In Pursuit of the Optimal Fed‐Batch Process for Monoclonal Antibody Production

Abstract

Fed-batch culture currently represents the most attractive choice for large scale production for monoclonal antibodies (MAbs), due to its operational simplicity, reliability, and flexibility for implementation in multipurpose facilities. Development of highly productive cell lines, maximization of cell culture longevity, and maintenance of high specific antibody secretion rates through genetic engineering techniques, nutrition supplementation, waste product minimization, and control of environmental conditions are important for the design of high-yield fed-batch processes. Initially simple supplementation protocols have evolved into sophisticated serum-free multi-nutrient feeds that result in MAb titers on the order of 1-2 g/L. Limited research has been published to date on the effect of various culture parameters on potentially important quality issues, such as MAb glycosylation and stability. Although most fed-batch protocols to date have relied on relatively simple control schemes, increasingly sophisticated algorithms must be applied in order to take full advantage of the potentially additive effects of manipulating nutrient and environmental parameters to maximize fed-batch process productivity.

Dynamic Modeling of Apoptosis and its Interaction with Cell Growth in Mammalian Cell Culture

“…A review of fed-batch culture in monoclonal antibody and other recombinant protein production can be found in (Wlaschin and Hu, 2006;Bibila and Robinson, 1995;.…”

Study on Interactions between Fed-Batch and Batch Operating Parameters for the Development of Monoclonal Antibody Fed-Batch using Design of Experiments

“…Fed batch cultures have been developed with the objective of achieving maximal increase in the culture viable cell concentrations and prolonging the culture lifetime for increased product concentrations [3,5,[11][12][13][14][15] Strategies such as development of the feeding solutions, feeding rate control, maintaining low residual glucose and/or glutamine concentrations, employing dialysis membranes to remove low molecular weight components from the culture, feeding based on Oxygen UptakeHence, based on the hypothesis that none of the factors affecting the production process can really be independent, fractional factorial design using design expert software was carried out to find the interaction between the batch (Dissolved Oxygen, Temperature and Seeding Density) and fed-batch (post-feed Glucose concentration) process parameters. The usage of design of experiments also facilitates shorter development time, hence more cost effective.…”

A serum substitute for fed-batch culturing of hybridoma cells

“…In vitro culturing of hybridoma cells has been extensively studied for a high production rate of monoclonal antibody for several decades, and many efficient nutrient feeding strategies have been developed (Glacken 1987;Bibila and Robinson 1995;Distefano et al 1996;Birch and Racher 2006). The most important strategy for doing fed-batch culture is to reduce the formation of byproducts, such as lactate and ammonia, and keep the nutrient concentration balanced and stable.…”

“…Their production can be partly decreased by reducing the glucose and glutamine concentrations in the medium. In recent studies, effective cultures of hybridoma and Chinese hamster ovary (CHO) cells have been developed through comprehensive research on nutrient metabolism (Bibila and Robinson 1995;Distefano et al 1996;Birch and Racher 2006). The models in these studies incorporated not only major pathways of glucose and glutamine metabolism but also pathways of other amino acids into the stoichiometric model.…”