论文标题
使用应用于生物制药的种子列车设计的多目标优化设计强大的生物技术过程
Designing Robust Biotechnological Processes Regarding Variabilities using Multi-Objective Optimization Applied to a Biopharmaceutical Seed Train Design
论文作者
论文摘要
用细胞培养的生物药物生产过程的开发和优化是成本和时必的,并且经常在经验上进行。有效地优化多个目标,例如过程时间,可行的细胞密度,操作步骤和种植量表,所需的中等,产品量以及产品质量描述了一种有希望的方法。该贡献介绍了一个工作流程,该工作流将基于不确定性的上游模拟并使用高斯流程进行优化。在仿真案例研究中,在过程开发中的相关工业任务,强大的细胞培养扩展过程(种子序列)的设计中证明了它的应用,这意味着,尽管存在有关细胞生长的不确定性和变异性,但在种子训练过程中可行的细胞密度的差异较低。与非优化的参考种子序列相比,使用5或4摇动烧瓶尺度和种子序列持续时间从576 h到520 h,优化的过程显示出有关生存的细胞密度(<〜10%而不是41.7%)的偏差率要低得多。总体而言,这表明应用贝叶斯优化可以通过几个优化的输入变量优化多目标优化函数,并且在相当多的约束下,计算工作较低。这种方法提供了以决策工具的形式使用的潜力,例如为了选择最佳且健壮的种子火车设计或在过程开发中进一步优化任务。
Development and optimization of biopharmaceutical production processes with cell cultures is cost- and time-consuming and often performed rather empirically. Efficient optimization of multiple-objectives like process time, viable cell density, number of operating steps & cultivation scales, required medium, amount of product as well as product quality depicts a promising approach. This contribution presents a workflow which couples uncertainty-based upstream simulation and Bayes optimization using Gaussian processes. Its application is demonstrated in a simulation case study for a relevant industrial task in process development, the design of a robust cell culture expansion process (seed train), meaning that despite uncertainties and variabilities concerning cell growth, low variations of viable cell density during the seed train are obtained. Compared to a non-optimized reference seed train, the optimized process showed much lower deviation rates regarding viable cell densities (<~10% instead of 41.7%) using 5 or 4 shake flask scales and seed train duration could be reduced by 56 h from 576 h to 520 h. Overall, it is shown that applying Bayes optimization allows for optimization of a multi-objective optimization function with several optimizable input variables and under a considerable amount of constraints with a low computational effort. This approach provides the potential to be used in form of a decision tool, e.g. for the choice of an optimal and robust seed train design or for further optimization tasks within process development.