注射用头孢菌素的关键质量属性分析  

Critical quality attributes of cephalosporins for injection

作　　者：张斗胜[1] 薛晶[1] 王晨[1] 姚尚辰[1] 胡昌勤[1] 

机构地区：[1]中国食品药品检定研究院,北京100050

出　　处：《中国新药杂志》2016年第22期2606-2613,共8页Chinese Journal of New Drugs

基　　金：国家"重大新药创制"科技重大专项(2015ZX09303001)

摘　　要：通过对历年国家评价性抽验涉及的15个注射用头孢菌素的系统回顾性分析,发现目前市场上的注射用头孢菌素,包括基本药物目录品种和市场上需求量较大的药品,基本能够保证患者用药的安全、有效,但"溶液的澄清度与颜色"是影响注射用头孢菌素质量的突出问题。以其作为关键质量属性(CQAs),发现头孢菌素原料的结晶工艺直接影响原料的稳定性和其与胶塞的相容性,进而影响注射剂的澄清度和颜色;采用镀膜/覆膜胶塞可以有效地阻断胶塞挥发物与头孢菌素的相互作用,改善头孢菌素与胶塞的相容性;即头孢菌素原料的晶型/亚晶型、成盐率和胶塞的质量是影响头孢菌素注射剂澄清度和颜色的CMAs。而细化原料结晶工艺中的关键工艺参数(CPPs)是获得头孢菌素理想原料的前提,这也是目前国产仿制药与原研药品之间的最大差异。Fifteen cephalosporins for injection involved in national drugs evaluation inspection over the years were summarized and retrospectively analyzed. It has been confirmed that cephalosporins for injection in market, including drugs in the list of essential medicines and drugs with large market demand, could guarantee the safety and efficiency in general. However, the primary problem affecting the quality of those injections was the clarity and color of solution. Thus, regarding the clarity and color of solution as the critical quality attributes （CQAs） , it has been confirmed that crystallization process of cephalosporins could influence the stability and the compatibility between rubber closures and drug substance directly, and then the clarity and color of solution for injection could be further affected. Moreover, the interaction between volatiles in rubber closures and cephalosporins could be effectively blocked by using the film-coating or film-covering rubber closures, so the compatibility of drug substance could be improved. According to that, the crystal form or subtype of crystal form, salifying rate for drug substance and the quality of rubber closures were the CQAs affecting the clarity and color of solution of cephalosporins for injection. Therefore, in order to obtain the injections with high quality, it was necessary to refine the critical process parameters （CPPs） in crystallization process of bulk materials of drug substance, which was significantly different between the domestic generics and the brand-name drugs at present.

关 键 词：注射用头孢菌素 溶液的澄清度与颜色 关键质量属性 关键原辅料属性 相容性 晶型/亚晶型 

分 类 号：R917.795[医药卫生—药物分析学]