Pool‐less processing to streamline downstream purification of monoclonal antibodies

With cell culture titers and productivity increasing in the last few years, pressure has been placed on downstream purification to look at alternative strategies to meet the demand of biotech products with high dose requirements. Even when the upstream process is not continuous (perfusion based), adopting a more productive and/or continuous downstream process can be of significant advantage. Due to the recent trend in exploring continuous processing options for biomolecules, several enabling technologies have been assessed at Biogen. In this paper, we evaluate the capability of one of these technologies to streamline and improve our downstream mAb purification platform. Current conventional downstream polishing steps at Biogen are operated in flow‐through mode to achieve higher loadings while maintaining good selectivity. As titers increase, this would result in larger columns and larger intermediate product pool holding tanks. A semicontinuous downstream process linking the second and third chromatography steps in tandem can reduce/eliminate intermediate holding tanks, reduce overall processing time, and combine unit operations to reduce validation burdens. A pool‐less processing technology utilizing inline adjustment functionality was evaluated to address facility fit challenges for three high titer mAbs. Two different configurations of polishing steps were examined: (i) anion exchange and hydrophobic interaction and (ii) anion exchange and mixed mode chromatography. Initial laboratory scale proof of concept studies showed comparable performance between the batch purification process and the pool‐less process configuration.

[1]  Konstantin B Konstantinov,et al.  White paper on continuous bioprocessing. May 20-21, 2014 Continuous Manufacturing Symposium. , 2015, Journal of pharmaceutical sciences.

[2]  Jochen Strube,et al.  Design and Operation of Continuous Countercurrent Chromatography in Biotechnological Production , 2014 .

[3]  Abhinav A Shukla,et al.  Recent advances in large-scale production of monoclonal antibodies and related proteins. , 2010, Trends in biotechnology.

[4]  Bernhardt L Trout,et al.  Achieving Continuous Manufacturing May 20-21 2014 Continuous Manufacturing Symposium. , 2015, Journal of pharmaceutical sciences.

[5]  Thomas De Beer,et al.  Process Analytical Technology for continuous manufacturing of solid-dosage forms , 2015 .

[6]  Huong Nguyen,et al.  A new large‐scale manufacturing platform for complex biopharmaceuticals , 2012, Biotechnology and bioengineering.

[7]  C. Horváth,et al.  Salt-mediated retention of proteins in hydrophobic-interaction chromatography. Application of solvophobic theory. , 1984, Journal of chromatography.

[8]  Richard D Braatz,et al.  Control systems engineering in continuous pharmaceutical manufacturing. May 20-21, 2014 Continuous Manufacturing Symposium. , 2015, Journal of pharmaceutical sciences.

[9]  Sanchayita Ghose,et al.  Purification of monoclonal antibodies by hydrophobic interaction chromatography under no-salt conditions , 2013, mAbs.

[10]  Richard D Braatz,et al.  Control Systems Engineering in Continuous Pharmaceutical Manufacturing May 20-21, 2014 Continuous Manufacturing Symposium. , 2015, Journal of pharmaceutical sciences.

[11]  Brian Hubbard,et al.  Downstream processing of monoclonal antibodies--application of platform approaches. , 2007, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[12]  Ekta Mahajan,et al.  Improving affinity chromatography resin efficiency using semi-continuous chromatography. , 2012, Journal of chromatography. A.

[13]  R. Nicoud The Amazing Ability of Continuous Chromatography To Adapt to a Moving Environment , 2014 .

[14]  Thomas Ryll,et al.  Maximizing productivity of CHO cell‐based fed‐batch culture using chemically defined media conditions and typical manufacturing equipment , 2010, Biotechnology progress.

[15]  A. Heinrich. Tanner Continuous casting : a revolution in steel : the worldwide success story of Concast AG, Zurich , 1998 .

[16]  Peter Poechlauer,et al.  Equipment and Analytical Companies Meeting Continuous Challenges May 20-21 2014 Continuous Manufacturing Symposium. , 2015, Journal of pharmaceutical sciences.

[17]  Paul Sharratt,et al.  Achieving Continuous Manufacturing: Technologies and Approaches for Synthesis, Workup, and Isolation of Drug Substance May 20-21, 2014 Continuous Manufacturing Symposium. , 2015, Journal of pharmaceutical sciences.

[18]  Konstantin B Konstantinov,et al.  The future of industrial bioprocessing: batch or continuous? , 2015, Biotechnology and bioengineering.

[19]  Charles L. Cooney,et al.  White Paper on Continuous Bioprocessing , 2014 .

[20]  Yao-ming Huang,et al.  Perfusion seed cultures improve biopharmaceutical fed‐batch production capacity and product quality , 2014, Biotechnology progress.

[21]  J. Coffman,et al.  A tandem laboratory scale protein purification process using Protein A affinity and anion exchange chromatography operated in a weak partitioning mode , 2013, Biotechnology and bioengineering.

[22]  Daniel Cummings,et al.  Integrated continuous production of recombinant therapeutic proteins , 2012, Biotechnology and bioengineering.