Integration of Mechanistic and Data-Driven Models to Support the Transition to Continuous Biomanufacturing

绝大多数制药工艺以分批或补料分批模式操作，因为这允许它们具有高度的灵活性和大量的生产路线。涉及重组细胞系的生产工艺也不例外，并且也以补料分批模式操作。补料分批操作允许在整个循环中补料营养物，从而防止培养物在达到生产目标之前营养物耗尽。尽管如此，制药行业已经投入了大量的精力将其操作从分批过渡到连续。其原因在于，连续模式下的操作具有多个优点，例如高容积生产率、减小的设备尺寸和低循环时间。此外，与批量操作相关的一些问题，如批次之间的产品变异性，也可以最小化。中国仓鼠卵巢（CHO）细胞系统是用于治疗性蛋白质生产的最常用的宿主细胞系之一。这些系统能够应用某些翻译后修饰，以获得与人类相容的蛋白质产物的特定结构。因此，CHO细胞系统非常重要，用于市场上70%的重组生物治疗药物。虽然CHO细胞系统通常以补料分批模式操作，但它们将极大地受益于连续操作，因为它将确保生产稳定和一致的产品，这在高度管制的制药行业中特别相关。重要的是要了解补料分批CHO细胞系统如何适应连续模式：什么是关键质量属性（CQA），如果它们保持不变，保证产品质量的新操作范围是什么;关键工艺参数是什么，它们将如何影响CQA。在这个项目中，我们提出了一个框架，计算和实验，允许从补料分批CHO细胞培养过渡到连续。我们将首先专注于适应CHO细胞系统的基因组规模模型（GeM）的连续设置。具有与连续操作兼容的模型是非常重要的，因为它使得能够在给定一组关键工艺参数的情况下预测CQA，从而降低实验费用。

The vast majority of pharmaceutical processes operate in both batch or fed-batch mode, as it allows them a high degree of flexibility and a large number of manufacturing routes. Production processes involving recombinant cell lines are no exception and are operated in fed-batch mode as well. Fed-batch operation allows nutrients to be fed throughout the cycle, thus preventing the culture from nutrient depletion before production goals are met. Nevertheless, the pharmaceutical industry has dedicated great effort into transitioning their operations from batch to continuous. The reason for this is that operating in continuous mode offers several advantages such as high-volumetric productivity, reduced equipment size and low-cycle times. Additionally, some of the problems associated with operating in batch, such as product variability between batches, can be minimized as well.Chinese hamster ovary (CHO) cell systems are one of the most used host cell lines for therapeutic protein production. These systems enable the application of certain post-translational modifications in order to obtain specific structures of protein products that are compatible with humans. Thus, CHO cell systems are of great importance, being used for 70% of all recombinant biotherapeutics on the market. Though CHO cell systems are typically operated in fed-batch mode, they would greatly benefit from continuous operation, since it would ensure the production of a stable and consistent product, which is particularly relevant within the highly regulated pharmaceutical industry.It is important to understand how fed-batch CHO cell systems can be adapted to a continuous mode: what are the critical quality attributes (CQA) and if they remain the same, what are the new ranges of operability that guarantee product quality; what are the critical process parameters and how will they impact CQAs. In this project, we propose a framework, both computational and experimental, that allows the transition from fed-batch CHO cell culture to continuous. We will initially focus on adapting a genome scale model (GeM) of a CHO cell system to a continuous setting. Having a model compatible with continuous operation is of great importance as it it enables the prediction of CQAs given a set of critical process parameters, thus reducing experimental expense.