目的:探讨注射用头孢硫脒质量差异的来源及其与临床不良反应(adverse reaction, ADR)发生的关联性。方法:基于国家评价性抽验和不良反应数据,利用多变量数据分析方法(单因素方差分析、多重比较、相关性分析、线性拟合等),从常规质控项目(质量属性)和晶型(工艺属性)2个角度探讨该药物粉针产品间质量差异及其对临床安全性的影响。结果:注射用头孢硫脒所有质控项目中,仅杂质B和ADR严重报告数呈显著相关,且其差异主要来源于原料贮存和运输或制剂无菌分装过程。晶型与杂质B间拟合相关性最高(相关系数r=0.72),且高ADR严重报告数制剂企业的药物晶型(晶型A和晶型B的混晶状态)区别于较低报告数企业的晶型(较单一晶型C),推测杂质B和晶型控制是有效降低ADR发生的关键因素。结论:可尝试通过优化结晶工艺来获取单一优势晶型C提高头孢硫脒稳定性,以降低药物在贮存或分装阶段的质量(尤其是杂质B)变化,以期达到降低注射用头孢硫脒临床ADR的发生率。
Objective: To investigate the correlation between the quality discrepancy of cefathiamidine for injection and the clinical adverse reaction. Methods: The data of national post market surveillance and clinical adverse reaction were collected. Multi-variances data analysis tools, for instance, single factor analysis of variance, multiple comparison, correlation analysis, linear regression, etc. were applied to explore the quality discrepancy of cefathiamidine for injection and the consequence on clinical safety. The analysis was focused on routine quality control parameters and crystal form. Results: Among all the quality control parameters, only impurity B was significantly correlated with the number of serious ADR reports, and its difference mainly came from sterilized sub-packaging and storage process. Moreover, there was a high fitting correlation between crystal form and impurity B with the correlation coefficient of 0.72. Mixed state of crystal A and crystal B was associated with high ADR frequency and crystal C form was reported low ADR frequency. It was assumed that crystal form and impurity B control was an important factor to reduce the ADR frequency. Conclusion: It would be possible to reduce the change of drug quality, especially impurity B, during the sterilized sub-packaging and storage process by optimize the crystallization process to obtain crystal C, so as to reduce the incidence of clinical ADR of cefathiamidine for injection.
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