Dynamic pH profiles drive higher cell-specific and volumetric productivity

Abstract

Mammalian cell cultures in bioreactors rely heavily on critical process parameter control to ensure optimal growth, productivity, and reproducibility to produce recombinant therapeutic proteins. Culture pH has been shown to be a critical parameter that influences growth, productivity, and critical quality attributes. Typically, pH is either controlled to a set-point throughout the culture or uses a single pH shift to achieve higher productivity and more desirable charge variant profiles. The pH is usually maintained by CO₂ and base additions. For CO₂ controlled cultures, using a set-point can result in an accumulation of CO₂, which has detrimental effects on mammalian cell growth and protein production. In this study, a dynamic pH profile was implemented that allowed the pH control in the bioreactor to mimic the natural uncontrolled pH profile observed in shake flask cultures. This dynamic pH profile employs multiple pH shifts during the exponential phase of a single IgG₁ producing CHO-K1 cell line. The results show that a dynamic pH profile was able to successfully alleviate CO₂ accumulation and increase the cell-specific, as well as overall culture productivity. Impacts of the dynamic pH profile on product quality attributes, including glycosylation and charge variants, were also evaluated, showing mixed impacts on the glycosylation pattern and a positive impact on charge variants. Since the ideal glycosylation pattern is highly dependent on the intended function of the recombinant antibody, impacts on product quality should be evaluated on a “per process” basis.