抗生素中相关杂质质量标准制定的指导原则 中英

30 June 2012EMA/CHMP/CVMP/QWP/199250/2009 corrCommittee for Medicinal Products for Human Use (CHMP)/ Committee for Medicinal Products for Veterinary Use (CVMP)Guideline on setting specifications for related impurities in antibiotics抗生素中相关杂质质量标准制定的指导原则Final 定稿学习之名（译注）Table of contents 目录Executive summary1. Introduction (background)2. Scope3. Legal basis4. General requirements5. Impurity profiling and reporting, identification and qualification thresholds6. New applications and variations7. Specifications for medicinal products8. Analytical proceduresDefinitionsAnnex 1: Explanatory note regarding thresholds.Annex 2: ThresholdsAnnex 3: Example of “fingerprint chromatogram” approach to control very complex impurity profiles 概要1、背景介绍2、范围3、法规依据4、一般要求5、杂质分布以及报告、鉴别和界定阈值6、新申请和变更7、制剂产品质量标准8、分析方法定义附件1：关于阈值的注释附件2：阈值附件3：利用基于“指纹图谱”的方法对非常复杂的杂质分布进行控制举例Executive summary 概要Antibiotics active substances currently on the market are produced by fermentation, by fermentation followed by one or more synthetic steps (semi-synthetic substances) or by chemical synthesis. Fermentation processes are, in comparison to synthetic processes, more variable and less controllable, so the impurity profile of an active substance whose manufacturing process involves fermentation may be more complex and less predictable than that of a purely synthetic product. For this reason fermentation products and semi-synthetic substances are not included in the scope of the ICH Q3 and the VICH GL10/GL11 guidelines, which set thresholds for the identification, reporting and qualification of related impurities in active substances manufactured by chemical synthesis.目前上市的抗生素类活性物质是由发酵、发酵加一步或几步合成步骤（半合成）、化学合成制得。

与合成工艺相比，发酵工艺更具多变性，不易控制，因此与单纯使用化学合成生产的产品相比，生产工艺含有发酵步骤的活性物质的杂质分布一般比较复杂和难以预测。

基于此原因，发酵产品和半合成产品并不适用于ICH Q3和VICH GL10/GL11指南。

因为这两个指南适用于由化学合成生产的活性物质。

This guideline has been developed in order to provide guidance on how specifications for related impurities in antibiotics that are fermentation products or semi-synthetic substances derived from fermentation products, and are therefore not included in the scope of the (V)ICH guidelines mentioned above, should be set.本指南旨在为不适用于ICH Q3指南的发酵产品或源于发酵产品的半合成物质中杂质质量标准的设定提供指导。

Thresholds are given in the guideline for reporting, identification and qualification of related impurities for antibiotics medicinal products whose active substance is produced by fermentation or semi- synthesis. In cases where the active substance consists of a mixture of closely related compounds, where it may be difficult to apply general thresholds, general guidance is given on how to set specific thresholds and specifications and on how to qualify impurity profiles. The relationships between the requirements in the guideline and the applicable Ph.Eur. chapters and monographs are also addressed. 对于活性成分为发酵或半合成来源的抗生素制剂产品的相关杂质，本指南给出了报告、鉴定和界定阈值。

在活性物质由多个密切相关的化合物混合组成情况下，对其应用一般的阈值存在困难。

针对此，本指南就如何设定阈值和如何论证杂质分布给出了指导。

对于本指南与欧洲药典要求的关系，本指南也做了阐述。

注：界定限（界定阈值）：指超过该限度的杂质需进行论证，包括安全性、设定的限度合理性等。

1. Introduction (background)背景介绍Most of the antibiotics currently on the market are produced by fermentation or chemical synthesis. In certain cases the chemical structure of the antibiotics obtained by fermentation is further modified by some synthetic steps, before the substance is used as an active substance in the manufacture of medicinal products (semi-synthetic substances).目前市售的大多数抗生素是由发酵或化学合成生产的。

一些情况下，由发酵生产的抗生素在可用作生产制剂的活性成分前，其结构会经过一些合成步骤进行修改（半合成物质）Fermentation processes involve biological systems which are less predictable, less controllable and more complex than straightforward chemical reactions. Because of this, the variability in products derived by fermentation is often greater than in products derived by chemical synthesis. Thus, the impurity profile of a fermentation product may be more complex and less predictable than that of a synthetic product.与直接化学方应相比，发酵工艺包含不易预测、控制和复杂的生物系统，发酵产品比化学合成产品更具多变性。

因此，发酵产品的杂质分布会比化学合成产品的更复杂和不易预测。

For this reason, fermentation products and semi-synthetic substances derived from them are notincluded in the scope of the ICH Q3 and the VICH GL10/GL11 guidelines that set thresholds for the identification, reporting and qualification of related impurities in active substances manufactured by chemical synthesis. These thresholds are defined in the guidelines as limits above which an impurity has to be either identified, reported or qualified, and the same limits are applied in the Ph.Eur. general monograph ‘Substances for Pharmaceutical Use’. Fermentation products and their semi synthetic derivatives are also excluded from the scope of this general monograph.基于此，发酵产品和源于发酵产品的半合成物质并不适用于ICH Q3和VICH GL10/GL11。