大型反应器内pH不均一性对CHO细胞流加培养过程的影响

Effect of pH Heterogeneity in Large-scale Bioreactor on Fed-batch Culture Process of CHO cells

为了研究大型反应器中p H不均一性对CHO细胞流加培养过程的影响,并将培养过程顺利地放大到生产规模,根据大型反应器的混合特性,构建了搅拌式反应器与平推流反应器串联的规模缩小装置用于模拟大型反应器中的p H不均一性。结果表明停留时间为30 s时,整个培养过程和对照相比并无显著的差异,这表明此时补碱所导致的p H不均一性并未对流加培养工艺造成影响。而随着停留时间的延长,反应器内p H不均一的程度越大,细胞生长和产物表达受到抑制越明显;与此同时,乳酸和氨的累积显著增加,而关键质量属性唾液酸和生物学活性也随之降低。

In order to study the effect of p H heterogeneity in large-scale bioreactor on cell culture process of CHO cells, we established a scale down model consistent of stirred tank reactor and plug flow reactor to simulate the p H heterogeneity of large-scale bioreactor based on the mixing characteristic. The results showed that the scale down process with 30 s residence time has no statically difference with the control process. However, significant effect on cell growth, cell metabolism and protein production were found when increased the residence time of PFR. Cell growth rate decreased accompanied by tremendously increase of ammonia and lactate when increased the p H heterogeneity. In addition, the titer, sialic acid content and bioactivity of antibody fusion protein were also decreased when increased the p H heterogeneity.