Bioseparation in Antibody Manufacturing: The Good, The Bad and The Ugly

Abstract

Improvements in upstream production have boosted productivity in the biomanufacturing industry, but this is leading to bottlenecks in downstream processing as current technology platforms reach their limits of throughput and scalability. Although chromatography remains an indispensible component of downstream processing due to its simplicity and high resolving power (The Good), there is virtually no economy of scale effect so more product translates almost linearly into greater production costs. Bind‐and‐elute processes (such as the initial capture step in antibody manufacturing) are volume‐driven and therefore have knock‐on effects that impact on the entire production facility since the space required for preparation, storage, and cleaning steps has to be similarly adapted (The Bad). During long‐term operations with multiple cycles, thorough cleaning is necessary to prevent progressive fouling and microbial contamination (The Ugly). Innovative solutions are required, which may include revisiting simpler and less expensive separation technologies, the use of disposable modules, and the integration of improved processes that are scalable to cope with increased demands. Among the alternatives that have been put forward, membrane adsorbers are beginning to make a real impact on the industry, particularly for flow‐through applications such as polishing and viral clearance.

Multi‐Stage Aqueous Two‐Phase Extraction for the Purification of Monoclonal Antibodies

“…The increase is related to product concentration rather than volume, making high-titer capture proportionally more expensive. As Protein A capture is currently considered to be reaching its physical optimization potential, future processes may have to consider alternative capture methods [4][5][6][7]. Furthermore, some future therapeutic proteins may not be easily captured using the Protein A affinity binding mechanism, raising the need for alternative capture unit operations.…”

Development of production and purification processes of recombinant fragment of pneumococcal surface protein A in Escherichia coli using different carbon sources and chromatography sequences

“…Studies of up-and downstream processing are usually performed separately (Hortsch and Weuster-Botz 2010;Goyal et al 2009;Azevedo et al 2010); however, if such studies were performed in an integrated manner, they can provide suitable results in order to develop more effective process (Balbas 2001;Gottschalk 2008;Roush and Lu 2008). Here, the influence of distinct carbon sources, glucose, and glycerol, at high cell density of E. coli BL21 (DE3) was compared for production and purification of the recombinant fragment of PspA3 in an attempt to obtain an effective process amenable to industrial scale-up.…”

Aqueous Two‐Phase Systems (ATPSs) for Extraction and Purification of Biomolecules and Bioparticles

“…Despite the essential role of packed bed chromatography owing to its simple and high resolving power, high titer processes have been imposing practical limitations, suggesting that the true bottleneck relies on the first adsorptive column. With an increasing scale, very large columns are needed; thus, the performance of the process decreases as additional costs of resins, buffers, and other consumables outstrip any savings made by increasing the productivity (5,23 …”