Abstract
Therapeutic monoclonal antibodies (mAbs) are the fastest-growing class of biotherapeutics. They are mainly used to treat cancer, inflammatory, metabolic and autoimmune diseases. Their commercial production processes are mainly based on Chinese hamster ovary (CHO) suspension cells, which are currently cultivated in fed-batch mode at cubic meter scale. The annually growing market for therapeutic mAbs and the pressure on producers to reduce their manufacturing costs have led to the increasing development of intensified and continuous production processes in recent years. Single-use systems are used in both upstream and downstream processing. This book chapter describes the main intensification approaches and operational architectures of continuous processes realized today, based on the developmental status of single-use technologies used for the up- and downstream processing of mAbs. In this context, the terms “process intensification” and “continuous process” are defined, while the preferential application of single-use systems is described using literature, and further by own studies. Based on the findings, the main challenges for the implementation of intensified and continuous mAb production using single-use systems are identified.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Köhler G, Milstein C (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495–497. https://doi.org/10.1038/256495a0
Carvalho LS, da Silva OB, da Almeida GC et al (2017) Production processes for monoclonal antibodies. In: Jozola A (ed) Fermentation processes. InTech, www.intechopen.com, pp 181–198
Walsh G (2018) Biopharmaceutical benchmarks 2018. Nat Biotechnol 36:1136–1145. https://doi.org/10.1038/nbt.4305
Lu RM, Hwang YC, Liu IJ et al (2020) Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci 27:1–30. https://doi.org/10.1186/s12929-019-0592-z
Bielser JM, Wolf M, Souquet J et al (2018) Perfusion mammalian cell culture for recombinant protein manufacturing – a critical review. Biotechnol Adv 36:1328–1340. https://doi.org/10.1016/j.biotechadv.2018.04.011
Kelley B (2009) Industrialization of mAb production technology: the bioprocessing industry at a crossroads. MAbs 1:443–452. https://doi.org/10.4161/mabs.1.5.9448
Becerra S, Berrios J, Osses N, Altamirano C (2012) Exploring the effect of mild hypothermia on CHO cell productivity. Biochem Eng J 60:1–8. https://doi.org/10.1016/j.bej.2011.10.003
Masterton RJ, Smales CM (2014) The impact of process temperature on mammalian cell lines and the implications for the production of recombinant proteins in CHO cells. Pharm Bioprocess 2:49–61. https://doi.org/10.4155/pbp.14.3
Torres M, Zúñiga R, Gutierrez M et al (2018) Mild hypothermia upregulates myc and xbp1s expression and improves anti-TNFα production in CHO cells. PLoS One 13:e0194510. https://doi.org/10.1371/journal.pone.0194510
Xu J, Xu X, Huang C et al (2020) Biomanufacturing evolution from conventional to intensified processes for productivity improvement: a case study. MAbs 12:1770669. https://doi.org/10.1080/19420862.2020.1770669
Konstantinov KB, Cooney CL (2015) White paper on continuous bioprocessing May 20–21 2014 continuous manufacturing symposium. J Pharm Sci 104:813–820. https://doi.org/10.1002/jps.24268
Pollock J, Ho SV, Farid SS (2013) Fed-batch and perfusion culture processes: economic, environmental, and operational feasibility under uncertainty. Biotechnol Bioeng 110:206–219. https://doi.org/10.1002/bit.24608
Lindskog EK (2017) The upstream process: principal modes of operation. In: Jagschies G, Lindskog E, Lacki K, Galliher P (eds) Biopharmaceutical processing: development, design, and implementation of manufacturing processes. Elsevier, pp 625–635
Gupta SK (2017) Upstream continuous process development. In: Subramanian G (ed) Continuous biomanufacturing – innovative technologies and methods. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, pp 201–232
Farid SS (2007) Process economics of industrial monoclonal antibody manufacture. J Chromatogr B 848:8–18. https://doi.org/10.1016/j.jchromb.2006.07.037
Gavara P, Bibi N, Sanchez M et al (2015) Chromatographic characterization and process performance of column-packed anion exchange fibrous adsorbents for high throughput and high capacity bioseparations. PRO 3:204–221. https://doi.org/10.3390/pr3010204
Broly H, Costioli MD, Guillemot-Potelle C, Mitchell-Logean C (2010) Cost of goods modeling and quality by design for developing cost-effective processes. BioPharm Int 23:26–35
Godawat R, Konstantinov K, Rohani M, Warikoo V (2015) End-to-end integrated fully continuous production of recombinant monoclonal antibodies. J Biotechnol 213:13–19. https://doi.org/10.1016/j.jbiotec.2015.06.393
Somasundaram B, Pleitt K, Shave E et al (2018) Progression of continuous downstream processing of monoclonal antibodies: current trends and challenges. Biotechnol Bioeng 115:2893–2907. https://doi.org/10.1002/bit.26812
Whitford WG (2013) Single-use technology supporting the comeback of continuous bioprocessing. Pharm Bioprocess 1:249–253. https://doi.org/10.4155/pbp.13.28
Langer ES, Rader RA (2014) Single-use technologies in biopharmaceutical manufacturing: a 10-year review of trends and the future. Eng Life Sci 14:238–243. https://doi.org/10.1002/elsc.201300090
Chulkova TY, Kurbanova EK, Novikov YN, Gusarov DA (2013) Single-use technologies in biopharmaceutical production: advantages and disadvantages. Upstream process solutions (mini-review). Russ J Biopharm 5:3–12
Rogge P, Müller D, Schmidt SR (2015) The single-use or stainless steel decision process: a CDMO perspective. Bioprocess Int 13:10–15
BioPlan Associates Inc. (2020) Seventeenth annual report and survey of biopharmaceutical manufacturing capacity and production. www.bioplanassociates.com
Kunas K, Horvath B, Frank G et al (2013) A generic growth test method for improving quality control of disposables in industrial cell culture. BioPharm Int 26:34–41
Sobańtka A, Weiner C (2019) Extractables/leachables from single-use equipment. In: Eibl R, Eibl D (eds) Single-use technology in biopharmaceutical manufacture, 2nd edn. Wiley, Hoboken, pp 143–158
Dorival-García N, Carillo S, Ta C et al (2018) Large-scale assessment of extractables and leachables in single-use bags for biomanufacturing. Anal Chem 90:9006–9015. https://doi.org/10.1021/acs.analchem.8b01208
Pahl I, Hauk A, Schosser L, Orlikowski S (2019) Considerations on performing quality risk analysis for production processes with single-use systems. In: Eibl R, Eibl D (eds) Single-use technology in biopharmaceutical manufacture, 2nd edn. Wiley, Hoboken, pp 211–218
Martin JM (2011) A brief history of single-use manufacturing. BioPharm Int 24(Suppl):5–7
Singh V (1999) Disposable bioreactor for cell culture using wave-induced agitation. Cytotechnology 30:149–158. https://doi.org/10.1023/a:1008025016272
Jossen V, Eibl R, Eibl D (2019) Single-use bioreactors – an overview. In: Eibl R, Eibl D (eds) Single-use technology in biopharmaceutical manufacture, 2nd edn. Wiley, Hoboken, pp 37–52
Stanton D (2019) ABEC breaks plastic ceiling again with 6,000 L single-use bioreactor. In: Bioprocess Int. https://bioprocessintl.com/bioprocess-insider/upstream-downstream-processing/abec-breaks-plastic-ceiling-again-with-6000-l-single-use-bioreactor/. Accessed 10 Nov 2020
Oosterhuis NMG, Junne S (2016) Design, applications, and development of single-use bioreactors. In: Mandenius C-F (ed) Bioreactors: design, operation and novel applications. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, pp 261–294
Kaiser SC, Kraume M, Eibl D, Eibl R (2015) Single-use bioreactors for animal and human cells. In: Al-Rubeai M (ed) Animal cell culture. Cell engineering, vol 9. Springer, Cham, pp 445–500
Oosterhuis NMG (2017) Single-use bioreactors for continuous bioprocessing: challenges and outlook. In: Subramanian G (ed) Continuous biomanufacturing – innovative technologies and methods. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, pp 131–148
Schirmer C, Müller J, Steffen N et al (2020) How to produce mAbs in a cube-shaped stirred single-use bioreactor at 200 L scale. In: Pörtner R (ed) Animal cell biotechnology: methods and protocols, 4th edn. Humana Press, New York, pp 169–186
Anderlei T, Eibl D, Eibl R et al (2017) Facility of the future. DECHEMA, Frankfurt a.M. ISBN 978-3-89746-199-4
Manser B, Glenz M, Bisschops M (2019) Single-use downstream processing for biopharmaceuticals. In: Eibl R, Eibl D (eds) Single-use technology in biopharmaceutical manufacture, 2nd edn. Wiley, Hoboken, pp 117–126
Clincke MF, Mölleryd C, Samani PK et al (2013) Very high density of Chinese hamster ovary cells in perfusion by alternating tangential flow or tangential flow filtration in WAVE bioreactor™-part II: applications for antibody production and cryopreservation. Biotechnol Prog 29:768–777. https://doi.org/10.1002/btpr.1703
Ozturk SS (1996) Engineering challenges in high density cell culture systems. Cytotechnology 22:3–16. https://doi.org/10.1007/BF00353919
Konstantinov K, Goudar C, Ng M et al (2006) The “push-to-low” approach for optimization of high-density perfusion cultures of animal cells. Adv Biochem Eng Biotechnol 101:75–98. https://doi.org/10.1007/10_016
Castilho LR, Medronho RA (2002) Cell retention devices for suspended-cell perfusion cultures. In: Schügerl K, Zeng A-P (eds) Advances in biochemical engineering/biotechnology, 74th edn. Springer, Berlin, Heidelberg, pp 129–169
Warnock JN, Al-Rubeai M (2006) Bioreactor systems for the production of biopharmaceuticals from animal cells. Biotechnol Appl Biochem 45:1–12. https://doi.org/10.1042/BA20050233
Chotteau V (2015) Perfusion processes. In: Al-Rubeai M (ed) Animal cell culture. Cell engineering, vol 9. Springer, Cham, pp 407–443
Voisard D, Meuwly F, Ruffieux P-A et al (2003) Potential of cell retention techniques for large-scale high-density perfusion culture of suspended mammalian cells. Biotechnol Bioeng 82:751–765. https://doi.org/10.1002/bit.10629
Clincke MF, Mölleryd C, Zhang Y et al (2013) Very high density of CHO cells in perfusion by ATF or TFF in WAVE bioreactor™: part I: effect of the cell density on the process. Biotechnol Prog 29:754–767. https://doi.org/10.1002/btpr.1704
Oosterhuis NMG (2014) Perfusion process design in a 2D rocking single-use bioreactor. In: Subramanian G (ed) Continuous processing in pharmaceutical manufacturing. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, pp 155–164
Whitford WG (2015) Single-use perfusion bioreactors support continuous biomanufacturing. Pharm Bioprocess 3:75–93. https://doi.org/10.4155/pbp.14.58
Karst DJ, Serra E, Villiger TK et al (2016) Characterization and comparison of ATF and TFF in stirred bioreactors for continuous mammalian cell culture processes. Biochem Eng J 110:17–26. https://doi.org/10.1016/j.bej.2016.02.003
Madsen B, Cobia J, Jones N (2019) S.U.B. enhancements for high-density perfusion cultures. Appl. Note. https://assets.thermofisher.com/TFS-Assets/BPD/Application-Notes/sub-enhancements-perfusion-cultures-app-note.pdf. Accessed 22 Nov 2020
Stepper L, Filser FA, Fischer S et al (2020) Pre-stage perfusion and ultra-high seeding cell density in CHO fed-batch culture: a case study for process intensification guided by systems biotechnology. Bioprocess Biosyst Eng 43:1431–1443. https://doi.org/10.1007/s00449-020-02337-1
Sieck JB, Schild C, von Hagen J (2017) Perfusion formats and their specific medium requirements. In: Subramanian G (ed) Continuous biomanufacturing – innovative technologies and methods. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, pp 171–200
Zhan C, Bidkhori G, Schwarz H et al (2020) Low shear stress increases recombinant protein production and high shear stress increases apoptosis in human cells. iScience 23:–101653. https://doi.org/10.1016/j.isci.2020.101653
Radoniqi F, Zhang H, Bardliving CL et al (2018) Computational fluid dynamic modeling of alternating tangential flow filtration for perfusion cell culture. Biotechnol Bioeng 115:2751–2759. https://doi.org/10.1002/bit.26813
Walther J, McLarty J, Johnson T (2019) The effects of alternating tangential flow (ATF) residence time, hydrodynamic stress, and filtration flux on high-density perfusion cell culture. Biotechnol Bioeng 116:320–332. https://doi.org/10.1002/bit.26811
Woodgate JM (2018) Perfusion N-1 culture—opportunities for process intensification. In: Jagschies G, Lindskog E, Łącki K, Galliher P (eds) Biopharmaceutical processing - development, design, and implementation of manufacturing processes. Elsevier, Amsterdam/Oxford/Cambridge, pp 755–768
Zamani L, Lundqvist M, Zhang Y et al (2018) High cell density perfusion culture has a maintained exoproteome and metabolome. Biotechnol J 13:1–11. https://doi.org/10.1002/biot.201800036
Padawer I, Ling WLW, Bai Y (2013) Case study: an accelerated 8-day monoclonal antibody production process based on high seeding densities. Biotechnol Prog 29:829–832. https://doi.org/10.1002/btpr.1719
Pohlscheidt M, Jacobs M, Wolf S et al (2013) Optimizing capacity utilization by large scale 3000 L perfusion in seed train bioreactors. Biotechnol Prog 29:222–229. https://doi.org/10.1002/btpr.1672
Yang WC, Lu J, Kwiatkowski C et al (2014) Perfusion seed cultures improve biopharmaceutical fed-batch production capacity and product quality. Biotechnol Prog 30:616–625. https://doi.org/10.1002/btpr.1884
Xu J, Rehmann MS, Xu M et al (2020) Development of an intensified fed-batch production platform with doubled titers using N-1 perfusion seed for cell culture manufacturing. Bioresour Bioprocess 7:17. https://doi.org/10.1186/s40643-020-00304-y
GE Healthcare (2016) One-step seed culture expansion from one vial of high-density cell bank to 2000 L production bioreactor. Appl. Note 29160932. https://www.cytivalifesciences.co.kr/wp-content/uploads/2020/04/One-step-seed-culture-expansion-from-one-vial-of-high-density-cell-bank-to-2000-L-production-bioreactor.pdf. Accessed 10 Nov 2020
Steffen N (2020) Neue Ansätze zur CHO-Zell-basierten Antikörperproduktion. Master thesis, Zürcher Hochschule für Angewandte Wissenschaften
BioPhorum Operations Group (2017) Continuous downstream processing for biomanufacturing: an industry review. https://www.biophorum.com/download/continuous-downstream-processing-for-biomanufacturing-an-industry-review/. Accessed 8 Nov 2020
Hwang I (2019) Samsung biologics implements large scale N-1 perfusion for commercial application. Press release. https://www.prnewswire.com/news-releases/samsung-biologics-implements-large-scale-n-1-perfusion-for-commercial-application-300899326.html. Accessed 10 Nov 2020
Jordan M, Mac Kinnon N, Monchois V et al (2018) Intensification of large-scale cell culture processes. Curr Opin Chem Eng 22:253–257. https://doi.org/10.1016/j.coche.2018.11.008
Grün M (2018) Scale-up strategie für eine CHO-Zell-basierte IgG-Produktion (Fed-Batch) in gerührten Single-Use Bioreaktoren. Master thesis, Zürcher Hochschule für Angewandte Wissenschaften
Yang WC, Minkler DF, Kshirsagar R et al (2016) Concentrated fed-batch cell culture increases manufacturing capacity without additional volumetric capacity. J Biotechnol 217:1–11. https://doi.org/10.1016/j.jbiotec.2015.10.009
Fenge C, Weyand J, Greller G, Adams T (2018) Large-scale perfusion and concentrated fed-batch operation of BIOSTAT ® STR single-use bioreactor. Appl. Note. https://www.sartorius.com/resource/blob/11984/8e3d506edce9939b03efd4e2352d7e6b/appl-large-scale-perfusion-sbt1018-e-data.pdf. Accessed 10 Nov 2020
Warikoo V, Godawat R, Brower K et al (2012) Integrated continuous production of recombinant therapeutic proteins. Biotechnol Bioeng 109:3018–3029. https://doi.org/10.1002/bit.24584
Zijlstra G, Touw K, Koch M, Monge M (2019) Design considerations towards an intensified single-use facility. In: Eibl R, Eibl D (eds) Single-use technology in biopharmaceutical manufacture, 2nd edn. Wiley, Hoboken, pp 181–192
Chon JH, Zarbis-Papastoitsis G (2011) Advances in the production and downstream processing of antibodies. New Biotechnol 28:458–463. https://doi.org/10.1016/j.nbt.2011.03.015
Butler M, Meneses-Acosta A (2012) Recent advances in technology supporting biopharmaceutical production from mammalian cells. Appl Microbiol Biotechnol 96:885–894. https://doi.org/10.1007/s00253-012-4451-z
Zijlstra GM, Hof RP, Schilder J (2006) Improved process for the culturing of cells. Patent WO2008006494A1, 14 July 2006
Ramos-de-la-Peña AM, González-Valdez J, Aguilar O (2019) Protein a chromatography: challenges and progress in the purification of monoclonal antibodies. J Sep Sci 42:1816–1827. https://doi.org/10.1002/jssc.201800963
Zarrineh M, Mashhadi IS, Farhadpour M, Ghassempour A (2020) Mechanism of antibodies purification by protein a. Anal Biochem 609:113909. https://doi.org/10.1016/j.ab.2020.113909
Gao Z-Y, Zhang Q-L, Shi C et al (2020) Antibody capture with twin-column continuous chromatography: effects of residence time, protein concentration and resin. Sep Purif Technol 253:117554. https://doi.org/10.1016/j.seppur.2020.117554
Hilbold N-J, Le Saoût X, Valery E et al (2017) Evaluation of several protein a resins for application to multicolumn chromatography for the rapid purification of fed-batch bioreactors. Biotechnol Prog 33:941–953. https://doi.org/10.1002/btpr.2465
Nadar S, Shooter G, Somasundaram B et al (2020) Intensified downstream processing of monoclonal antibodies using membrane technology. Biotechnol J:2000309. https://doi.org/10.1002/biot.202000309
Follman DK, Fahrner RL (2004) Factorial screening of antibody purification processes using three chromatography steps without protein A. J Chromatogr A 1024:79–85. https://doi.org/10.1016/j.chroma.2003.10.060
Lain B, Cacciuttolo M, Zarbis-Papastoitsis G (2009) Development of a high-capacity MAb capture step based on cation-exchange chromatography. Bioprocess Int 7:26–34
Hammerschmidt N, Tscheliessnig A, Sommer R et al (2014) Economics of recombinant antibody production processes at various scales: industry-standard compared to continuous precipitation. Biotechnol J 9:766–775. https://doi.org/10.1002/biot.201300480
Gronemeyer P, Ditz R, Strube J (2014) Trends in upstream and downstream process development for antibody manufacturing. Bioengineering 1:188–212. https://doi.org/10.3390/bioengineering1040188
Kateja N, Agarwal H, Saraswat A et al (2016) Continuous precipitation of process related impurities from clarified cell culture supernatant using a novel coiled flow inversion reactor (CFIR). Biotechnol J 11:1320–1331. https://doi.org/10.1002/biot.201600271
Martinez M, Spitali M, Norrant EL, Bracewell DG (2019) Precipitation as an enabling technology for the intensification of biopharmaceutical manufacture. Trends Biotechnol 37:237–241. https://doi.org/10.1016/j.tibtech.2018.09.001
Smejkal B, Agrawal NJ, Helk B et al (2013) Fast and scalable purification of a therapeutic full-length antibody based on process crystallization. Biotechnol Bioeng 110:2452–2461. https://doi.org/10.1002/bit.24908
Rosa PAJ, Azevedo AM, Ferreira IF et al (2007) Affinity partitioning of human antibodies in aqueous two-phase systems. J Chromatogr A 1162:103–113. https://doi.org/10.1016/j.chroma.2007.03.067
Kruse T, Kampmann M, Rüddel I, Greller G (2020) An alternative downstream process based on aqueous two-phase extraction for the purification of monoclonal antibodies. Biochem Eng J 161:107703. https://doi.org/10.1016/j.bej.2020.107703
Boi C (2019) Membrane chromatography for biomolecule purification. In: Basile A, Charcosset C (eds) Current trends and future developments on (Bio-) membranes. Elsevier, Amsterdam/Oxford/Cambridge, pp 151–166
Mothes B, Pezzini J, Schroeder-Tittmann K, Villain L (2016) Accelerated, seamless antibody purification: process intensification with continuous disposable technology. BioProcess Int 14:34–58
Weaver J, Husson SM, Murphy L, Wickramasinghe SR (2013) Anion exchange membrane adsorbers for flow-through polishing steps: part II. Virus, host cell protein, DNA clearance, and antibody recovery. Biotechnol Bioeng 110:500–510. https://doi.org/10.1002/bit.24724
Jacquemart R, Stout J (2017) Membrane adsorbers, columns: single-use alternatives to resin chromatography. Bioprocess Int 14:18–19
Lim JAC, Sinclair A, Kim DS, Gottschalk U (2007) Economic benefits of single-use membrane chromatography in polishing – a cost of goods model. Bioprocess Int 5:60–64
Bisschops M, Schofield M, Grace J (2017) Two mutually enabling trends: continuous bioprocessing and single-use technologies. In: Subramanian G (ed) Continuous biomanufacturing – innovative technologies and methods. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, pp 149–170
Zhang K, Liu X (2016) Mixed-mode chromatography in pharmaceutical and biopharmaceutical applications. J Pharm Biomed Anal 128:73–88. https://doi.org/10.1016/j.jpba.2016.05.007
Saufi SM, Fee CJ (2012) Preparation of multiple interaction membrane chromatography using mixed matrix membrane preparation concept. Procedia Eng 44:133–135. https://doi.org/10.1016/j.proeng.2012.08.335
Freitag R, Splitt H, Reif OW (1996) Controlled mixed-mode interaction chromatography on membrane adsorbers. J Chromatogr A 728:129–137. https://doi.org/10.1016/0021-9673(95)01024-6
Casey C, Rogler K, Gjoka X et al (2016) Cadence™ Single-pass TFF Coupled with Chromatography Steps Enables Continuous Bioprocessing while Reducing Processing Times and Volumes. In: Am Pharm Rev. https://www.americanpharmaceuticalreview.com/Featured-Articles/239951-Cadence-Single-pass-TFF-Coupled-with-Chromatography-Steps-Enables-Continuous-Bioprocessing-while-Reducing-Processing-Times-and-Volumes/. Accessed 12 Nov 2020
Kossik J (2002) Think small: pharmaceutical facilities could boost capacity and slash costs by trading in certain batch operations for continuous versions. In: Pharma Manuf. https://www.pharmamanufacturing.com/articles/2002/6/. Accessed 13 Nov 2020
Stanton D (2019) Up titer: WuXi breaks 50g/L with continuous CHO process. In: Bioprocess Int. https://bioprocessintl.com/bioprocess-insider/upstream-downstream-processing/up-titer-wuxi-breaks-50g-l-with-continuous-cho-process/. Accessed 2 Nov 2020
Yu L (2016) Continuous manufacturing has a strong impact on drug quality. In: FDA voice. https://www.pharmaceuticalprocessingworld.com/continuous-manufacturing-has-a-strong-impact-on-drug-quality/. Accessed 13 Nov 2020
U.S. Food and Drug Administration (2004) PAT—a framework for innovative pharmaceutical development, manufacturing, and quality assurance. https://www.fda.gov/node/379301. Accessed 13 Nov 2020
Arnold L, Lee K, Rucker-Pezzini J, Lee JH (2019) Implementation of fully integrated continuous antibody processing: effects on productivity and COGm. Biotechnol J 14:1800061. https://doi.org/10.1002/biot.201800061
Genengnews (2020) First mAb produced via fully continuous biomanufacturing. https://www.genengnews.com/news/first-mab-produced-via-fully-continuous-biomanufacturing/. Accessed 7 Nov 2020
Biosimilar Development (2020) BiosanaPharma announces successful outcome of comparative Phase I Study of BP001 A Biosimilar Candidate To Xolair (omalizumab). https://www.biosimilardevelopment.com/doc/biosanapharma-announces-successful-phase-i-study-of-bp-a-biosimilar-xolair-omalizumab-0001. Accessed 13 Nov 2020
Bonham-Carter J, Shevitz J (2011) A brief history of perfusion biomanufacturing. Bioprocess Int 9:24–28
Bayer M, Castan A, Eibl R et al (2020) Technical state-of-the-art and risk analysis on single-use equipment in continuous processing steps. DECHEMA, Frankfurt a.M. ISBN 978-3-89746-226-7
Thermo Fisher Scientific Inc. (2020) HyPerforma DynaDrive single-use bioreactor (S.U.B.). https://assets.thermofisher.com/TFS-Assets/BPD/brochures/dynadrive-sub-brochure.pdf. Accessed 10 Nov 2020
Walther J, Godawat R, Hwang C et al (2015) The business impact of an integrated continuous biomanufacturing platform for recombinant protein production. J Biotechnol 213:3–12. https://doi.org/10.1016/j.jbiotec.2015.05.010
Hummel J, Pagkaliwangan M, Gjoka X et al (2019) Modeling the downstream processing of monoclonal antibodies reveals cost advantages for continuous methods for a broad range of manufacturing scales. Biotechnol J 14:1700665. https://doi.org/10.1002/biot.201700665
Steinebach F, Müller-Späth T, Morbidelli M (2016) Continuous counter-current chromatography for capture and polishing steps in biopharmaceutical production. Biotechnol J 11:1126–1141. https://doi.org/10.1002/biot.201500354
Ötes O, Flato H, Vazquez Ramirez D et al (2018) Scale-up of continuous multicolumn chromatography for the protein a capture step: from bench to clinical manufacturing. J Biotechnol 281:168–174. https://doi.org/10.1016/j.jbiotec.2018.07.022
Ichihara T, Ito T, Kurisu Y et al (2018) Integrated flow-through purification for therapeutic monoclonal antibodies processing. MAbs 10:325–334. https://doi.org/10.1080/19420862.2017.1417717
Yoshimoto N, Hasegawa S, Yamamoto S (2019) A method for designing flow-through chromatography processes. MATEC Web Conf 268:01004. https://doi.org/10.1051/matecconf/201926801004
Gupte P, Gavasane M, Samagod A et al (2018) Establishing effective high-throughput contaminant removal with membrane chromatography. Bioprocess Int 16:60–63
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (1999) Viral Safety Evaluation of Bbiotechnology Products Derived from Cell Lines of Human or Animal Origin Q5A(R1). www.ich.org
Parker SA, Amarikwa L, Vehar K et al (2018) Design of a novel continuous flow reactor for low pH viral inactivation. Biotechnol Bioeng 115:606–616. https://doi.org/10.1002/bit.26497
Klutz S, Lobedann M, Bramsiepe C, Schembecker G (2016) Continuous viral inactivation at low pH value in antibody manufacturing. Chem Eng Process Process Intensif 102:88–101. https://doi.org/10.1016/j.cep.2016.01.002
Kavara A, Sokolowski D, Collins M, Schofield M (2020) Recent advances in continuous downstream processing of antibodies and related products. In: Matte A (ed) Approaches to the purification, analysis and characterization of antibody-based therapeutics. Elsevier, Amsterdam/Oxford/Cambridge, pp 81–103
Lute S, Kozaili J, Johnson S et al (2020) Development of small-scale models to understand the impact of continuous downstream bioprocessing on integrated virus filtration. Biotechnol Prog 36:e2962. https://doi.org/10.1002/btpr.2962
Bohonak D, Mehta U, Weiss ER, Voyta G (2020) Adapting virus filtration to enable intensified and continuous mAb processing. Biotechnol Prog. https://doi.org/10.1002/btpr.3088
Klutz S, Magnus J, Lobedann M et al (2015) Developing the biofacility of the future based on continuous processing and single-use technology. J Biotechnol 213:120–130. https://doi.org/10.1016/j.jbiotec.2015.06.388
David L, Niklas J, Budde B et al (2019) Continuous viral filtration for the production of monoclonal antibodies. Chem Eng Res Des 152:336–347. https://doi.org/10.1016/j.cherd.2019.09.040
Yehl CJ, Zydney AL (2020) Single-use, single-pass tangential flow filtration using low-cost hollow fiber modules. J Memb Sci 595:117517. https://doi.org/10.1016/j.memsci.2019.117517
Casey C, Gallos T, Alekseev Y et al (2011) Protein concentration with single-pass tangential flow filtration (SPTFF). J Memb Sci 384:82–88. https://doi.org/10.1016/j.memsci.2011.09.004
BioPharm International Editors (2017) Pall debuts new inline diafiltration modules for continuous bioprocessing. In: BioPharm Int. https://www.biopharminternational.com/view/pall-debuts-new-inline-diafiltration-modules-continuous-bioprocessing-0. Accessed 8 Nov 2020
Nambiar AMK, Li Y, Zydney AL (2018) Countercurrent staged diafiltration for formulation of high value proteins. Biotechnol Bioeng 115:139–144. https://doi.org/10.1002/bit.26441
Yang O, Qadan M, Ierapetritou M (2020) Economic analysis of batch and continuous biopharmaceutical antibody production: a review. J Pharm Innov 15:182–200
Yang O, Prabhu S, Ierapetritou M (2019) Comparison between batch and continuous monoclonal antibody production and economic analysis. Ind Eng Chem Res 58:5851–5863. https://doi.org/10.1021/acs.iecr.8b04717
Jacquemart R, Vandersluis M, Zhao M et al (2016) A single-use strategy to enable manufacturing of affordable biologics. Comput Struct Biotechnol J 14:309–318. https://doi.org/10.1016/j.csbj.2016.06.007
Brower M, Hou Y, Pollard D (2014) Monoclonal antibody continuous processing enabled by single use. In: Subramanian G (ed) Continuous processing in pharmaceutical manufacturing. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, pp 255–296
Pollard D, Brower M, Abe Y et al (2016) Standardized economic cost modeling for next-generation MAb production. Bioprocess Int 14:14–23
Kornecki M, Schmidt A, Lohmann L et al (2019) Accelerating biomanufacturing by modeling of continuous bioprocessing—piloting case study of monoclonal antibody manufacturing. PRO 7:495. https://doi.org/10.3390/pr7080495
Acknowledgment
We would like to thank Nina Steffen and Maren Grün for their support in generating the data of our intensified mAb productions at laboratory scale.
Conflict of Interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2021 The Author(s), under exclusive license to Springer Nature Switzerland AG
About this chapter
Cite this chapter
Müller, J. et al. (2021). Intensified and Continuous mAb Production with Single-Use Systems. In: Pörtner, R. (eds) Cell Culture Engineering and Technology. Cell Engineering, vol 10. Springer, Cham. https://doi.org/10.1007/978-3-030-79871-0_13
Download citation
DOI: https://doi.org/10.1007/978-3-030-79871-0_13
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-79870-3
Online ISBN: 978-3-030-79871-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)