Enhancing protein A productivity and resin utilization within integrated or intensified processes

Abstract

Recent interest in continuous manufacturing of biologics has driven the development and evaluation of multicolumn chromatography systems to drive down resin costs by increasing productivity and maximizing resin utilization, especially for the expensive protein A capture step. Single‐pass tangential flow filtration can be used to reduce the volume of perfusion harvest, enabling a further increase in the productivity of the capture step by up to fivefold. However, there are expected to be practical limits for the productivity of the capture step, which must be determined based on the manufacturing batch size, duration, and frequency, especially as it relates to efficient utilization of the column lifetime. For short fed‐batch manufacturing campaigns, intensified capture processes may result in up to 82% lower resin consumption, while avoiding the long‐term storage of used resin. For perfusion processes and longer fed‐batch campaigns, it may be more efficient to operate at a lower productivity that enables the column lifetime to be routinely achieved and achieves the desired resin and buffer savings without introducing unnecessary process risk or complexity. An intensified batch capture process, “super‐batch,” will be compared as an alternative to multicolumn chromatography processes to achieve high productivity and resin utilization with a potentially simpler process.

An automated high inoculation density fed‐batch bioreactor, enabled through N‐1 perfusion, accommodates clonal diversity and doubles titers

“…Connecting the HID process with intensified capture technologies, such as higher binding capacity resins, and simulated moving bed chromatography, have been used to increase the capture step capacity to handle increased bioreactor titers. 25 Overall, although downstream bottlenecks can arise when intensifying upstream bioreactor processes, some of these can be addressed by adoption of new technologies for limiting unit operations. Continuing innovation in downstream technologies is needed to continue to keep pace with upstream titer increases.…”

Concentration of clarified pool by single‐pass tangential flow filtration to improve productivity of protein A capture step: Impact of clarification strategies

“…Therefore, the challenges of implementing new technology will need to be weighed against the benefits that flocculation provides to both the SPTFF and protein A chromatography performance. In addition, the cost of goods versus productivity benefits must be weighed against each other as described in the past literature (Brinkmann & Elouafiq, 2021).…”

“…Single‐pass tangential flow filtration (SPTFF) has been previously used for inline concentration of the clarified CCF (Arunkumar et al, 2017; Brinkmann & Elouafiq, 2021; Brinkmann et al, 2018; Lutz, 2008). As the name suggests, SPTFF operates in a fashion such that the feed to be concentrated passes through the pump, and TFF filters only once, resulting in a seamless management of the process fluid compared to traditional concentration methods (MilliporeSigma, 2018).…”

Reviewing the process intensification landscape through the introduction of a novel, multitiered classification for downstream processing

“…Nevertheless, Level 1 intensification is likely to become more standard for chromatography as time passes, especially with consumables like convective membrane chromatography devices. Implementation of Level 1 intensification through systems or methodology should become more common for protein‐based therapeutics as time goes on due to the productivity cap associated with batch chromatography using resin‐based consumables (Brinkmann & Elouafiq, 2021). For filtration‐based steps to be included as a standard in intensification, it will be influenced in conjunction with the adoption of Level 1 chromatography steps, as developers seek to find ways to expand intensification from just one unit operation (Level 1) to multiple, connected unit operations (Level 2).…”