Pilot‐scale demonstration of an end‐to‐end integrated and continuous biomanufacturing process

Abstract

There has been increasing momentum recently in the biopharmaceutical industry to transition from traditional batch processes to next‐generation integrated and continuous biomanufacturing. This transition from batch to continuous is expected to offer several advantages which, taken together, could significantly improve access to biologics drugs for patients. Despite this recent momentum, there has not been a commercial implementation of a continuous bioprocess reported in the literature. In this study, we describe a successful pilot‐scale proof‐of‐concept demonstration of an end‐to‐end integrated and continuous bioprocess for the production of a monoclonal antibody (mAb). This process incorporated all of the key unit operations found in a typical mAb production process, including the final steps of virus removal filtration, ultrafiltration, diafiltration, and formulation. The end‐to‐end integrated process was operated for a total of 25 days and produced a total of 4.9 kg (200 g/day or 2 g/L BRX/day) of the drug substance from a 100‐L perfusion bioreactor (BRX) with acceptable product quality and minimal operator intervention. This successful proof‐of‐concept demonstrates that end‐to‐end integrated continuous bioprocessing is achievable with current technologies and represents an important step toward the realization of a commercial integrated and continuous bioprocessing process.

Effects of pyruvate on primary metabolism and product quality for a high‐density perfusion process

“…The high pressure to reduce production costs drives innovation towards new approaches such as intensified fed‐batches (Chen et al, 2018; Jordan et al, 2018; Xu et al, 2020; W. C. Yang et al, 2016), perfusion cultures and/or continuous production (J.‐M. Bielser et al, 2018; Coolbaugh et al, 2021; Daniel Johannes Karst et al, 2018; Warikoo et al, 2012; Wolf et al, 2020). The highest volumetric productivity per reactor volume is promised by perfusion processes, while the low residence time of the protein in the reactor can be beneficial for some quality attributes (J. M. Bielser et al, 2019).…”

Model‐based control for column‐based continuous viral inactivation of biopharmaceuticals

“…While design variables have been explored quite extensively in past work in continuous viral inactivation (Amarikwa et al, 2019; Coolbaugh et al, 2021; Gillespie et al, 2019; Klutz et al, 2016; Orozco et al, 2017; Parker et al, 2018), disturbance rejection has not been discussed directly. Disturbance rejection is especially important to consider when operating continuously for an extended period of time.…”

“…work in continuous viral inactivation (Amarikwa et al, 2019;Coolbaugh et al, 2021;Gillespie et al, 2019;Klutz et al, 2016;Orozco et al, 2017;Parker et al, 2018), disturbance rejection has not been discussed directly.…”

“…Methods for adapting low-pH hold to continuous processing have involved cyclic batch operation (Pall Life Sciences, 2018), continuousflow tubular reactors (Amarikwa et al, 2019;Coolbaugh et al, 2021;Gillespie et al, 2019;Klutz et al, 2016;Orozco et al, 2017;Parker et al, 2018), and continuous-flow column-based reactors (Arnold et al, 2019;Martins et al, 2019Martins et al, , 2020Senčar et al, 2020). None of the continuous-flow reactors, however, directly address control considerations with operating the systems.…”

White paper on high‐throughput process development for integrated continuous biomanufacturing

“…However, Godawat et al ( 2015 ) were able to combine a perfusion bioreactor with two periodic PCC units for initial capture and successive ion‐exchange steps, showing it is feasible to fully create and integrate an end‐to‐end continuous bioprocessing platform. More recently, Coolbaugh et al ( 2021 ) have demonstrated such end‐to‐end continuous processes are scalable by showing a successful proof‐of‐concept at pilot‐scale.…”