Skip to main content
SpringerLink
Log in
Book cover

New Bioprocessing Strategies: Development and Manufacturing of Recombinant Antibodies and Proteins pp 401–441Cite as

High-Throughput Process Development for Biopharmaceuticals

  • Chapter
  • First Online:

Part of the book series: Advances in Biochemical Engineering/Biotechnology ((ABE,volume 165))

Abstract

The ability to conduct multiple experiments in parallel significantly reduces the time that it takes to develop a manufacturing process for a biopharmaceutical. This is particularly significant before clinical entry, because process development and manufacturing are on the “critical path” for a drug candidate to enter clinical development. High-throughput process development (HTPD) methodologies can be similarly impactful during late-stage development, both for developing the final commercial process as well as for process characterization and scale-down validation activities that form a key component of the licensure filing package. This review examines the current state of the art for HTPD methodologies as they apply to cell culture, downstream purification, and analytical techniques. In addition, we provide a vision of how HTPD activities across all of these spaces can integrate to create a rapid process development engine that can accelerate biopharmaceutical drug development.

Graphical Abstract

This is a preview of subscription content, log in via an institution.

References

  1. Shukla A, Hubbard B, Tressel T, Guhan S, Low D (2007) Downstream processing of monoclonal antibodies – application of platform approaches. J Chromatogr B 848:28–39

    CAS  Google Scholar 

  2. Shukla A, Thommes J (2010) Advances in large-scale production of monoclonal antibodies and related proteins. Trends Biotechnol 28(5):253–261

    CAS  Google Scholar 

  3. Kelley B (2009) Industrialization of mAb production technology: the biotechnology industry at a crossroads. MAbs 1(5):443–452

    PubMed Central  Google Scholar 

  4. Ecker D, Jones SD, Levine H (2015) The therapeutic monoclonal antibody market. MAbs 7(1):9–14

    CAS  Google Scholar 

  5. Reichert J (2015) Antibodies to watch in 2015. MAbs 7(1):1–8

    CAS  Google Scholar 

  6. Rathore A, Winkle H (2006) Quality by design for biopharmaceuticals. Nature 27:26–34

    Google Scholar 

  7. Jiang C, Flansburg L, Ghose S, Jorjorian P, Shukla A (2010) Defining process design space for a hydrophobic interaction chromatography purification step: application of QbD principles. Biotechnol Bioeng 107(6):989–1001

    Google Scholar 

  8. Abu-Absi S, Yang L, Thompson P, Jiang C, Kandula S, Schilling B, Shukla A (2010) Defining process design space for monoclonal antibody cell culture. Biotechnol Bioeng 106(6):894–905

    CAS  Google Scholar 

  9. Legmann R, Schreyer H, Combs R, McCormick E, Russo A, Rodgers S (2009) A predictive high throughput scale-down model of mAb production in CHO cells. Biotechnol Bioeng 104(6):1107–1120

    CAS  Google Scholar 

  10. Lamping S, Zhang H, Allen B, Ayazi Shamlou P (2003) Design of a prototype miniature bioreactor for high throughput automated processing. Chem Eng Sci 58:747–758

    CAS  Google Scholar 

  11. Isett K, George H, Herber W, Amanullah A (2007) Twenty four well plate miniature bioreactor high throughput system: assessment for microbial cultivation. Biotechnol Bioeng 98:1017–1028

    CAS  Google Scholar 

  12. De Jesus M, Girard P, Bourgeois M, Baumgartner G, Jacko B, Amstutz H, Wurm F (2004) TubeSpin satellites: a fast track approach for process development with animal cells using shaking technology. Biochem Eng J 17:217–223

    Google Scholar 

  13. Janakiraman V, Kwiatkowski C, Kshirsagar R, Ryll T, Huang Y (2015) Application of high throughput mini-bioreactor system for systematic scale-down modeling, process characterization and control strategy development. Biotechnol Prog 31:1623–1632

    CAS  Google Scholar 

  14. Rameez S, Mostafa S, Miller C, Shukla A (2014) High-throughput miniaturized bioreactors for cell culture process development – reproducibility, scalability and control. Biotechnol Prog 30(3):718–727

    CAS  Google Scholar 

  15. Hsu WT, Aulakh RP, Traul DL, Yuk IH (2012) Advanced microscale bioreactor system: a representative scale-down model for bench-top bioreactors. Cytotechnology 64:667–678

    CAS  PubMed Central  Google Scholar 

  16. Lewis G, Lugg R, Lee K, Wales R (2010) Novel automated microscale bioreactor technology: a qualitative and quantitative mimic for early process development. Bioprocess J 9:22–25

    CAS  Google Scholar 

  17. Moses S, Manahan M, Ambrogelly A, Ling WW (2012) Assessment of AMBR™ as a model for high-throughput cell culture process development strategy. Adv Biosci Biotechnol 3:918–927

    Google Scholar 

  18. Neinow AW, Rielly CD, Brosnan K, Barg K, Lee K, Coopman K, Hewitt CJ (2013) The physical characterisation of a microscale parallel bioreactor platform with an industrial CHO cell line expressing an IgG4. Biochem Eng J 76:25–36

    Google Scholar 

  19. Tai M, Ly A, Leung I, Nayar G (2015) Efficient high-throughput biological process characterization: definitive screening design with the ambr250 bioreactor system. Biotechnol Prog 31:1338–1395

    Google Scholar 

  20. Xu P, Clark C, Ryder T, Sparks C, Zhou J, Wang M, Russel R, Scott C (2016) Characterization of TAP ambr 250 disposable bioreactors, as a reliable scale-down model for biologics process development. Biotechnol Prog 33:478–479

    Google Scholar 

  21. Bareither R, Bargh N, Oakeshott R, Watts K, Pollard D (2013) Automated disposable small scale reactor for high throughput bioprocess development: a proof of concept study. Biotechnol Prog 110:3126–3138

    CAS  Google Scholar 

  22. Micheletti M, Lye GJ (2006) Microscale bioprocess optimisation. Curr Opin Biotechnol 17(6):611–618

    CAS  Google Scholar 

  23. Vallejos JR, Kostov Y, Ram A, French JA, Marten MR, Rao G (2006) Optical analysis of liquid mixing in a minibioreactor. Biotechnol Bioeng 93(5):906–911

    CAS  Google Scholar 

  24. Coffman JL, Kramarczyk JF, Kelley BD (2008) High-throughput screening of chromatographic separations: I. Method development and column modeling. Biotechnol Bioeng 100:605–618

    CAS  Google Scholar 

  25. Kelley BD (2008) High-throughput screening of chromatographic separations: IV. Ion-Exch Biotechnol Bioeng 100:950–963

    CAS  Google Scholar 

  26. Kramarczyk JF, Kelley BD, Coffman JL (2008) High-throughput screening of chromatographic separations: II. Hydrophobic interaction. Biotechnol Bioeng 100:707–720

    CAS  Google Scholar 

  27. Petroff MG, Bao H, Welsh JP, van Beuningen-de Vaan M, Pollard JM, Roush DJ, Kandula S, Machielsen P, Tugcu N, Linden TO (2016) High throughput chromatography strategies for potential use in the formal process characterization of a monoclonal antibody. Biotechnol Bioeng 113:1273–1283

    CAS  Google Scholar 

  28. Bhambure R, Kumar K, Rathore A (2011a) High-throughput process development for biopharmaceutifcal drug substances. Trends Biotechnol 29(3):127–135

    CAS  Google Scholar 

  29. Vincentelli R, Canaan S, Campanacci V, Valencia C, Maurin D, et al. (2004) High-throughput automated refolding screening of inclusion bodies. Protein Sci 13:2782–2792

    CAS  PubMed Central  Google Scholar 

  30. Kramarczyk JF (2003) High-throughput screening of chromatographic resins and excipients for optimizing selectivity. Tufts University, Medford

    Google Scholar 

  31. Bergander T et al. (2008) High-throughput process development: determination of dynamic binding capacity using microtiter filter plates filled with chromatography resin. Biotechnol Prog 24(3):632–639

    CAS  Google Scholar 

  32. Wensel DL, Kelley BD, Coffman JL (2008) High-throughput screening of chromatographic separations: III. Monoclonal antibodies on ceramic hydroxyapatite. Biotechnol Bioeng 100:839–854

    CAS  Google Scholar 

  33. Sanaie N, Cecchini D, Pieracci J (2012) Applying high-throughput methods to develop a purification process for a highly glycosylated protein. Biotechnol J 7:1242–1255

    CAS  Google Scholar 

  34. Kökpinar Ö, Harkensee D, Kasper C, Scheper T, Zeidler R, Reif O-W, Ulber R (2006) Innovative modular membrane adsorber system for high-throughput downstream screening for protein purification. Biotechnol Prog 22:1215–1219

    Google Scholar 

  35. Kang Y, Ng S, Lee J, Adaelu J, Qi B, Persaud K, Ludwig D, Balderes P (2012) Development of an alternative monoclonal antibody polishing step. Biopharm Int 25(5):34–36, 38–42, 44–46

    Google Scholar 

  36. McDonald P, Tran B, Williams C, Wong M, Zhao T, Kelley B, Lester P (2016) The rapid identification of elution conditions for therapeutic antibodies from cation-exchange chromatography resins using high-throughput screening. J Chromatogr A 1433:66–74

    CAS  Google Scholar 

  37. Connell-Crowley L, Larimore EA, Gillespie R (2013) Using high throughput screening to define virus clearance by chromatography resins. Biotechnol Bioeng 110:1984–1994

    CAS  Google Scholar 

  38. Lacki K (2012) High-throughput process development of chromatography steps: advantages and limitations of different formats used. Biotechnol J 7:1192–1202

    CAS  Google Scholar 

  39. Wenger M, DePhillips P, Price C, Bracewell D (2007) An automated microscale chromatographic purification of VLPs as a strategy for process development. Biotechnol Appl Biochem 47(2):131–139

    CAS  Google Scholar 

  40. Chhatre S, Bracewell DG, Titcherner-Hooker NJ (2009) A microscale approach for predicting the performance of chromatography columns used to recover therapeutic polyclonal antibodies. J Chromatogr A 1216:7806–7815

    CAS  Google Scholar 

  41. Williams JG, Tomer KB (2004) Disposable chromatography for a highthroughput nano-ESI/MS and nano-ESI/MS-MS platform. J Am Soc Mass Spectrom 15:1333–1340

    CAS  Google Scholar 

  42. Welsh JP, Petroff MG, Rowicki P, Bao H, Linden T, Roush DJ, Pollard JM (2014) A practical strategy for using miniature chromatography columns in a standard high-throughput workflow for purification development of monoclonal antibodies. Biotechnol Prog 30(3):626–635

    CAS  Google Scholar 

  43. Keller WR, Evans ST, Ferreiera G, Robbins D, Cramer SM (2015) Use of minicolumns for linear isotherm parameter estimation and predication of benchtop column performance. J Chromatogr A 1418:94–102

    CAS  Google Scholar 

  44. Brenac Brochier V, Schapman A, Santambien P, Britsch L (2008) Fast purification process optimization using mixed-mode chromatography sorbents in pre-packed mini-columns. J Chromatogr A 1177(2):226–233

    CAS  Google Scholar 

  45. Feliciano J, Berrill A, Ahnfelt M, Brekkan E, Evans B, Fung Z, Godavarti R, Nilsson-Välimaa K, Salm J, Saplakoglu U, Switzer M, Łącki K (2016) Evaluating high-throughput scale-down chromatography platforms for increased process understanding. Eng Life Sci 16:169–178

    CAS  Google Scholar 

  46. Kolzowski S, Swann P (2006) Current and utures issues in manufacting and development of monoclonal antibodies. Adv Drug Delivery Rev 58:707–722

    Google Scholar 

  47. Gilg D, Riedl B, Zier A, Zimmermann M (1996) Analytical methods for the characterization and quality control of pharmaceutical peptides and proteins, using erythropoietin as an example. Pharm Acta Helv 71:384–394

    Google Scholar 

  48. Rege K, Pepsin M, Falcon B, Steele L, Heng M (2005) High-throughput process development for recombinant protein purification. Biotechnol Bioeng 93:618–630

    Google Scholar 

  49. Fahrner RL et al. (2001) Industrial purification of pharmaceutical antibodies: development, operation, and validation of chromatography processes. Biotechnol Genet Eng Rev 18:301–327

    CAS  Google Scholar 

  50. Flatman S, Alam I, Gerard J, Mussa N (2007) Process analytics for purification of monoclonal antibodies. J Chromtogr B 848:79–87

    CAS  Google Scholar 

  51. Pais DAM, Carrondo MJT, Alves PM, Teixeira AP (2014) Towards real-time monitoring of therapeutic protein quality in mammalian cell processes. Curr Opin Biotechnol 30:161–167

    CAS  Google Scholar 

  52. den Engelsman J et al. (2011) Strategies for the assessment of protein aggregates in pharmaceutical biotech product development. Pharm Res 28:920–933

    Google Scholar 

  53. Gervais D (2016) Protein deamidation in biopharmaceutical manufacture: understanding, control and impact. J Chem Technol Biotechnol 91:569–575

    CAS  Google Scholar 

  54. Harris RJ et al. (2001) Identification of multiple sources of charge heterogeneity in a recombinant antibody. J Chromatogr B Biomed Sci Appl 752:233–245

    CAS  Google Scholar 

  55. Kroon DJ, Baldwin-Ferro A, Lalan P (1992) Identification of sites of degradation in a therapeutic monoclonal antibody by peptide mapping. Pharm Res 9:1386–1393

    CAS  Google Scholar 

  56. Perkins M, Theiler R, Lunte S, Jeschke M (2000) Determination of the origin of charge heterogeneity in a murine monoclonal antibody. Pharm Res 17:1110–1117

    CAS  Google Scholar 

  57. Khawli LA et al. (2010) Charge variants in IgG1. MAbs 2:613–624

    PubMed Central  Google Scholar 

  58. Kostal V, Katzenmeyer J, Arriaga EA (2008) Capillary electrophoresis in bioanalysis. Anal Chem 80:4533–4550

    Google Scholar 

  59. Goetze AM, Schenauer MR, Flynn GC (2010) Assessing monoclonal antibody product quality attribute criticality through clinical studies. MAbs 2:500–507

    Google Scholar 

  60. An Y, Zhang Y, Mueller H-M, Shameem M, Chen X (2014) A new tool for monoclonal antibody analysis: application of IdeS proteolysis in IgG domain-specific characterization. MAbs 6:879–893

    PubMed Central  Google Scholar 

  61. Bertolotti-Ciarlet A, Wang W, Lownes R, Pristatsky R, Fang Y, McKelvey T, Li Y, Li Y, Drumond J, Prueksaritanont T, et al. (2009) Impact of methionine oxidation on the binding of human IgG1 to FcRn and Fcγ receptors. Mol Immunol 46:1878–1882

    CAS  Google Scholar 

  62. Pan H, Chen K, Chu L, Kinderman F, Apostol I, Huang G (2009) Methionine oxidation in human IgG2 Fc decreases binding affinities to protein A and FcRn. Protein Sci 18:424–433

    CAS  Google Scholar 

  63. van Beers MMC, Bardor M (2012) Minimizing immunogenicity of biopharmaceuticals by controlling critical quality attributes of proteins. Biotechnol J 7:1473–1484

    Google Scholar 

  64. Roberts CJ (2017) Protein aggregation and its impact on product quality. Curr Opin Biotechnol 30:211–217

    Google Scholar 

  65. Jiskoot W et al. (2011) Protein instability and immunogenicity: roadblocks to clinical application of injectable protein delivery systems for sustained release. J Pharm Sci 101:946–954

    Google Scholar 

  66. Hong P, Koza S, Bovier ES (2012) A review size-exclusion chromatography for the analysis of protein biotherapeutics and their aggregates. J Liq Chromatogr Relat Technol 35:2923–2950

    CAS  PubMed Central  Google Scholar 

  67. Zhang R, Tang I-C, Wang J, Yang S-T (2012) Cell-based assays in high-throuput screening for drug discovery. Int J Biotechnol Wellness Ind 1:31–51

    Google Scholar 

  68. Gupta S et al. (2007) Recommendations for the design, optimization, and qualification of cell-based assays used for the detection of neutralizing antibody responses elicited to biological therapeutics. J Immunol Methods 321:1–18

    CAS  Google Scholar 

  69. Shrock RD (2012) Cell-based potency assays: expectation and realities. Bioprocess J 11:4–12

    Google Scholar 

  70. Cox KL, Devanarayan V, Kriauciunas A, Manetta J, Montrose C, Sittampalam S (2014) NCBI – assay guidance manual [internet]. https://www.ncbi.nlm.nih.gov/books/NBK92434/. Accessed 1 Feb 2017

  71. Hahnefeld C, Drewianka S, Herberg FW (2004) Methods in molecular medicine. Humana Press Inc., Totowa

    Google Scholar 

  72. Joelsson D, Moravec P, Troutman M, Pigeon J, DePhillips P (2008) Optimizing ELISAs for precision and robustness using laboratory automation and statistical design of experiments. J Immunol Methods 337:35–41

    CAS  Google Scholar 

  73. FDA (2014) Immunogenicity assessment for therapeutic protein products. Guidance for industry. U.S. Department of Health and Human Services, August 2014

    Google Scholar 

  74. Rey G, Wendeler MW (2012) Full automation and validation of a flexible ELISA platform for host cell protein and protein A impurity detection in biopharmaceuticals. J Pharm Biomed Anal 70:580–586

    CAS  Google Scholar 

  75. Bracewell DG, Francis R, Smales CM (2015) The future of host cell protein (HCP) identification during process development and manufacturing linked to a risk-based management for their control. Biotechnol Bioeng 112:1727–1737

    CAS  PubMed Central  Google Scholar 

  76. Stadlmann J, Pabst M, Altmann F (2010) Analytical and functional aspects of antibody sialylation. J Clin Immunol 30:15–19

    PubMed Central  Google Scholar 

  77. Solá RJ, Griebenow K (2011) Glycosylation of therapeutic proteins: an effective strategy to optimize efficacy. BioDrugs 24:9–21

    Google Scholar 

  78. Beck A et al. (2008) Trends in glycosylation, glycoanalysis and glycoengineering of therapeutic antibodies and Fc-fusion proteins. Curr Pharm Biotechnol 9:482–501

    CAS  Google Scholar 

  79. Rogers RS, Nightlinger NS, Livingston B, Campbell P, Bailey R, Balland A (2015) Development of a quantitative mass spectrometry multi-attribute method for characterization, quality control testing and disposition of biologics. mAbs 7:881–890

    CAS  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Process Development and Manufacturing, KBI Biopharma Inc., 2 Triangle Drive, Research Triangle Park, Durham, NC, 27709, USA

    Abhinav A. Shukla, Shahid Rameez, Leslie S. Wolfe & Nathan Oien

Authors
  1. Abhinav A. Shukla
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shahid Rameez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Leslie S. Wolfe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nathan Oien
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Abhinav A. Shukla .

Editor information

Editors and Affiliations

  1. Sutro Biopharma Inc., San Francisco, CA, USA

    Bob Kiss

  2. Lonza, Basel, Switzerland

    Uwe Gottschalk

  3. Solothurn Manufacturing Facility, Biogen International GmbH, Luterbach, Switzerland

    Michael Pohlscheidt

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Shukla, A.A., Rameez, S., Wolfe, L.S., Oien, N. (2017). High-Throughput Process Development for Biopharmaceuticals. In: Kiss, B., Gottschalk, U., Pohlscheidt, M. (eds) New Bioprocessing Strategies: Development and Manufacturing of Recombinant Antibodies and Proteins. Advances in Biochemical Engineering/Biotechnology, vol 165. Springer, Cham. https://doi.org/10.1007/10_2017_20

Download citation

Publish with us

Policies and ethics

Search

Navigation