Cell culture processes for monoclonal antibody production

Abstract

Animal cell culture technology has advanced significantly over the last few decades and is now generally considered a reliable, robust and relatively mature technology. A range of biotherapeutics are currently synthesized using cell culture methods in large scale manufacturing facilities that produce products for both commercial use and clinical studies. The robust implementation of this technology requires optimization of a number of variables, including 1) cell lines capable of synthesizing the required molecules at high productivities that ensure low operating cost; 2) culture media and bioreactor culture conditions that achieve both the requisite productivity and meet product quality specifications; 3) appropriate on-line and off-line sensors capable of providing information that enhances process knowledge; and 4) good understanding of culture performance at different scales to ensure smooth scale-up. Successful implementation also requires appropriate strategies for process development, scale-up and process characterization and validation that enable robust operation that is compliant with current regulations. This review provides an overview of the state-of-the art technology in key aspects of cell culture, e.g., engineering of highly productive cell lines and optimization of cell culture process conditions. We also summarize the current thinking on appropriate process development strategies and process advances that might affect process development.

Complete Knockout of the Lactate Dehydrogenase A Gene is Lethal in Pyruvate Dehydrogenase Kinase 1, 2, 3 Down-Regulated CHO Cells

“…Moreover, high levels of lactate accumulation in a pH-controlled environment will prompt alkali addition and lead to high osmolality, which can itself inhibit cell growth and protein production [8]. Therefore, reducing lactate accumulation is often desired for the development of robust production processes, and clones making low levels of lactate are generally preferred in large-scale production [9,10].…”

Whole‐cell Escherichia coli lactate biosensor for monitoring mammalian cell cultures during biopharmaceutical production

“…One particular metabolite of interest is lactic acid (lactate), a metabolic waste product produced as a byproduct of glycolysis. High concentrations of lactate can negatively affect cell growth and productivity (Li et al, 2010; Zhou et al, 2011) and can, via acidification of the medium, cause changes in glycosylation patterns (Yoon et al, 2005). …”

Synthetic biology of cell signaling

“…Antibiotic-inducible, bacterial transcription factors (TFs) can add another level of control (Deuschle et al 1995;Weber et al 2002;Fussenegger et al 2000;Gossen and Bujard 1992). Four important instances of synthetic signaling pathway engineering in mammalian cells have been the utilization of chimeric antigen receptors in cancer treatment (Pule et al 2005;Curran et al 2012), using of GPCR receptors to rewire extracellular metabolite or light toward outcomes with potential therapeutic utility (Ye et al 2011;Auslaender et al 2014), transplantation of pathways into mammalian cells (Hansen et al 2014), and metabolic engineering for the production of biologics (Li et al 2010;Le et al 2013).…”