Title: Quasi-Steady-State Approach for Efficient Multiscale Simulation and Optimization of mAb Glycosylation in CHO Cell Culture Show Chinese title

Title: 基于准稳态方法的CHO细胞培养中单克隆抗体糖基化的高效多尺度仿真与优化

Abstract: Glycosylation is a critical quality attribute for monoclonal antibody (mAb) production, influenced by both process conditions and cellular mechanisms. Multiscale mechanistic models, spanning from the bioreactor to the Golgi apparatus, have been proposed for analyzing the glycosylation process. However, these models are computationally intensive to solve when using traditional methods, making optimization and control challenging. In this work, we propose a quasi-steady-state (QSS) approach for efficiently solving the multiscale glycosylation model. By introducing the QSS assumption and assuming negligible nucleotide sugar donor (NSD) flux for glycosylation in the Golgi, the large-scale partial differential algebraic equation system is converted into a series of independent differential algebraic equation systems. Based on that representation, we develop a three-step QSS simulation method and further reduce computational time through parallel computing and nonuniform time grid strategies. Case studies in simulation, parameter estimation, and dynamic optimization demonstrate that the QSS approach can be more than 300-fold faster than the method of lines, with less than 1.6% relative errors. This work establishes a solid foundation for multiscale model-based optimization and control of the glycosylation process, supporting the implementation of quality by design. Show Chinese abstract

Abstract: 糖基化是单克隆抗体（mAb）生产中的关键质量属性，受工艺条件和细胞机制的影响。 从生物反应器到高尔基体的多尺度机制模型已被提出用于分析糖基化过程。 然而，当使用传统方法时，这些模型求解计算量大，使得优化和控制变得具有挑战性。 在本工作中，我们提出了一种准稳态（QSS）方法，以高效求解多尺度糖基化模型。 通过引入QSS假设并假设在高尔基体中糖基化过程的核苷酸糖供体（NSD）通量可以忽略不计，将大规模偏微分代数方程组转换为一系列独立的微分代数方程组。 基于该表示，我们开发了一种三步QSS仿真方法，并通过并行计算和非均匀时间网格策略进一步减少计算时间。 仿真、参数估计和动态优化的案例研究显示，QSS方法比线法快超过300倍，相对误差小于1.6%。 本工作为糖基化过程的多尺度模型优化和控制奠定了坚实的基础，支持了设计质量的实施。