Economic Analysis of Batch and Continuous Biopharmaceutical Antibody Production: a Review



There is a growing interest in continuous biopharmaceutical processing due to the advantages of small footprint, increased productivity, consistent product quality, high process flexibility and robustness, facility cost-effectiveness, and reduced capital and operating cost. To support the decision making of biopharmaceutical manufacturing, comparisons between conventional batch and continuous processing are provided.


Various process unit operations in different operating modes are summarized. Software implementation as well as computational methods used are analyzed pointing to the advantages and disadvantages that have been highlighted in the literature. Economic analysis methods and their applications in different parts of the processes are also discussed with examples from publications in the last decade.


The results of the comparison between batch and continuous process operation alternatives are discussed. Possible improvements in process design and analysis are recommended. The methods used here do not reflect Lilly’s cost structures or economic evaluation methods.


This paper provides a review of the work that has been published in the literature on computational process design and economic analysis methods on continuous biopharmaceutical antibody production and its comparison with a conventional batch process.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4


  1. 1.

    Newswire PR. Monoclonal antibodies (mAbs) market analysis by source (chimeric, murine, humanized, human), by type of production, by indication (cancer, autoimmune, inflammatory, infectious, microbial, viral diseases), by end-use and segment forecasts, 2013–2024. LON-Reportbuyer: Y; 2017.

  2. 2.

    Gjoka X, Gantier R, Schofield M. Transfer of a three step mAb chromatography process from batch to continuous: optimizing productivity to minimize consumable requirements. J Biotechnol. 2017;242:11–8.

    Article  PubMed  CAS  Google Scholar 

  3. 3.

    Gjoka X, Rogler K, Martino RA, Gantier R, Schofield M. A straightforward methodology for designing continuous monoclonal antibody capture multi-column chromatography processes. J Chromatogr A. 2015;1416:38–46.

    Article  PubMed  CAS  Google Scholar 

  4. 4.

    Ng CKS, Rousset F, Valery E, Bracewell DG, Sorensen E. Design of high productivity sequential multi-column chromatography for antibody capture. Food Bioprod Process. 2014;92(C2):233–41.

    Article  CAS  Google Scholar 

  5. 5.

    America PRaMo. Medicines in development: biologics 2013 report. Pharmaceutical Research and Manufacturers of America. 2013. Accessed 01 June 2018.

  6. 6.

    Ecker DM, Jones SD, Levine HL. The therapeutic monoclonal antibody market. Mabs-Austin. 2015;7(1):9–14.

    Article  CAS  Google Scholar 

  7. 7.

    Newswire PR. Monoclonal antibodies (mAbs) market Size worth $138.6 billion by 2024: grand view research, Inc. bc-Grand-View-Research: Y; 2016.

  8. 8.

    Gronemeyer P, Ditz R, Strube J. Trends in upstream and downstream process development for antibody manufacturing. Bioengineering. 2014;1(4):188–212.

    Article  PubMed  CAS  Google Scholar 

  9. 9.

    Zydney AL. Continuous downstream processing for high value biological products: a review. Biotechnol Bioeng. 2016;113(3):465–75.

    Article  CAS  Google Scholar 

  10. 10.

    Whitford WG. Single-use systems support continuous bioprocessing by perfusion culture. In: Subramanian G, editor. Continuous processing in pharmaceutical manufacturing. 2014, .

    Google Scholar 

  11. 11.

    Godawat R, Konstantinov K, Rohani M, Warikoo V. End-to-end integrated fully continuous production of recombinant monoclonal antibodies. J Biotechnol. 2015;213:13–9.

    Article  PubMed  CAS  Google Scholar 

  12. 12.

    Taracena FL. An economic analysis for product and process design. Qual Eng. 2006;18(1):33–7.

    Article  Google Scholar 

  13. 13.

    Farid SS. Process economics of industrial monoclonal antibody manufacture. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;848(1):8–18.

    Article  PubMed  CAS  Google Scholar 

  14. 14.

    Farid SS, Pollock J, Ho SV. Evaluating the economic and operational feasibility of continuous processes for monoclonal antibodies. Continuous Processing in Pharmaceutical Manufacturing. Wiley-VCH Verlag GmbH & Co. KGaA; 2014;433–56.

    Google Scholar 

  15. 15.

    Torres-Acosta MA, Ruiz-Ruiz F, Benavides J, Rito-Palomares M. Process economics: evaluation of the potential of ATPS as a feasible alternative to traditional fractionation techniques. Food Eng Ser. 2017;1:161–78.

    Article  Google Scholar 

  16. 16.

    Xu S, Gavin J, Jiang R, Chen H. Bioreactor productivity and media cost comparison for different intensified cell culture processes. Biotechnol Prog. 2016;33:867–78.

    Article  CAS  Google Scholar 

  17. 17.

    Pollock J, Coffman J, Ho SV, Farid SS. Integrated continuous bioprocessing: economic, operational, and environmental feasibility for clinical and commercial antibody manufacture. Biotechnol Prog. 2017;33:854–66.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. 18.

    Hammerschmidt N, Tscheliessnig A, Sommer R, Helk B, Jungbauer A. Economics of recombinant antibody production processes at various scales: industry-standard compared to continuous precipitation. Biotechnol J. 2014;9(6):766–75.

    Article  PubMed  CAS  Google Scholar 

  19. 19.

    Walther J, Godawat R, Hwang C, Abe Y, Sinclair A, Konstantinov K. The business impact of an integrated continuous biomanufacturing platform for recombinant protein production. J Biotechnol. 2015;213:3–12.

    Article  PubMed  CAS  Google Scholar 

  20. 20.

    Bunnak P, Allmendinger R, Ramasamy SV, Lettieri P, Titchener-Hooker NJ. Life-cycle and cost of goods assessment of fed-batch and perfusion-based manufacturing processes for mAbs. Biotechnol Prog. 2016;32(5):1324–35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. 21.

    Pollock J, Ho SV, Farid SS. Fed-batch and perfusion culture processes: economic, environmental, and operational feasibility under uncertainty. Biotechnol Bioeng. 2013;110(1):206–19.

    Article  PubMed  CAS  Google Scholar 

  22. 22.

    Petrides D. Bioprocess design and economics. In: Roger G. Harrison PWT, Scott R. Rudge and Demetri P. Petrides, editor. Bioseparations Science and Engineering 2ed., 2015.

  23. 23.

    Chatterjee S, editor. FDA perspective on continuous manufacturing. IFPAC Annual Meeting; 2012; Baltimore: FDA U.S. Food and Drug Administration Protecting and Promoting Public Health.

  24. 24.

    Jain E, Kumar A. Upstream processes in antibody production: evaluation of critical parameters. Biotechnol Adv. 2008;26(1):46–72.

    Article  PubMed  CAS  Google Scholar 

  25. 25.

    Novais JL, Titchener-Hooker NJ, Hoare M. Economic comparison between conventional and disposables-based technology for the production of biopharmaceuticals. Biotechnol Bioeng. 2001;75(2):143–53.

    Article  CAS  Google Scholar 

  26. 26.

    Hutterer KM, Hong RW, Lull J, Zhao X, Wang T, Pei R, et al. Monoclonal antibody disulfide reduction during manufacturing: untangling process effects from product effects. Mabs-Austin. 2013;5(4):608–13.

    Article  Google Scholar 

  27. 27.

    Liu HF, Ma J, Winter C, Bayer R. Recovery and purification process development for monoclonal antibody production. Mabs-Austin. 2010;2(5):480–99.

    Article  Google Scholar 

  28. 28.

    Jungbauer A. Continuous downstream processing of biopharmaceuticals. Trends Biotechnol. 2013;31(8):479–92.

    Article  PubMed  CAS  Google Scholar 

  29. 29.

    Kelley B. Industrialization of mAb production technology: the bioprocessing industry at a crossroads. Mabs-Austin. 2009;1(5):443–52.

    Article  Google Scholar 

  30. 30.

    Yang WC, Minkler DF, Kshirsagar R, Ryll T, Huang Y-M. Concentrated fed-batch cell culture increases manufacturing capacity without additional volumetric capacity. J Biotechnol. 2016;217:1–11.

    Article  PubMed  CAS  Google Scholar 

  31. 31.

    Patil R, Walther J. Continuous manufacturing of recombinant therapeutic proteins: upstream and downstream technologies. Adv Biochem Eng Biotechnol. 2017.

    Google Scholar 

  32. 32.

    Arunkumar A, Singh N, Peck M, Borys MC, Li ZJ. Investigation of single-pass tangential flow filtration (SPTFF) as an inline concentration step for cell culture harvest. J Membrane Sci. 2017;524:20–32.

    Article  CAS  Google Scholar 

  33. 33.

    Clincke MF, Molleryd C, Zhang Y, Lindskog E, Walsh K, Chotteau V. 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. 2013;29(3):754–67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. 34.

    Bielser JM, Wolf M, Souquet J, Broly H, Morbidelli M. Perfusion mammalian cell culture for recombinant protein manufacturing—a critical review. Biotechnol Adv. 2018;36(4):1328–40.

    Article  PubMed  CAS  Google Scholar 

  35. 35.

    Xenopoulos A. A new, integrated, continuous purification process template for monoclonal antibodies: process modeling and cost of goods studies. J Biotechnol. 2015;213:42–53.

    Article  PubMed  CAS  Google Scholar 

  36. 36.

    Eggersgluess JK, Richter M, Dieterle M, Strube J. Multi-stage aqueous two-phase extraction for the purification of monoclonal antibodies. Chem Eng Technol. 2014;37(4):675–82.

    Article  CAS  Google Scholar 

  37. 37.

    Schmidt A, Richter M, Rudolph F, Strube J. Integration of aqueous two-phase extraction as cell harvest and capture operation in the manufacturing process of monoclonal antibodies. Antibodies. 2017;6(4):21.

    Article  PubMed Central  CAS  Google Scholar 

  38. 38.

    Gonzalez-Valdez J, Mayolo-Deloisa K, Rito-Palomares M. Novel aspects and future trends in the use of aqueous two-phase systems as a bioengineering tool. J Chem Technol Biot. 2018;93(7):1836–44.

    Article  CAS  Google Scholar 

  39. 39.

    Torres-Acosta MA, Mayolo-Deloisa K, González-Valdez J, Rito-Palomares M. Aqueous two-phase systems at large scale: challenges and opportunities. Biotechnol J. 0(0):1800117.

    Article  CAS  Google Scholar 

  40. 40.

    Godawat R, Brower K, Jain S, Konstantinov K, Riske F, Warikoo V. Periodic counter-current chromatography—design and operational considerations for integrated and continuous purification of proteins. Biotechnol J. 2012;7(12):1496–508.

    Article  PubMed  CAS  Google Scholar 

  41. 41.

    Dutta AK, Tan J, Napadensky B, Zydney AL, Shinkazh O. Performance optimization of continuous countercurrent tangential chromatography for antibody capture. Biotechnol Prog. 2016;32(2):430–9.

    Article  PubMed  CAS  Google Scholar 

  42. 42.

    Napadensky B, Shinkazh O, Teella A, Zydney AL. Continuous countercurrent tangential chromatography for monoclonal antibody purification. Sep Sci Technol. 2013;48(9):1289–97.

    Article  CAS  Google Scholar 

  43. 43.

    Shinkazh O, inventor Countercurrent tangential chromatography methods, systems, and apparatus. US2011.

  44. 44.

    Shinkazh O, Kanani D, Barth M, Long M, Hussain D, Zydney AL. Countercurrent tangential chromatography for large-scale protein purification. Biotechnol Bioeng. 2011;108(3):582–91.

    Article  PubMed  CAS  Google Scholar 

  45. 45.

    Espitia-Saloma E, Vazquez-Villegas P, Aguilar O, Rito-Palomares M. Continuous aqueous two-phase systems devices for the recovery of biological products. Food Bioprod Process. 2014;92(C2):101–12.

    Article  CAS  Google Scholar 

  46. 46.

    Rosa PAJ, Azevedo AM, Sommerfeld S, Bäcker W, Aires-Barros MR. Continuous aqueous two-phase extraction of human antibodies using a packed column. J Chromatogr B. 2012;880(Supplement C):148–56.

    Article  CAS  Google Scholar 

  47. 47.

    Ransohoff TC. Bisschops MAT. Google Patents: Continuous processing methods for biological products; 2013.

    Google Scholar 

  48. 48.

    Coffman J, Goby J, Godfrey S, Orozco R, Vogel JH. Methods, apparatuses, and systems for continuously inactivating a virus during manufacture of a biological product. Google Patents; 2017.

  49. 49.

    Klutz S, Lobedann M, Bramsiepe C, Schembecker G. Continuous viral inactivation at low pH value in antibody manufacturing. Chem Eng Process: Process Intensif. 2016;102(Supplement C):88–101.

    Article  CAS  Google Scholar 

  50. 50.

    Orozco R, Godfrey S, Coffman J, Amarikwa L, Parker S, Hernandez L, et al. Design, construction, and optimization of a novel, modular, and scalable incubation chamber for continuous viral inactivation. Biotechnol Prog. 2017;33(4):954–65.

    Article  PubMed  CAS  Google Scholar 

  51. 51.

    Steinebach F, Muller-Spath T, Morbidelli M. Continuous counter-current chromatography for capture and polishing steps in biopharmaceutical production. Biotechnol J. 2016;11(9):1126–41.

    Article  PubMed  CAS  Google Scholar 

  52. 52.

    Rucker-Pezzini J, Arnold L, Hill-Byrne K, Sharp T, Avazhanskiy M, Forespring C. Single pass diafiltration integrated into a fully continuous mAb purification process. Biotechnol Bioeng. 2018;115(8):1949–57.

    Article  PubMed  CAS  Google Scholar 

  53. 53.

    Nambiar AMK, Li Y, Zydney AL. Countercurrent staged diafiltration for formulation of high value proteins. Biotechnol Bioeng. 2018;115(1):139–44.

    Article  PubMed  CAS  Google Scholar 

  54. 54.

    Kateja N, Kumar D, Sethi S, Rathore AS. Non-protein A purification platform for continuous processing of monoclonal antibody therapeutics. J Chromatogr A. 2018;1579:60–72.

    Article  PubMed  CAS  Google Scholar 

  55. 55.

    Somasundaram B, Pleitt K, Shave E, Baker K, Lua LHL. Progression of continuous downstream processing of monoclonal antibodies: current trends and challenges. Biotechnol Bioeng. 2018;115:2893–907.

    Article  PubMed  CAS  Google Scholar 

  56. 56.

    Rathore AS, Kateja N, Kumar D. Process integration and control in continuous bioprocessing. Curr Opin Chem Eng. 2018;22:18–25.

    Article  Google Scholar 

  57. 57.

    Flickinger MC. Upstream industrial biotechnology. John Wiley & Sons.

  58. 58.

    Castilho LR. Continuous animal cell perfusion processes: the first step toward integrated continuous biomanufacturing. In: Subramanian G, editor. Continuous Processing in Pharmaceutical Manufacturing 2015.

  59. 59.

    Lee R, Mikol V, Allen E, Ruetsch N, Cameron B, Oligino T et al. Humanized anti-CXCR5 antibodies, derivatives thereof and their use. Google Patents; 2011.

  60. 60.

    Jozala AF, Geraldes DC, Tundisi LL, Feitosa VD, Breyer CA, Cardoso SL, et al. Biopharmaceuticals from microorganisms: from production to purification. Braz J Microbiol. 2016;47:51–63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. 61.

    Pollock J, Bolton G, Coffman J, Ho SV, Bracewell DG, Farid SS. Optimising the design and operation of semi-continuous affinity chromatography for clinical and commercial manufacture. J Chromatogr A. 2013;1284:17–27.

    Article  PubMed  CAS  Google Scholar 

  62. 62.

    Liu S, Simaria AS, Farid SS, Papageorgiou LG. Designing cost-effective biopharmaceutical facilities using mixed-integer optimization. Biotechnol Prog. 2013;29(6):1472–83.

    Article  PubMed  CAS  Google Scholar 

  63. 63.

    Li YF, Venkatasubramanian V. Integrating design of experiments and principal component analysis to reduce downstream cost of goods in monoclonal antibody production. J Pharm Innov. 2016;11(4):352–61.

    Article  Google Scholar 

  64. 64.

    Klutz S, Holtmann L, Lobedann M, Schembecker G. Cost evaluation of antibody production processes in different operation modes. Chem Eng Sci. 2016;141:63–74.

    Article  CAS  Google Scholar 

  65. 65.

    Torres-Acosta MA, Aguilar-Yanez JM, Rito-Palomares M, Titchener-Hooker NJ. Economic analysis of uricase production under uncertainty: contrast of chromatographic purification and aqueous two-phase extraction (with and without PEG recycle). Biotechnol Prog. 2016;32(1):126–33.

    Article  PubMed  CAS  Google Scholar 

  66. 66.

    Liu S, Farid SS, Papageorgiou LG. Integrated optimization of upstream and downstream processing in biopharmaceutical manufacturing under uncertainty: a chance constrained programming approach. Ind Eng Chem Res. 2016;55(16):4599–612.

    Article  CAS  Google Scholar 

  67. 67.

    Arnold L, Lee K, Rucker-Pezzini J, Lee JH. Implementation of fully integrated continuous antibody processing: effects on productivity and COGm. Biotechnol J. 2018.

    Article  CAS  Google Scholar 

  68. 68.

    Hummel J, Pagkaliwangan M, Gjoka X, Davidovits T, Stock R, Ransohoff T, et al. Modeling the downstream processing of monoclonal antibodies reveals cost advantages for continuous methods for a broad range of manufacturing scales. Biotechnol J. 2018.

    Article  CAS  Google Scholar 

  69. 69.

    Grilo AL, Mateus M, Aires-Barros MR, Azevedo AM. Monoclonal antibodies production platforms: an opportunity study of a non-protein-A chromatographic platform based on process economics. Biotechnol J. 2017;12(12).

    Article  CAS  Google Scholar 

  70. 70.

    The biopharmaceutical industry’s leading process analysis and economic modelling package. In: BioSolve Process 7. Biopharm. 2016. Accessed 8/9 2017.

  71. 71.

    Aspentech. Aspen Batch Process Developer Accessed 12/19 2018.

  72. 72.

    Aspentech. Aspen Chromatogrpahy. Accessed 12/19 2018.

  73. 73.

    Ashouri P. A dynamic simulation framework for biopharmaceutical capacity management: University College London; 2011.

    Google Scholar 

  74. 74.

    Sachidananda M, Erkoyuncu J, Steenstra D, Michalska S. Discrete event simulation modelling for dynamic decision making in biopharmaceutical manufacturing. Procedia CIRP. 2016;49:39–44.

    Article  Google Scholar 

  75. 75.

    Towler G, Sinnott RK. Chemical engineering design: principles, practice and economics of plant and process design: Elsevier; 2012.

  76. 76.

    Hernandez I, Bott SW, Patel AS, Wolf CG, Hospodar AR, Sampathkumar S, et al. Pricing of monoclonal antibody therapies: higher if used for cancer? Am J Manag Care. 2018;24(2):109–+.

    PubMed  Google Scholar 

  77. 77.

    Pannell DJ. Sensitivity analysis: strategies, methods, concepts, examples. Agric Econ. 1997;16:139–52.

    Article  Google Scholar 

  78. 78.

    Torres-Acosta MA, Aguilar-Yanez JM, Rito-Palomares M, Titchener-Hooker NJ. Economic analysis of Royalactin production under uncertainty: evaluating the effect of parameter optimization. Biotechnol Prog. 2015;31(3):744–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. 79.

    Vermasvuori R, Hurme M. Economic comparison of diagnostic antibody production in perfusion stirred tank and in hollow fiber bioreactor processes. Biotechnol Prog. 2011;27(6):1588–98.

    Article  PubMed  CAS  Google Scholar 

  80. 80.

    Repligen inspiring advances in bioprocessing. Frequently asked questions—perfusion. Repligen inspiring advances in bioprocessing official web-site. 2017. Accessed 1 June 2018.

  81. 81.

    Konstantinov KB, Cooney CL. White paper on continuous bioprocessing. May 20–21, 2014 continuous manufacturing symposium. J Pharm Sci. 2015;104(3):813–20.

    Article  PubMed  CAS  Google Scholar 

  82. 82.

    Roque ACA, Lowe CR, Taipa MÂ. Antibodies and genetically engineered related molecules: production and purification. Biotechnol Prog. 2004;20(3):639–54.

    Article  CAS  Google Scholar 

  83. 83.

    Azevedo AM, Rosa PAJ, Ferreira IF, Aires-Barros MR. Chromatography-free recovery of biopharmaceuticals through aqueous two-phase processing. Trends Biotechnol. 2009;27(4):240–7.

    Article  PubMed  CAS  Google Scholar 

  84. 84.

    Farid SS. Economic drivers and trade-offs in antibody purification processes. BioPharm International. 2009; 2009(7).

  85. 85.

    Karst DJ, Serra E, Villiger TK, Soos M, Morbidelli M. Characterization and comparison of ATF and TFF in stirred bioreactors for continuous mammalian cell culture processes. Biochem Eng J. 2016;110:17–26.

    Article  CAS  Google Scholar 

  86. 86.

    Espitia-Saloma E, Vazquez-Villegas P, Rito-Palomares M, Aguilar O. An integrated practical implementation of continuous aqueous two-phase systems for the recovery of human IgG: from the microdevice to a multistage bench-scale mixer-settler device. Biotechnol J. 2016;11(5):708–16.

    Article  PubMed  CAS  Google Scholar 

  87. 87.

    Angarita M, Muller-Spath T, Baur D, Lievrouw R, Lissens G, Morbidelli M. Twin-column CaptureSMB: a novel cyclic process for protein A affinity chromatography. J Chromatogr A. 2015;1389:85–95.

    Article  PubMed  CAS  Google Scholar 

  88. 88.

    Varadaraju H, Schneiderman S, Zhang L, Fong H, Menkhaus TJ. Process and economic evaluation for monoclonal antibody purification using a membrane-only process. Biotechnol Prog. 2011;27(5):1297–305.

    Article  PubMed  CAS  Google Scholar 

  89. 89.

    Liu SS, Papageorgiou LG. Multi-objective optimisation for biopharmaceutical manufacturing under uncertainty. Comput Chem Eng. 2018;119:383–93.

    Article  CAS  Google Scholar 

  90. 90.

    Popova D, Stonier A, Pain D, Titchener-Hooker NJ, Farid SS. Integrated economic and experimental framework for screening of primary recovery technologies for high cell density CHO cultures. Biotechnol J. 2016;11(7):899–909.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. 91.

    Torres-Acosta MA, Pereira JFB, Freire MG, Aguilar-Yanez JM, Coutinho JAP, Titchener-Hooker NJ, et al. Economic evaluation of the primary recovery of tetracycline with traditional and novel aqueous two-phase systems. Sep Purif Technol. 2018;203:178–84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. 92.

    Lopes AG. Single-use in the biopharmaceutical industry: a review of current technology impact, challenges and limitations. Food Bioprod Process. 2015;93:98–114.

    Article  Google Scholar 

  93. 93.

    Berthold Boedeker JM. Opportunities and limitations of continuous processing and use of disposables. Am Pharm Rev. 2017.

  94. 94.

    Shukla AA, Gottschalk U. Single-use disposable technologies for biopharmaceutical manufacturing. Trends Biotechnol. 2013;31(3):147–54.

    Article  PubMed  CAS  Google Scholar 

  95. 95.

    Langer ES, Rader RA. Single-use technologies in biopharmaceutical manufacturing: a 10-year review of trends and the future. Engineering in Life Sciences. 2014;14(3):238–43.

    Article  CAS  Google Scholar 

  96. 96.

    Marc Bisschops LF, Scott Fulton, Tom Ransohoff. Single-use, continuous-countercurrent, multicolumn chromatography. BioProcess International. 2009.

  97. 97.

    Michael LaBreck MP. An economic analysis of single—use tangential flow filtration for biopharmaceutical applications. BioProcess International. 2010;2010 Supplement(8).

  98. 98.

    Jacquemart R, Vandersluis M, Zhao MC, Sukhija K, Sidhu N, Stout J. A single-use strategy to enable manufacturing of affordable biologics. Comput Struct Biotec. 2016;14:309–18.

    Article  CAS  Google Scholar 

  99. 99.

    Shirahata H, Hirao M, Sugiyama H. Decision-support method for the choice between single-use and multi-use technologies in sterile drug product manufacturing. J Pharm Innov. 2017;12(1):1–13.

    Article  Google Scholar 

  100. 100.

    Magnus J, Temming M, Schwan P, Micovic J, Lobedam M, Sievers S, editors. A biomanufacturing facility based on continuous processing and single use technology2015.

  101. 101.

    Yang WC, Lu J, Kwiatkowski C, Yuan H, Kshirsagar R, Ryll T, et al. Perfusion seed cultures improve biopharmaceutical fed-batch production capacity and product quality. Biotechnol Prog. 2014;30(3):616–25.

    Article  PubMed  CAS  Google Scholar 

  102. 102.

    Farid SS. Established bioprocesses for producing antibodies as a basis for future planning. In: Hu W-S, editor. Cell Culture Engineering. Berlin, Heidelberg: Springer Berlin Heidelberg; 2006. p. 1–42.

    Google Scholar 

  103. 103.

    Rathore AS, Agarwal H, Sharma AK, Pathak M, Muthukumar S. Continuous processing for production of biopharmaceuticals. Prep Biochem Biotechnol. 2015;45(8):836–49.

    Article  PubMed  CAS  Google Scholar 

  104. 104.

    St Amand MM, Hayes J, Radhakrishnan D, Fernandez J, Meyer B, Robinson AS, et al. Identifying a robust design space for glycosylation during monoclonal antibody production. Biotechnol Prog. 2016;32(5):1149–62.

    Article  PubMed  CAS  Google Scholar 

  105. 105.

    Radhakrishnan D, Robinson AS, Ogunnaike BA. Controlling the glycosylation profile in mAbs using time-dependent media supplementation. Antibodies. 2018;7(1):1.

    Article  CAS  Google Scholar 

  106. 106.

    Ogonah OW, Polizzi KM, Bracewell DG. Cell free protein synthesis: a viable option for stratified medicines manufacturing? Curr Opin Chem Eng. 2017;18:77–83.

    Article  Google Scholar 

  107. 107.

    Stech M, Kubick S. Cell-free synthesis meets antibody production: a review. Antibodies. 2015;4(1):12–33.

    Article  CAS  Google Scholar 

  108. 108.

    Martin RW, Majewska NI, Chen CX, Albanetti TE, Jimenez RBC, Schmelzer AE, et al. Development of a CHO-based cell-free platform for synthesis of active monoclonal antibodies. ACS Synth Biol. 2017;6(7):1370–9.

    Article  PubMed  CAS  Google Scholar 

  109. 109.

    Shirokov VA, Simonenko PN, Biryukov SV, Spirin AS. Continuous-flow and continuous-exchange cell-free translation systems and reactors. In: Spirin AS, editor. Cell-free translation systems. Berlin, Heidelberg: Springer Berlin Heidelberg; 2002. p. 91–107.

    Google Scholar 

  110. 110.

    Stech M, Nikolaeva O, Thoring L, Stocklein WFM, Wustenhagen DA, Hust M, et al. Cell-free synthesis of functional antibodies using a coupled in vitro transcription-translation system based on CHO cell lysates. Sci Rep-Uk. 2017;7:12030.

    Article  CAS  Google Scholar 

  111. 111.

    Dutta AK, Tran T, Napadensky B, Teella A, Brookhart G, Ropp PA, et al. Purification of monoclonal antibodies from clarified cell culture fluid using Protein A capture continuous countercurrent tangential chromatography. J Biotechnol. 2015;213:54–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. 112.

    Dutta AK, Fedorenko D, Tan J, Costanzo JA, Kahn DS, Zydney AL, et al. Continuous countercurrent tangential chromatography for mixed mode post-capture operations in monoclonal antibody purification. J Chromatogr A. 2017;1511:37–44.

    Article  PubMed  CAS  Google Scholar 

  113. 113.

    Rosa PA, Azevedo AM, Sommerfeld S, Mutter M, Backer W, Aires-Barros MR. Continuous purification of antibodies from cell culture supernatant with aqueous two-phase systems: from concept to process. Biotechnol J. 2013;8(3):352–62.

    Article  PubMed  CAS  Google Scholar 

  114. 114.

    Rosa PAJ, Azevedo AM, Sommerfeld S, Bäcker W, Aires-Barros MR. Aqueous two-phase extraction as a platform in the biomanufacturing industry: economical and environmental sustainability. Biotechnol Adv. 2011;29(6):559–67.

    Article  PubMed  CAS  Google Scholar 

  115. 115.

    Rosa PAJ, Ferreira IF, Azevedo AM, Aires-Barros MR. Aqueous two-phase systems: a viable platform in the manufacturing of biopharmaceuticals. J Chromatogr A. 2010;1217(16):2296–305.

    Article  PubMed  CAS  Google Scholar 

  116. 116.

    Fisher AC, Kamga MH, Agarabi C, Brorson K, Lee SL, Yoon S. The current scientific and regulatory landscape in advancing integrated continuous biopharmaceutical manufacturing. Trends Biotechnol. 2018.

    Article  CAS  Google Scholar 

  117. 117.

    Fisher AC, Lee SL, Harris DP, Buhse L, Kozlowski S, Yu L, et al. Advancing pharmaceutical quality: an overview of science and research in the U.S. FDA’s Office of Pharmaceutical Quality. Int J Pharm. 2016;515(1–2):390–402.

    Article  PubMed  CAS  Google Scholar 

  118. 118.

    Raftery JP, DeSessa MR, Karim MN. Economic improvement of continuous pharmaceutical production via the optimal control of a multifeed bioreactor. Biotechnol Prog. 2017;33(4):902–12.

    Article  PubMed  CAS  Google Scholar 

Download references


This work was supported by Eli Lilly and company.

Author information



Corresponding author

Correspondence to Marianthi Ierapetritou.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yang, O., Qadan, M. & Ierapetritou, M. Economic Analysis of Batch and Continuous Biopharmaceutical Antibody Production: a Review. J Pharm Innov 15, 182–200 (2020).

Download citation


  • Economic analysis
  • Batch and continuous biopharmaceutical manufacturing
  • Antibody production
  • Simulation software