麻疹减毒活疫苗冻干工艺的优化

Optimization of Procedure for Lyophilization of Live Attenuated Measles Vaccine

目的优化麻疹减毒活疫苗的冻干工艺。方法以预冻过程(温度、时间)、升华干燥过程(温度、时间、真空控制值)、解析干燥过程(温度、时间、真空控制值)冻干参数为影响因素,应用L(827)正交试验设计冻干曲线,对8批麻疹减毒活疫苗半成品进行冻干,采用直观分析法的综合平均值R()iⅠ和极差R(i)j分析不同批次冻干制品的干损率、病毒滴度、热稳定性和残余水分,筛选最优因素水平组合,并对其进行适用性验证。结果优化的麻疹减毒活疫苗冻干工艺参数为:预冻:温度5～-25℃、时间0.5h,温度-25～-40℃采用大于1℃/min的冻结速率,温度-40℃、保持时间3h;升华干燥:温度-40～-20℃、时间1.5h、真空控制值0.16mbar,温度-20℃、保持时间8h、真空控制值0.16mbar,温度-20～30℃、时间5h、真空控制值0.16mbar;解析干燥:温度保持30℃、时间6h、真空控制值0.005mbar,以优化的麻疹减毒活疫苗冻干工艺冻干的制品成型良好,干损率平均为1.36%,稳定性好,残余水分在1.62%～1.67%之间。结论优化的麻疹减毒活疫苗冻干工艺适合麻疹疫苗大规模生产。

Objective To optimize the procedure for lyophilization of live attenuated measles vaccine.Methods Lyophilization curves were designed by L（82）7orthogonal test using the parameters during pre-freezing（temperature and time）,main drying（temperature,time and vacuum value）and final drying（temperature,time and vacuum value）as influencing factors,according to which eight batches of live attenuated measles vaccine were lyophilized.The dry loss,virus titer,thermal stability and residual moisture content of various batches were analyzed with the comprehensive mean R（）iⅠ and range R（i）j of object analysis,based on which the optimal combination of factors and levels was screened and verified for adaptivity.Results The parameters for lyophilization procedure of live attenuated measles vaccine were optimized as follows：（1）pre-freezing：5 ～-25℃,0.5 h;-25 ～-40℃,at a freezing rate of more than 1℃/min;-40℃,3 h;（2）main drying：-40 ～-20℃,1.5 h,0.16 mbar;-20℃,8 h,0.16 mbar;-20 ～ 30℃,5 h,0.16 mbar;（3）final drying：30℃,6 h,0.005 mbar.The vaccine lyophilized by the optimized procedure was well-shaped with a mean dry loss of 1.36% and showed high stability,in which the residual moisture content was 1.62% ～ 1.67%.Conclusions The optimized procedure for lyophilization of live attenuated measles vaccine was suitable for large-scale production.