A Single-use Strategy to Enable Manufacturing of Affordable Biologics

The current processing paradigm of large manufacturing facilities dedicated to single product production is no longer an effective approach for best manufacturing practices. Increasing competition for new indications and the launch of biosimilars for the monoclonal antibody market have put pressure on manufacturers to produce at lower cost. Single-use technologies and continuous upstream processes have proven to be cost-efficient options to increase biomass production but as of today the adoption has been only minimal for the purification operations, partly due to concerns related to cost and scale-up. This review summarizes how a single-use holistic process and facility strategy can overcome scale limitations and enable cost-efficient manufacturing to support the growing demand for affordable biologics. Technologies enabling high productivity, right-sized, small footprint, continuous, and automated upstream and downstream operations are evaluated in order to propose a concept for the flexible facility of the future.

[1]  Andrew Sinclair,et al.  The Environmental Impact of Disposable Technologies , 2008 .

[2]  Geoffrey S F Ling,et al.  Battlefield Medicine: Paradigm Shift for Pharmaceuticals Manufacturing , 2014, PDA Journal of Pharmaceutical Science and Technology.

[3]  Manas Tandon,et al.  Orphan drug: Development trends and strategies , 2010, Journal of pharmacy & bioallied sciences.

[4]  Aaron S Kesselheim,et al.  Progress and Hurdles for Follow-on Biologics. , 2015, The New England journal of medicine.

[5]  Oliver Kaltenbrunner,et al.  Continuous bind‐and‐elute protein A capture chromatography: Optimization under process scale column constraints and comparison to batch operation , 2016, Biotechnology progress.

[6]  Sandeep Nema,et al.  Process Development Considerations for Therapeutic Monoclonal Antibodies in Mammalian Cell Culture , 2007 .

[7]  Andrew D. Tustian,et al.  Development of purification processes for fully human bispecific antibodies based upon modification of protein A binding avidity , 2016, mAbs.

[8]  Douglas S Watson,et al.  At‐line process analytical technology (PAT) for more efficient scale up of biopharmaceutical microfiltration unit operations , 2016, Biotechnology progress.

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

[10]  Alex Xenopoulos,et al.  A new, integrated, continuous purification process template for monoclonal antibodies: Process modeling and cost of goods studies. , 2015, Journal of biotechnology.

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

[12]  Benjamin Minow,et al.  High – Cell-Density Clarification By Single-Use Diatomaceous Earth Filtration , 2014 .

[13]  Stanley,et al.  Development of an acidic / neutral antibody flow-through polishing step using salt-tolerant anion exchange chromatography , 2016 .

[14]  Mark Brower,et al.  Advective hydrogel membrane chromatography for monoclonal antibody purification in bioprocessing , 2015, Biotechnology progress.

[15]  T. Peuker,et al.  Equipment design and facility layout for flexible biomanufacturing processes , 2011 .

[16]  Steven Rose,et al.  Mammalian Cell Culture , 2002 .

[17]  Dieter Eibl,et al.  Single-Use Technology in Biopharmaceutical Manufacture , 2011 .

[18]  Duncan Low,et al.  Future of antibody purification. , 2007, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[19]  Hans Hummel,et al.  Paradigm shift for vaccine manufacturing facilities: The next generation of flexible, modular facilities , 2014 .

[20]  Gerhard Schembecker,et al.  Developing the biofacility of the future based on continuous processing and single-use technology. , 2015, Journal of biotechnology.

[21]  Alois Jungbauer,et al.  Continuous downstream processing of biopharmaceuticals. , 2013, Trends in biotechnology.

[22]  M. Butler,et al.  Recent advances in technology supporting biopharmaceutical production from mammalian cells , 2012, Applied Microbiology and Biotechnology.

[23]  Alexandros Koulouris,et al.  Throughput Analysis and Debottlenecking of Biomanufacturing Facilities , 2002 .

[24]  Keith L Carson.  Flexibility—the guiding principle for antibody manufacturing , 2005, Nature Biotechnology.

[25]  Victor A. Vinci,et al.  Handbook of industrial cell culture , 2002 .

[26]  S. Hill,et al.  Cost-effectiveness analysis for clinicians , 2012, BMC Medicine.

[27]  Massimo Morbidelli,et al.  Comparison of batch and continuous multi-column protein A capture processes by optimal design. , 2016, Biotechnology journal.

[28]  Suzanne S. Farid,et al.  Evaluating the economic and operational feasibility of continuous processes for monoclonal antibodies , 2014 .

[29]  Stephan Kaiser,et al.  Disposable bioreactors: the current state-of-the-art and recommended applications in biotechnology , 2010, Applied Microbiology and Biotechnology.

[30]  K Jones.  Process Scale Bioseparations for the Biopharmaceutical Industry by A. A. Shukla, M. R. Etzel and S. Gadam (eds) CRC Press, Taylor and Francis Group, Boca Raton, USA, pp 575, ISBN-13: 978-1-57444-517-6, Price: GBP 97">. , 2007 .

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

[32]  Massimo Morbidelli,et al.  Twin-column CaptureSMB: a novel cyclic process for protein A affinity chromatography. , 2015, Journal of chromatography. A.

[33]  E. Berndt,et al.  Pricing in the Market for Anticancer Drugs , 2014, The journal of economic perspectives : a journal of the American Economic Association.

[34]  W. Holmes,et al.  Blood-Brain Barrier-Penetrating 6-Halogenopurines Suitable as Pro-Probes for Positron Emission Tomography are Substrates for Human Glutathione Transferases , 2015 .

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

[36]  Gregory Zarbis-Papastoitsis,et al.  A single-use purification process for the production of a monoclonal antibody produced in a PER.C6 human cell line. , 2011, Biotechnology journal.

[37]  Yuansheng Yang,et al.  Advance chromatin extraction improves capture performance of protein A affinity chromatography. , 2016, Journal of chromatography. A.

[38]  Uwe Gottschalk,et al.  Bioseparation in Antibody Manufacturing: The Good, The Bad and The Ugly , 2008, Biotechnology progress.

[39]  Massimo Morbidelli,et al.  Chromatographic separation of three monoclonal antibody variants using multicolumn countercurrent solvent gradient purification (MCSGP) , 2008, Biotechnology and Bioengineering.

[40]  Abhinav A. Shukla,et al.  Process Scale Bioseparations for the Biopharmaceutical Industry , 2006 .

[41]  Uwe Gottschalk,et al.  Single-use disposable technologies for biopharmaceutical manufacturing. , 2013, Trends in biotechnology.

[42]  Scott M. Husson,et al.  A new multimodal membrane adsorber for monoclonal antibody purifications , 2015 .

[43]  Andrew Sinclair,et al.  An environmental life cycle assessment comparison of single-use and conventional process technology for the production of monoclonal antibodies , 2013 .

[44]  Mario Jolicoeur,et al.  A Study of the Interaction of HEK‐293 Cells with Streamline Chelating Adsorbent in Expanded Bed Operation , 2008, Biotechnology progress.

[45]  Andrew L. Zydney,et al.  Continuous Countercurrent Tangential Chromatography for Monoclonal Antibody Purification , 2013 .

[46]  F. Wurm.  Production of recombinant protein therapeutics in cultivated mammalian cells , 2004, Nature Biotechnology.

[47]  Telma Barroso,et al.  Functional monolithic platforms: Chromatographic tools for antibody purification , 2013, Biotechnology journal.

[48]  Brian Kelley,et al.  Industrialization of mAb production technology: The bioprocessing industry at a crossroads , 2009, mAbs.

[49]  Anurag S. Rathore,et al.  Quality by design for biopharmaceuticals : principles and case studies , 2009 .

[50]  Murray Moo-Young,et al.  Recent advances in bioprocessing application of membrane chromatography. , 2013, Biotechnology advances.

[51]  Hans Lee,et al.  A cytotoxic leachable compound from single‐use bioprocess equipment that causes poor cell growth performance , 2014, Biotechnology progress.

[52]  Howard L. Levine,et al.  Efficient, Flexible Facilities for the 21st Century , 2012 .

[53]  Eric S. Langer,et al.  Single‐use technologies in biopharmaceutical manufacturing: A 10‐year review of trends and the future , 2014 .

[54]  Y. Durocher,et al.  At-line monitoring of bioreactor protein production by Surface Plasmon Resonance. , 2008, Biotechnology and bioengineering.

[55]  Feng Wang,et al.  High Yield of Human Monoclonal Antibody Produced by Stably Transfected Drosophila Schneider 2 Cells in Perfusion Culture Using Wave Bioreactor , 2012, Molecular Biotechnology.

[56]  Daniel G Bracewell,et al.  Nanofiber adsorbents for high productivity continuous downstream processing. , 2015, Journal of biotechnology.

[57]  Thomas Linden,et al.  Visualising protein adsorption to ion-exchange membranes by confocal microscopy , 2002 .

[58]  Ernst R Berndt,et al.  Decline in economic returns from new drugs raises questions about sustaining innovations. , 2015, Health affairs.

[59]  Eric Langer,et al.  Continuous Bioprocessing and Perfusion: Wider Adoption Coming as Bioprocessing Matures , 2014 .

[60]  John Bonham-Carter,et al.  A Brief History of Perfusion , 2011 .

[61]  Mario Jolicoeur,et al.  At-line quantification of bioactive antibody in bioreactor by surface plasmon resonance using epitope detection. , 2008, Analytical biochemistry.