Progression of continuous downstream processing of monoclonal antibodies: Current trends and challenges

Abstract

Rapid advances in intensifying upstream processes for biologics production have left downstream processing as a bottleneck in the manufacturing scheme. Biomanufacturers are pursuing continuous downstream process development to increase efficiency and flexibility, reduce footprint and cost of goods, and improve product consistency and quality. Even after successful laboratory trials, the implementation of a continuous process at manufacturing scale is not easy to achieve. This paper reviews specific challenges in converting each downstream unit operation to a continuous mode. Key elements of developing practical strategies for overcoming these challenges are detailed. These include equipment valve complexity, favorable column aspect ratio, protein-A resin selection, quantitative assessment of chromatogram peak size and shape, holistic process characterization approach, and a customized process economic evaluation. Overall, this study provides a comprehensive review of current trends and the path forward for implementing continuous downstream processing at the manufacturing scale.

Understanding mAb aggregation during low pH viral inactivation and subsequent neutralization

“…At the same time, the biopharmaceutical industry has matured considerably since its inception in the 1980s, for example through the advent of generic drugs (so‐called biosimilars; Udpa & Million, ). This evolutions has led to increased cost pressure on manufacturing and fueled the desire for higher productivity (Gottschalk, Brorson, & Shukla, ; Karst, Steinebach, & Morbidelli, ; Somasundaram, Pleitt, Shave, Baker, & Lua, ; Vogg, Wolf, & Morbidelli, ; Walther et al, ).…”

“…Chemical inactivation by temporary exposure to low pH is known to be a robust procedure for dealing with enveloped viruses (Brorson et al, 2003;Miesegaes, Lute, & Brorson, 2010) and is therefore an integral part of mAb manufacturing. Typically, protein A affinity chromatography is the first purification step for the clarified cell culture harvest (Somasundaram et al, 2018;Vogg, Müller-Späth, & Morbidelli, 2018). Elution of the mAb from the column is achieved by reducing mobile phase pH to a range from 3 to 4 (Hober, Nord, & Linhult, 2007;Pabst, Thai, & Hunter, 2018).…”

The Current Status, Trend, and Development Strategies of Chinese Biopharmaceutical Industry With a Challenging Perspective

“…Biopharmaceutical industry is now characterized by high technology, high investment, high risk, high profitability, and long cycle. It is one of the most active and fastest growing fields in bioengineering application and development (Eissa, 2017;Farid, 2019;Huang et al, 2011;Hummel et al, 2018;Kadam et al, 2016;Kensaku et al, 2019;Somasundaram et al, 2018;Walsh, 2014;Zhang et al, 2007). For instance, monoclonal antibodies continue their march on the markets, and the optimized so-called bio-better versions of existing biologies are gaining ground too (Eissa, 2017;Farid, 2019;Hummel et al, 2018;Somasundaram et al, 2018;Walsh, 2014).…”

UQ eSpace

“…Research and development has been focused on the improvement of upstream processes, resulting in higher titres. This has thus created a bottleneck in the initial capture step of downstream processing due to the batch nature of traditional chromatography (Somasundaram et al, 2018). With recent advances, continuous chromatography is becoming more feasible, with new process skids being developed and available for purchase from laboratory scale to commercial scale.…”

“…A recent trend in research for downstream processing to improve overall efficiency, reduce costs and reduce the footprint of the process is continuous processing. Although this has already been established in upstream processing with perfusion reactors, development is still required before continuous chromatography can be approved and used commercially (Somasundaram et al, 2018). Only recently, continuous chromatography skids for small-scale manufacture are being released by the large biopharmaceutical vendors.…”