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in Wiley InterScience (www.interscience.wiley.com).Host cell protein (HCP) contaminant clearance is a significant concern during downstream process development for biopharmaceuticals. Protein A chromatography as a capture step for monoclonal antibodies and Fc fusion proteins can clear a large proportion of these impurities from cell culture harvest. Nevertheless, remaining levels of this process-related impurity class do present significant constraints on the rapid development of effective and robust polishing steps. Conventionally, an intermediate pH wash is employed between column loading and elution to minimize HCP levels after Protein A chromatography. A significant mechanistic finding presented in this work is that HCP contaminants that persist following Protein A capture predominantly comprise species that associate with the product in preference to direct interaction with the chromatographic resin. This suggests that the development of improved column wash techniques to maximize HCP clearance ought to focus on disrupting protein-HCP interactions rather than Protein A-HCP interactions. A higher wash pH to preserve product -Protein A binding along with the use of additive combinations to disrupt interactions between HCPs and the product are investigated. This strategy was successfully applied to develop a broadly applicable wash condition that has the potential for eliminating the need for product specific optimization of wash conditions. A combination of 1 M urea and 10% isopropanol in the wash buffer were successfully applied as a platform wash condition for Protein A chromatography. Use of this (and other similar) wash conditions are anticipated to aid the rapid development of effective downstream processes for monoclonal antibodies and Fc fusion proteins resulting in their rapid introduction into clinical trials.

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Monoclonal antibodies (mAbs) have established themselves as the leading biopharmaceutical therapeutic modality. The establishment of robust manufacturing platforms are key for antibody drug discovery efforts to seamlessly translate into clinical and commercial successes. Several drivers are influencing the design of mAb manufacturing processes. The advent of biosimilars is driving a desire to achieve lower cost of goods and globalize biologics manufacturing. High titers are now routinely achieved for mAbs in mammalian cell culture. These drivers have resulted in significant evolution in process platform approaches. Additionally, several new trends in bioprocessing have arisen in keeping with these needs. These include the consideration of alternative expression systems, continuous biomanufacturing and non‐chromatographic separation formats. This paper discusses these drivers in the context of the kinds of changes they are driving in mAb production processes.