目前市场上的抗生素活性物质是通过化学合成、发酵或发酵后一次或多次合成步骤(半合成物质)等方式制造的。与合成工艺相比,发酵工艺中可变性更大,可控性更低,因此与纯合成产品相比,在生产中含有发酵工艺的活性物质的杂质谱可能更复杂及难以预测。由于上述原因,发酵产品和半合成产品未包括在ICH Q3和VICH 10/11指导原则之内,这些指导原则就化学合成活性物质中引入的杂质的鉴定、报告和控制限度制订了质量标准。指导原则中对限度的定义是,如果超出了该限度,该杂质即应该被鉴定、报告或控制,该限度同样适用于欧洲药典总论“药用物质”。发酵产品及其半合成衍生物不在该总论范围内。没有其他指导原则的情况下,这些产品中的有关物质曾经根据一对一(case-by-case)的方式进行评估,这导致了相同抗生素或同类抗生素中的不同化合物(如头孢菌素)可能存在不同的杂质限度。因此,在批准新抗生素时能有连贯一致的措施来制定杂质限度是十分必要的。因此,2010年7月欧洲药物管理局(EMA)制定颁布了《制订抗生素有关物质质量标准的指导原则》。本指导原则旨在为未包括在上述(V)ICH指导原则中的内容提供如下指导,即如何规范发酵产品或源于发酵产品的半合成物质的抗生素中的有关物质。指导原则中制订了抗生素药品中有关物质的报告、鉴定和控制限度,这些药品中的活性物质通过发酵或半合成得到。对于某些情况,如活性物质由几种密切相关的化合物混合组成,可能难以适用通行的限度,提供了常规原则,就如何制定具体限度、标准以及如何确定杂质谱限度进行了规定。对于指导原则中的要求与欧洲药典中对应章节及各论之间的关系也进行了解释。 Antibiotic active substances currently on the market are manufactured by one or more synthesis steps (semi-synthetic substances) after chemical synthesis, fermentation or fermentation. The variability in the fermentation process is greater and the controllability is lower compared to the synthesis process, so the impurity profile of the active material containing the fermentation process in production can be more complicated and unpredictable than purely synthesized products. For these reasons, fermented and semi-synthetic products are not covered by the ICH Q3 and VICH 10/11 guidelines, which set the quality standards for the identification, reporting and control of impurities introduced into chemically synthesized actives. The limit in the Guiding Principles is defined as that the impurity should be identified, reported or controlled beyond this limit, which also applies to the general pharmacopoeia of the European Pharmacopoeia. Fermented products and their semi-synthetic derivatives are beyond the scope of this summary. In the absence of other guiding principles, the relevant substances in these products have been evaluated on a case-by-case basis, leading to the possibility that different compounds (such as cephalosporins) in the same antibiotic or similar antibiotic may There are different impurity limits. Therefore, it is essential that there be consistent measures to establish impurity limits when approving new antibiotics. Therefore, in July 2010, the European Medicines Agency (EMA) formulated and promulgated the “Guiding Principles for the Development of Antibiotic-Related Substances Quality Standards”. This guidance is intended to provide guidance on what is not covered by the ICH Guidelines (V) above as a guide to how to regulate substances in the antibiotics used to ferment products or semisynthetic materials derived from fermented products. Guiding principles have been developed for the reporting, identification and control of the relevant substances in antibiotic drugs where the active substance is obtained by fermentation or semi-synthesis. In some cases, where the active material consists of a mixture of several closely related compounds, it may be difficult to apply the limits of traffic and provide general principles on how to set specific limits, standards, and how to determine the limits of impurity spectra. The requirements of the Guiding Principles are also explained in relation to the corresponding chapters and the monographs in the European Pharmacopoeia.