Process and metabolic engineering perspectives of lactate production in mammalian cell cultures

Mammalian cells present the main expression platforms for production of recombinant therapeutic proteins. To cope with the increased demand for these therapeutics, more productive manufacturing processes have been developed using high-density cultures and enriched feeds/media. This has dramatically increased the productivity of mammalian cells in culture but this is accompanied by an increased production and accumulation of lactate in cultures, with the pattern of phasic production and consumption of lactate associated with the cell productivity in culture. Although primarily defined as a waste product, it is clear that lactate metabolism presents a control node for determination of process control and effectiveness of manufacturing strategies. This review focuses on recent understanding of the phasic nature of lactate metabolism, the impact of culture environment (media, feeds) on lactate metabolism, the link between lactate metabolic status and cell status and the culture/metabolic engineering approaches that have been applied to generate the lactate metabolic phenotype associated with a highly productive manufacturing process.