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

绝大多数制药过程都以分批或进料分批模式运行，因为它允许它们具有高度的灵活性和大量的制造路线。涉及重组细胞系的生产过程也不例外，也是以流加批次的模式进行操作。补料分批操作允许营养物质在整个周期中被喂养，从而防止在实现生产目标之前培养物中的营养物质枯竭。尽管如此，制药行业已经投入了巨大的努力，将他们的业务从批量运营过渡到连续运营。这样做的原因是，在连续模式下运行具有几个优势，例如高容量生产率、减小设备尺寸和缩短周期时间。此外，与分批操作相关的一些问题，如批次之间的产品差异，也可以最小化。中国仓鼠卵巢(CHO)细胞系统是治疗蛋白生产最常用的宿主细胞系之一。这些系统允许应用某些翻译后修饰，以获得与人类相容的蛋白质产品的特定结构。因此，CHO细胞系统非常重要，市场上70%的重组生物治疗药物都使用了CHO细胞系统。尽管CHO细胞系统通常在流加分批模式下运行，但它们将从连续操作中获得极大的好处，因为这将确保生产稳定一致的产品，这在高度监管的制药行业中尤为重要。了解如何使流水分批CHO细胞系统适应连续模式非常重要：关键质量属性(CQA)是什么？如果它们保持不变，保证产品质量的新的可操作性范围是什么；关键工艺参数是什么，它们将如何影响CQA。在这个项目中，我们提出了一个计算和实验的框架，允许从补料批次CHO细胞培养过渡到连续培养。我们首先将重点放在使CHO细胞系统的基因组规模模型(GEM)适应于连续设置。建立一个与连续操作兼容的模型是非常重要的，因为它可以在给定一组关键工艺参数的情况下预测CQA，从而减少实验费用。

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.