Implementation of Fully Integrated Continuous Antibody Processing: Effects on Productivity and COGm

Abstract

The changing landscape of the biopharmaceutical market is driving a paradigm shift toward continuous manufacturing. To date, integrated continuous bioprocessing has not been realized as enabling technologies are nascent. In this work, a fully integrated continuous process is successfully demonstrated from pilot scale bioreactor to drug substance. Comparable product quality is observed between the continuous process and a 500 L fed-batch conventional process. The continuous process generated material at a rate of 1 kg of purified mAb every 4 days, achieving a 4.6-fold increase in productivity compared to the fed-batch process A plant throughput analysis using BioSolve software shows that a fed-batch facility with 4 × 12 500 L stainless steel bioreactors and purification train of the corresponding scale can be replaced by a continuous facility consisting of 5 × 2000 L single use bioreactors and smaller purification train, with a cost reduction of 15%.

Process‐wide control and automation of an integrated continuous manufacturing platform for antibodies

“…Significant efforts have been made to successfully develop unit operations capable to handle continuous streams both for upstream and downstream processing (Angarita et al, 2015; Jungbauer, 2013; Rathore, Agarwal, Sharma, Pathak, & Muthukumar, 2015; Rathore, Kateja, & Agarwal, 2017; Steinebach, Müller‐Späth, & Morbidelli, 2016; Rathore et al, 2017; Wolf et al, 2018). Primary drivers are economic benefits as discussed in different studies (Arnold, Lee, Rucker‐Pezzini, & Lee, 2019; Hummel et al, 2019; Pollock, Coffman, Ho, & Farid, 2017; Walther et al, 2015), higher efficiency of counter‐current chromatographic purification units (Pfister, Nicoud, & Morbidelli, 2018) as well as more homogeneous product quality through uniformity of the microenvironment and reduced residence time in continuous bioreactors (Karst et al, 2018; Karst, Steinebach, Soos, & Morbidelli, 2017; Liu, Gaza‐Bulseco, Faldu, Chumsae, & Sun, 2008; Pacis, Yu, Autsen, Bayer, & Li, 2011; Zydney, 2015). Furthermore, by integrating all unit operations in a single manufacturing platform, processing time, production efficiency, and equipment footprint can be further optimized (Arnold et al, 2019; Karst et al, 2017).…”

“…Primary drivers are economic benefits as discussed in different studies (Arnold, Lee, Rucker‐Pezzini, & Lee, 2019; Hummel et al, 2019; Pollock, Coffman, Ho, & Farid, 2017; Walther et al, 2015), higher efficiency of counter‐current chromatographic purification units (Pfister, Nicoud, & Morbidelli, 2018) as well as more homogeneous product quality through uniformity of the microenvironment and reduced residence time in continuous bioreactors (Karst et al, 2018; Karst, Steinebach, Soos, & Morbidelli, 2017; Liu, Gaza‐Bulseco, Faldu, Chumsae, & Sun, 2008; Pacis, Yu, Autsen, Bayer, & Li, 2011; Zydney, 2015). Furthermore, by integrating all unit operations in a single manufacturing platform, processing time, production efficiency, and equipment footprint can be further optimized (Arnold et al, 2019; Karst et al, 2017). All of this translates into less expensive and more efficient and safe drugs for the benefit of the patients and therefore has received the strong support of regulatory agencies for years (FDA, 2019; Nasr et al, 2017).…”

“…However, only a limited number of successful implementations of bench‐scale end‐to‐end integrated processes has been demonstrated for the production of biologics (Arnold et al, 2019; Godawat, Konstantinov, Rohani, & Warikoo, 2015; Luttmann et al, 2015; Steinebach et al, 2017). Possible explanations are the increased product and system complexity, lack of real‐time process information as well as difficulties to handle disturbances and drifts due to changes in raw materials or biological systems when dealing with a continuously operating sequence of units.…”

Shift to high‐intensity, low‐volume perfusion cell culture enabling a continuous, integrated bioprocess

“…Additionally, depending on the cell retention device used, intermediate steps such as centrifugation and depth filtration may be eliminated. Continuous loading of Protein A affinity capture columns (ProA) can increase resin utilization and reduce the required column size …”

Integrated Continuous Biomanufacturing: Industrialization on the Horizon

“…On the end‐to‐end front, MedImmune share experiences implementing a fully integrated continuous antibody process with commentary on productivity and cost of goods impacts.…”