艾司奥美拉唑镁微丸肠溶包衣工艺的风险评估与设计空间考察

Risk Assessment and Design Space Exploration of Coating Process for Esomeprazole Magnesium Enteric-coated Pellets

基于质量源于设计(Qb D)的理念,采用尤特奇~?丙烯酸树脂和流化床底喷包衣工艺制备艾司奥美拉唑镁肠溶微丸。根据研发生产经验和科学知识进行风险评估,确定以微丸收率和药物释放度作为关键质量属性(CQAs),以进风风量、物料温度、喷液速度和雾化压力为关键工艺参数(CPPs),以均匀设计方法安排试验,获得关联CQAs与CPPs的2个二次响应面回归模型,回归方程相关系数平方和分别为0.999 7和1.000 0,模型方差分析的P值均小于0.05。在设定的95%置信区间,建立了应用尤特奇~?丙烯酸树脂实施肠溶微丸包衣工艺的上述4个参数的设计空间。验证结果表明,在该设计空间内实施微丸包衣,可以保证产品的质量,降低产品质量风险,提高工艺过程的稳健性和灵活性。

The design space of coating process for esomeprazole magnesium enteric-coated pellets was established through the risk assessment within the framework of quality by design （QbD）, where the Eudragit acrylic polymer and bottom spray technology of the fluidized bed were utilized. The pellets yield and drug release were identified as the critical quality attributes （CQAs） ; As well as the inlet air volume, product temperature, spray rate and atomization pressure of coating fluid were identified as the critical process parameters （CPPs）. The uniform design was used to investigate the effects of these factors and their levels on CQAs. The correlation equations of CQAs and CPPs were established based on the quadratic response surface regression model, in which the R-squared values were 0.999 7 and 1.000 0, the P values were less than 0.05, respectively. Two dimensional （2D） contour plots were used to visualize the effects of CPPs and their levels on the two CQAs, respectively. Afterwards, the design space of CPPs was constructed with the addition of 95 % confidence interval. The validated results within the design space indicted that the product quality was well controlled and the robustness and flexibility of the coating process had been demonstrated.