有向病人或目标动物提供任何好处，甚至可能会带来风险。因此，应限制原料药污染物在一个对所有人群认为是安全的水平。阈值(每日允许暴露 (PDE) 或毒理学相关阈值 (TTC))应来自结构化的对包括非临床和临床数据的所有药理学与毒理学数据科学评价。当科学数据不支持安全阈值(例如，来自高敏感物料潜在致敏)或风险不能通过操作，和/或，技术措施充分或其他有效办法的情况下，需要为这些高风险药品生产提供专用设施。 | |||
1. Introduction (background) 第一章：介绍(背景) | |||
Due to the perceived risk, certain class of active substances have previously been required to be manufactured in dedicated or gregated lf-contained facilities including, “certain antibiotics, certain hormones, certain cytotoxic and certain highly active drugs”. Pharmaceuticals not considered to be covered under the criteria were addresd by a cleaning validation process involving reduction of the concentration of residual active substance to a level where the maximum carryover from the total equipment train would result in no greater than 1/1000th of the lowest clinical do of the contaminating substance in the maximum daily dosage of the next product to be manufactured. This criterion was applied concurrently with a maximum permitted contamination of 10 ppm of the previous active substance in the next product manufactured. Whichever of the criteria resulted in the lowest carryover, constituted the limit applied for cleaning validation. However, the limits do not take account of the available pharmacological and toxicological data and may be too restrictive or not restrictive enough. Hence, a more scientific ca by ca approach is warranted for all class of pharmaceutical substances. 由于已经察觉到风险，以前已经要求某些类别的原料药在专用或隔离密闭的设施内生产，其包括“某些抗生素、某些激素、某些细胞毒及某些高活性药物”。在这些标准中没有覆盖的药品用一个清洁验证过程中来解决，其涉及减少残留原料浓度到一个全部设备链最大带入到下个即将生产产品最大日计量中污染物不大于1/1000最小临床剂量。这一标准是与最大允许先前原料药在下个生产场次中不大于10ppm污染一致。无论哪个标准导致最低的带入，所构成的限度须应用到清洁验证。不过，这些限度没有考虑可用的药理学与毒理学数据，并可能是限制性严格或没有足够的限制性。因此，考虑用一种更科学的个案方法来保证所有类别。 | |||
In order to accommodate a more scientific approach, Chapters 3 and 5 of the GMP guideline have been revid and refer to a “toxicological evaluation” for establishing threshold values for risk identification. The objective of this guideline is to recommend an approach to review and evaluate pharmacological and toxicological data of individual active substances and thus enable determination of safe threshold levels as referred to in the GMP guideline. 为了容纳更多的科学方法，《药品生产质量管理规范指南》（译者注：欧盟人用和兽用药品管理法规第四卷-药品生产质量管理规范(GMP)指南）的第三与第五章已经进行修订，并参考一个“毒理学评价”来建立风险辨识的阈值。本指南的目的是推荐一个方法来审核并评价每个原料药的药理学与毒理学数据，从而能按照《药品生产质量管理规范指南》来判断安全阈值水平。 | |||
In cas where scientific data does not support threshold values (e.g. allergenic potential from highly nsitizing materials) or where the risk cannot be adequately controlled by operational and/ or technical measures, dedicated facilities are required for manufacturing the high risk medicinal products. 当科学数据不能支持阈值的情况下(例如，高敏感物料潜在引起变态反应)或不能通过操作中，和/或，技术措施，充分控制风险，需要专用设施来生产这些高风险药品。 | |||
2. Scope 第二章：范围 | |||
This guideline applies to all human and veterinary medicinal products, including investigational medicinal products, and all active substances that are intended for manufacture in premis ud for the manufacture of other products or active substances. 本指南应用于包括预期在用来生产其它产品或原料药的厂房中生产的所有的人用与兽用药品，临床研究用药，以及所有的原料药。 | |||
The scope of the prent guideline is to ensure the safety of human patients and target animals expod to residual active substances via medicinal products as well as consumers potentially expod to residual active substances in products derived from treated food producing animals. Moreover, this document aims to recommend an approach for deriving a scientifically bad threshold value for individual active substances to be applied for risk identification. This guideline also outlines how the data on which the threshold value is derived should be prented in the risk asssment report in order to achieve a clear and harmonious approach across pharmaceutical industry. 现行指南的范围是通过药品以及消费者潜在暴露到来自处理的食用生产动物在产品中残留原料药，确保暴露到残留原料药人类患者与目标动物安全。因此，本文旨在为某个原料药推荐一个科学的、基于风险辨识建立阈值的方法。本指南包含，在风险评估报告中应提交哪些阈值数据，从而达到一个清晰的、协调的药品工业生产的方法。 | |||
3. Legal basis 第三章：法律基础 | |||
This guideline should be read in conjunction with: 本指南应该和以下文献一道阅读： | |||
EudraLex - Volume 4 Good manufacturing practice (GMP) Guidelines, Chapter 3 and 5. 欧盟药品管理法规-第四卷：药品生产质量管理规范(GMP)指南第三章和第五章。 | |||
Update on the revision of Chapters 3 and 5 of the GMP guide: “Dedicated Facilities” EMA/INS/GMP/809387/2009. 药品生产质量管理规范指南第三章与第五章修订更新版“专用设施”EMA/INS/GMP/809387/2009。 | |||
Note for Guidance on Impurities: Residual Solvents (CPMP/ICH/283/95 in conjunction with CPMP/ICH/1507/02, CPMP/ICH/1940/00 corr, CPMP/QWP/450/03, EMEA/CVMP/511/03 and CPMP/QWP/8567/99). 杂质指南：残留溶媒注释(CPMP/ICH/283/95与CPMP/ICH/1507/02一道, CPMP/ICH/1940/00更正, CPMP/QWP/450/03, EMEA/CVMP/511/03与CPMP/QWP/8567/99)。 | |||
VICH GL18(R): Impurities: Residual solvents in new veterinary medicinal products, active substances and excipients (EMA/CVMP/VICH/502/99-Rev.1). VICH GL18(R):杂质：在新兽药、原料药和辅料中残留溶媒(EMA/CVMP/VICH/502/99-第一版)。 | |||
Guideline on the Limits of Genotoxic Impurities (EMEA/CHMP/QWP/251344/2006 and CPMP/SWP/5199/02). 遗传毒性杂质限度指南(EMEA/CHMP/QWP/251344/2006与CPMP/SWP/5199/02)。 | |||
4. Determination of health bad exposure limits 第四章：确定基于健康暴露限度 | |||
The procedure propod in this document for determination of health bad exposure limits for a residual active substance is bad on the method for establishing the so-called Permitted Daily Exposure (PDE) as described in Appendix 3 of ICH Q3C (R4) “Impurities: Guideline for Residual Solvents” and Appendix 3 of VICH GL 18 on “residual solvents in new veterinary medicinal products, active substances and excipients (Revision)”. The PDE reprents a substance-specific do that is unlikely to cau an adver effect if an individual is expod at or below this do every day for a lifetime. 本指南建议基于健康的一个原料药暴露限度的判定是一个建立在ICH-Q3C(R4)“杂质：残留溶媒” 附件4中及VICH-GL18“新兽药、原料药与辅料残留溶媒(修订)”附件3中描述的所谓的“每天允许暴露值”方法的基础。每天允许暴露值(PDE)代表一个物质-特定剂量，如果一次性或在生命周期内每天暴露在该剂量下或低于该计量，不可能造成不良影响。 | |||
Determination of a PDE involves (i) hazard identification by reviewing all relevant data, (ii) identification of “critical effects”, (iii) determination of the no-obrved-effect level (NOEL) of the findings that are considered to be critical effects, and (iv) u of veral adjustment factors to account for various uncertainties. Appendices 3 of the ICH Q3C and VICH GL 18 guidelines prent the following equation for the derivation of the PDE: 每天允许暴露值(PDE)确定包含：(i)通过审核所有相关数据辨识危险源，(ii)辨识“关键影响”，(iii)确定无明显损害作用水平(NOEL)，及(iv)使用个调整因素来确定多种不确定性。 ICH-Q3C附件3与VICH-GL18指南用下列公式来计算每天允许暴露值(PDE)： | |||
In relation to the establishment of carryover limits that can be accepted in veterinary medicinal products, it would in principle, be possible to u the PDE approach to establish different limits for different target species. However, this would be highly impractical. Conquently, it is considered pragmatic that PDEs should be derived using the assumption that it is the human patient that will be expod. The level of contamination that can be accepted is then calculated from the human PDE, even when the product that will be contaminated is a veterinary medicinal product. This is considered to reprent a pragmatic approach and is in line with the approach taken in VICH GL 18, in which human PDEs are ud to calculate residual solvent limits applied for veterinary medicinal products. 与建立带入限度有关，其课题宜在兽药产品中接受，在基本原则上，应使用每天允许暴露值(PDE)的方式来建立目标动物种群的不同限度，然而，这将是非常不切实际的。因此，每天允许暴露值(PDE)应来源于假设是人类患者的暴露限度可能更实际。可以接受用人类每天允许暴露值(PDE)所计算的污染水平，甚至即将被污染的产品是一个兽用药品的研究亦可。这可认为是代表一个世纪的方式，并符合在VICH-GL18中采用的方法，其中，用人的每天允许暴露值(PDE)来计算兽药残留溶媒限度。 | |||
The derivation of carryover limits will need to take account of the do to be administered, which will be influenced by the body weight of the species to be treated. In order to facilitate this the PDE should be calculated on a mg/kg bw basis (i.e. using a weight adjustment figure of 1) rather than on a per person basis. 推导的带入限度将需要考虑到给药剂量，将会受到即将对待的该物种体重影响。为了便利，每天允许暴露值(PDE)应在mg/kg体重的基础上计算(即在上述公式中使用重量调节)，而不是在每个人的基础上。 | |||
Alternative approaches to the NOEL such as the Benchmark do may also be ud. 也可使用如基准剂量方法来替代无明显损害作用水平(NOEL)方法。 | |||
Data requirements for hazard identification 危险源辨识数据需求 | |||
Hazard identification is the qualitative appraisal of the inherent property of a substance to produce adver effects. For hazard identification, a review of all available animal and human data should be performed for each compound. Data for hazard identification would include non-clinical pharmacodynamic data, repeat-do toxicity studies, carcinogenicity studies, studies of genotoxicity in vitro and in vivo, reproductive and developmental toxicity studies as well as clinical data on therapeutic and adver effects. The availability of data for an active substance will vary depending on the stage of development and indication. If data ts are incomplete, the identified gaps need to be critically assd with regard to the uncertainty impact this might have on deriving a reliable health bad exposure limit. 危险源辨识是对一个物质所带来的副作用固有特性的定性评估。对于危险源辨识，应对每个物质审核所有获得的动物与人类的数据。危险源辨识的数据应包含非临床药效学数据、重复剂量毒性研究、致癌性研究，体内和体外的基因毒性研究、生殖与发育毒性研究，以及治疗与副作用临床数据。一个原料药的有效性会以开发阶段与适应症的不同而不同。如果数据不完整，已经辨识的差距需要进行在不确定性影响方面严格评估，其将导出认为可靠的健康暴露限度。 | |||
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