Trends in Upstream and Downstream Process Development for Antibody Manufacturing

Abstract

A steady increase of product titers and the corresponding change in impurity composition represent a challenge for development and optimization of antibody production processes. Additionally, increasing demands on product quality result in higher complexity of processes and analytics, thereby increasing the costs for product work-up. Concentration and composition of impurities are critical for efficient process development. These impurities can show significant variations, which primarily depend on culture conditions. They have a major impact on the work-up strategy and costs. The resulting "bottleneck" in downstream processing requires new optimization, technology and development approaches. These include the optimization and adaptation of existing unit operations respective to the new separation task, the assessment of alternative separation technologies and the search for new methods in process development. This review presents an overview of existing methods for process optimization and integration and indicates new approaches for future developments.

Biopharmaceuticals from microorganisms: from production to purification

“…Upstream process is defined as the microbial growth required to produce biopharmaceuticals or other biomolecules and involves a series of events including the selection of cell line, culture media, growth parameters, and process optimization to achieve optimal conditions for cell growth and biopharmaceutical production. The main goal of the upstream process is the transformation of substrates into the desired metabolic products 29 . This requires well-controlled conditions and involves the use of large-scale bioreactors.…”

Improving the secretory capacity of Chinese hamster ovary cells by ectopic expression of effector genes: Lessons learned and future directions

“…The two most widely used gene amplification systems are the DHFR system and the glutamine synthetase system (Noh et al, 2013). Nowadays, companies report titers of >10 g/L for MAb production (Gronemeyer et al, 2014). As an alternative to random transgene integration, piggyBac or sleeping beauty-mediated transposition can be used, where transgene integration into highly transcribed regions of the host genome is favoured.…”

The business impact of an integrated continuous biomanufacturing platform for recombinant protein production

“…Extensive research has improved understanding around the costs of goods (COGs) for recombinant protein production, leading to large reductions (as much as 100-fold) in operating expenses via process improvements and operational efficiencies (Sinclair and Monge, 2002;Rathore et al, 2004;Werner, 2004;Rajapakse et al, 2005;Farid, 2013). Key examples of process improvements include cell culture titer increases (Croughan, 2008) and improved downstream yields (Gronemeyer et al, 2014). Examples of operational efficiencies include template platform processes (Kelley, 2007;Shukla and Thömmes, 2010) and operational improvement programs (Han et al, 2010) allowing better utilization of existing infrastructure.…”