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Recent advances in large-scale production of monoclonal antibodies and related proteins

2010; Elsevier BV; Volume: 28; Issue: 5 Linguagem: Inglês

10.1016/j.tibtech.2010.02.001

0167-9430

Abhinav Shukla, Jörg Thömmes,

Protein purification and stability

The rapid development of high-yielding and robust manufacturing processes for monoclonal antibodies is an area of significant focus in the biopharmaceutical landscape. Advances in mammalian cell culture have taken titers to beyond the 5 g/l mark. Platform approaches to downstream process development have become widely established. Continuous evolution of these platforms is occurring as experience with a wider range of products is accrued. The increased cell culture productivity has shifted the attention of bioprocess development to operations downstream of the production bioreactor. This has rejuvenated interest in the use of non-chromatographic separation processes. Here, we review the current state-of-the-art industrial production processes, focusing on downstream technologies, for antibodies and antibody-related products and discuss future avenues for evolution. The rapid development of high-yielding and robust manufacturing processes for monoclonal antibodies is an area of significant focus in the biopharmaceutical landscape. Advances in mammalian cell culture have taken titers to beyond the 5 g/l mark. Platform approaches to downstream process development have become widely established. Continuous evolution of these platforms is occurring as experience with a wider range of products is accrued. The increased cell culture productivity has shifted the attention of bioprocess development to operations downstream of the production bioreactor. This has rejuvenated interest in the use of non-chromatographic separation processes. Here, we review the current state-of-the-art industrial production processes, focusing on downstream technologies, for antibodies and antibody-related products and discuss future avenues for evolution. the first downstream processing step that captures the product from the harvested cell broth, concentrates the product, and achieves separation from impurities that are most unlike the product (e.g. cells, cell debris, DNA, most proteins). productivity of a cell culture expressed in terms of amount of protein produced per cell per unit time. A conventional unit for mammalian cell culture is pg/cell/day. process steps associated with the purification of a recombinant protein and removal of impurities. a production process based upon feeding a growth limiting nutrient to the culture. This allows the achievement of a high cell density in the production bioreactor and facilitates metabolic control of the cells to avoid generation of side products. biopharmaceuticals that are deemed comparable in quality, safety and efficacy to a reference product from an innovator company. N-glycolylneuraminic acid that can form the terminal saccharide unit for an N-linked oligosaccharide structure. Presence of NGNA has been linked to possible immunogenicity. The usual terminal sugar unit is typically NANA (N-acetylneuraminic acid). steps that occur after the initial capture step that are aimed at removal of smaller levels of impurities left in the product stream that have more similarity to the product (e.g. aggregated forms of the product, protein structural and sequence variants). procedures that destroy contaminating microorganisms on a piece of equipment used for bioprocessing. For chromatographic columns, mild alkaline solutions or high concentrations of chaotropes (e.g. urea) are used for sanitization to achieve bioburden control while preserving the resin. process of introducing DNA into a host cell by non-viral means such that the genetic material is not inserted into the nuclear genome. As a result, the genetic material is lost over time through mitosis. process steps associated with the production of a recombinant protein by culture and propagation of the host cells.