With increasing bioreactor volumes, the mixing time of the reactor increases as well, which creates an inhomogeneous environment for the cells. This can result in impaired process performance in large‐scale production reactors. Particularly the addition of base through the reactor headspace can be problematic, since it creates an area, where cells are repeatedly exposed to an increased pH. The aim of this study is to simulate this large‐scale phenomenon at lab‐scale and investigate its impact. Two different cell lines were exposed to pH amplitudes of a maximal magnitude of 0.05 units (pH of 6.95). Both cell lines showed similar responses, like decreased viable cell counts, but unaffected lactate levels. However, cell line B showed an initially increased specific productivity in response to the introduced amplitudes, whereas cell line A showed a consistently lower specific productivity. Furthermore, the time point at which base addition is started influences the impact, which pH amplitudes have on process performance. When pH control was started earlier in the process, maximal viable cell counts decreased and the lactate metabolic shift was less pronounced. These results show that the potential negative impact of pH amplitudes can be minimized by strategic process design.

中文翻译：

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研究细胞系对 pH 不均匀性的特异性反应以及工艺设计的后果


随着生物反应器体积的增加，反应器的混合时间也增加，这为细胞创造了不均匀的环境。这可能会导致大规模生产反应器的工艺性能受损。特别是通过反应器顶部空间添加碱可能会产生问题，因为它会产生一个区域，使细胞反复暴露于升高的 pH 值。本研究的目的是在实验室规模模拟这种大规模现象并研究其影响。两种不同的细胞系暴露于最大幅度为 0.05 个单位的 pH 值（pH 为 6.95）。两种细胞系都表现出相似的反应，例如活细胞计数减少，但乳酸水平不受影响。然而，细胞系 B 最初表现出响应引入的幅度而增加的比生产力，而细胞系 A 表现出持续较低的比生产力。此外，开始添加碱的时间点也会影响 pH 值幅度对工艺性能的影响。当在此过程中较早开始 pH 控制时，最大活细胞计数会减少，乳酸代谢变化也不那么明显。这些结果表明，通过策略性的工艺设计可以最大限度地减少 pH 值幅度的潜在负面影响。