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Chapter 14: Practical Considerations in High Concentration Formulation Development for Monoclonal Antibody Drug Products

  • Qingyan Hu
  • Bowen Jiang
  • Dingjiang (Dean) LiuEmail author
  • Xiaolin (Charlie) Tang
  • Thomas Daly
  • Mohammed Shameem
Chapter
  • 87 Downloads
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 35)

Abstract

This book chapter covers practical consideration and strategies in developing high concentration formulations and drug products for commercial use. The discussions presented in this chapter are based on authors’ hands-on experience supplemented with literature findings, and focus on formulation and analytical aspects, as well as primary container considerations unique for high concentration formulation development.

Keywords

Monoclonal antibody High concentration formulation Drug product development Solubility Aggregation Primary container selection Frozen storage stability Subcutaneous formulation Viscosity reduction High protein concentration 

Notes

Acknowledgments

The authors would like to thank Dr. Suhaas Aluri and Dr. David Hauss for reviewing the manuscript.

References

  1. 1.
    Jameel F, Hershenson S. Formulation and process development strategies for manufacturing biopharmaceuticals. New York: Wiley; 2010.CrossRefGoogle Scholar
  2. 2.
    Shire SJ, Shahrokh Z, Liu J. Challenges in the development of high protein concentration formulations. J Pharm Sci. 2004;93:1390–402.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Warne NW. Development of high concentration protein biopharmaceuticals: the use of platform approaches in formulation development. Eur J Pharm Biopharm. 2011;78:208–12.CrossRefGoogle Scholar
  4. 4.
    Hofmann M, Gieseler H. Predictive screening tools used in high-concentration protein formulation development. J Pharm Sci. 2018;107:772–7.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Piedmonte, D. M., Gu, J. H., Brych, S. R., & Goss, M. M. (2018). Practical considerations for high concentration protein formulations. In Challenges in protein product development (pp. 163–187). Springer, Cham.Google Scholar
  6. 6.
    Yamniuk AP, Ditto N, Patel M, Dai J, Sejwal P, Stetsko P, et al. Application of a kosmotrope-based solubility assay to multiple protein therapeutic classes indicates broad use as a high-throughput screen for protein therapeutic aggregation propensity. J Pharm Sci. 2013;102:2424–39.CrossRefGoogle Scholar
  7. 7.
    Banks DD, Latypov RF, Ketchem RR, Woodard J, Scavezze JL, Siska CC, et al. Native-state solubility and transfer free energy as predictive tools for selecting excipients to include in protein formulation development studies. J Pharm Sci. 2012;101:2720–32.CrossRefGoogle Scholar
  8. 8.
    Zhang L, Tan H, Fesinmeyer RM, Li C, Catrone D, Le D, et al. Antibody solubility behavior in monovalent salt solutions reveals specific anion effects at low ionic strength. J Pharm Sci. 2012;101:965–77.CrossRefGoogle Scholar
  9. 9.
    Hofmann M, Winzer M, Weber C, Gieseler H. Limitations of polyethylene glycol-induced precipitation as predictive tool for protein solubility during formulation development. J Pharm Pharmacol. 2018;70:648–54.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Kiese S, Papppenberger A, Friess W, Mahler H-C. Shaken, not stirred: mechanical stress testing of an IgG1 antibody. J Pharm Sci. 2008;97:4347–66.CrossRefGoogle Scholar
  11. 11.
    Abdul-Fattah AM, Kalonia DS, Pikal MJ. The challenge of drying method selection for protein pharmaceuticals: product quality implications. J Pharm Sci. 2007;96:1886–916.CrossRefGoogle Scholar
  12. 12.
    Pindrus M, Shire SJ, Kelley RF, Bl D, Wong R, Xu Y, et al. Solubility challenges in high concentration monoclonal antibody formulations: relationship with amino acid sequence and intermolecular interactions. Mol Pharm. 2015;12:3896–907.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Xu, Y., Wang, D., Mason, B., Rossomando, T., Li, N., Liu, D., ... & Nowak, C. (2019, February). Structure, heterogeneity and developability assessment of therapeutic antibodies. In MAbs (Vol. 11, No. 2, pp. 239–264). Taylor & Francis.Google Scholar
  14. 14.
    Luo H, Lee N, Wang X, Li Y, Schmelzer A, Hunter AK, et al. Liquid-liquid phase separation causes high turbidity and pressure during low pH elution process in Protein A chromatography. J Chromatogr A. 2017;1488:57–67.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Raut AS, Kalonia DS. Opalescence in monoclonal antibody solutions and its correlation with intermolecular interactions in dilute and concentrated solutions. J Pharm Sci. 2015;104:1263–74.CrossRefGoogle Scholar
  16. 16.
    Arakawa T, Timasheff S. Theory of protein solubility. Methods Enzymol. 1985;114:49.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Kheddo P, Bramham JE, Dearman RJ, Uddin S, van der Walle CF, Golovanov AP. Investigating liquid–liquid phase separation of a monoclonal antibody using solution-state NMR spectroscopy: effect of Arg· Glu and Arg· HCl. Mol Pharm. 2017;14:2852–60.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Ohtake S, Kita Y, Arakawa T. Interactions of formulation excipients with proteins in solution and in the dried state. Adv Drug Deliv Rev. 2011;63:1053–73.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Kamerzell TJ, Esfandiary R, Joshi SB, Middaugh CR, Volkin DB. Protein–excipient interactions: mechanisms and biophysical characterization applied to protein formulation development. Adv Drug Deliv Rev. 2011;63:1118–59.CrossRefGoogle Scholar
  20. 20.
    Chavez BK, Agarabi CD, Read EK, Boyne I, Michael T, Khan MA, et al. Improved stability of a model IgG3 by DoE-based evaluation of buffer formulations. Biomed Res Int. 2016;2016Google Scholar
  21. 21.
    Gibson TJ, Mccarty K, Mcfadyen IJ, Cash E, Dalmonte P, Hinds KD, et al. Application of a high-throughput screening procedure with PEG-induced precipitation to compare relative protein solubility during formulation development with IgG1 monoclonal antibodies. J Pharm Sci. 2011;100:1009–21.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Garidel P, Kuhn AB, Schäfer LV, Karow-Zwick AR, Blech M. High-concentration protein formulations: how high is high? Eur J Pharm Biopharm. 2017;119:353–60.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Moussa EM, Panchal JP, Moorthy BS, Blum JS, Joubert MK, Narhi LO, et al. Immunogenicity of therapeutic protein aggregates. J Pharm Sci. 2016;105:417–30.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Roberts CJ, Das TK, Sahin E. Predicting solution aggregation rates for therapeutic proteins: approaches and challenges. Int J Pharm. 2011;418:318–33.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Joubert MK, Luo Q, Nashed-Samuel Y, Wypych J, Narhi LO. Classification and characterization of therapeutic antibody aggregates. J Biol Chem. 2011;286(28):25118–33.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Roberts CJ. Therapeutic protein aggregation: mechanisms, design, and control. Trends Biotechnol. 2014;32:372–80.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Rathore AS, Joshi V, Yadav N. Aggregation of monoclonal antibody products: formation and removal. BioPharm Int. 2013;26:40–5.Google Scholar
  28. 28.
    Moore JM, Patapoff TW, Cromwell ME. Kinetics and thermodynamics of dimer formation and dissociation for a recombinant humanized monoclonal antibody to vascular endothelial growth factor. Biochemistry. 1999;38:13960–7.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Paul R, Graff-Meyer A, Stahlberg H, Lauer ME, Rufer AC, Beck H, et al. Structure and function of purified monoclonal antibody dimers induced by different stress conditions. Pharm Res. 2012;29:2047–59.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Plath F, Ringler P, Graff-Meyer A, Stahlberg H, Lauer ME, Rufer AC, et al. Characterization of mAb dimers reveals predominant dimer forms common in therapeutic mAbs: MAbs: Taylor & Francis; 2016. p. 928–40.Google Scholar
  31. 31.
    Woods CE. Understanding therapeutic monoclonal antibody aggregation mechanisms through biophysical, biochemical and biological characterization of two types of immunoglobulin G dimers. University of Kansas; 2015.Google Scholar
  32. 32.
    Thiagarajan G, Semple A, James JK, Cheung JK, Shameem M. A comparison of biophysical characterization techniques in predicting monoclonal antibody stability: MAbs: Taylor & Francis; 2016. p. 1088–97.Google Scholar
  33. 33.
    Kayser V, Chennamsetty N, Voynov V, Helk B, Forrer K, Trout BL. Evaluation of a non-Arrhenius model for therapeutic monoclonal antibody aggregation. J Pharm Sci. 2011;100:2526–42.CrossRefGoogle Scholar
  34. 34.
    Brummitt RK, Nesta DP, Roberts CJ. Predicting accelerated aggregation rates for monoclonal antibody formulations, and challenges for low-temperature predictions. J Pharm Sci. 2011;100:4234–43.CrossRefGoogle Scholar
  35. 35.
    Piedmonte DM, Summers C, McAuley A, Karamujic L, Ratnaswamy G. Sorbitol crystallization can lead to protein aggregation in frozen protein formulations. Pharm Res. 2007;24:136–46.CrossRefGoogle Scholar
  36. 36.
    Singh SK, Kolhe P, Mehta AP, Chico SC, Lary AL, Huang M. Frozen state storage instability of a monoclonal antibody: aggregation as a consequence of trehalose crystallization and protein unfolding. Pharm Res. 2011;28:873–85.CrossRefGoogle Scholar
  37. 37.
    Gu JH, Beekman A, Wu T, Piedmonte DM, Baker P, Eschenberg M, et al. Beyond glass transitions: studying the highly viscous and elastic behavior of frozen protein formulations using low temperature rheology and its potential implications on protein stability. Pharm Res. 2013;30:387–401.CrossRefGoogle Scholar
  38. 38.
    Whitaker N, Xiong J, Pace SE, Kumar V, Middaugh CR, Joshi SB, et al. A formulation development approach to identify and select stable ultra–high-concentration monoclonal antibody formulations with reduced viscosities. J Pharm Sci. 2017;106:3230–41.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Wang W, Lilyestrom WG, Hu ZY, Scherer TM. Cluster size and quinary structure determine the rheological effects of antibody self-association at high concentrations. J Phys Chem B. 2018;122:2138–54.CrossRefGoogle Scholar
  40. 40.
    Tomar DS, Kumar S, Singh SK, Goswami S, Li L. Molecular basis of high viscosity in concentrated antibody solutions: strategies for high concentration drug product development: MAbs: Taylor & Francis; 2016. p. 216–28.Google Scholar
  41. 41.
    Zhang Z, Liu Y. Recent progresses of understanding the viscosity of concentrated protein solutions. Curr Opin Chem Eng. 2017;16:48–55.CrossRefGoogle Scholar
  42. 42.
    Kanai S, Liu J, Patapoff TW, Shire SJ. Reversible self-association of a concentrated monoclonal antibody solution mediated by Fab–Fab interaction that impacts solution viscosity. J Pharm Sci. 2008;97:4219–27.CrossRefGoogle Scholar
  43. 43.
    Yadav S, Liu J, Shire SJ, Kalonia DS. Specific interactions in high concentration antibody solutions resulting in high viscosity. J Pharm Sci. 2010;99:1152–68.CrossRefGoogle Scholar
  44. 44.
    Yearley EJ, Godfrin PD, Perevozchikova T, Zhang H, Falus P, Porcar L, et al. Observation of small cluster formation in concentrated monoclonal antibody solutions and its implications to solution viscosity. Biophys J. 2014;106:1763–70.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Schmit JD, He F, Mishra S, Ketchem RR, Woods CE, Kerwin BA. Entanglement model of antibody viscosity. J Phys Chem B. 2014;118:5044–9.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Buck PM, Chaudhri A, Kumar S, Singh SK. Highly viscous antibody solutions are a consequence of network formation caused by domain–domain electrostatic complementarities: insights from coarse-grained simulations. Mol Pharm. 2014;12:127–39.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Neergaard MS, Kalonia DS, Parshad H, Nielsen AD, Møller EH, van de Weert M. Viscosity of high concentration protein formulations of monoclonal antibodies of the IgG1 and IgG4 subclass–Prediction of viscosity through protein–protein interaction measurements. Eur J Pharm Sci. 2013;49:400–10.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Yadav S, Shire SJ, Kalonia DS. Viscosity behavior of high-concentration monoclonal antibody solutions: correlation with interaction parameter and electroviscous effects. J Pharm Sci. 2012;101:998–1011.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Liu Y, Caffry I, Wu J, Geng SB, Jain T, Sun T, et al. High-throughput screening for developability during early-stage antibody discovery using self-interaction nanoparticle spectroscopy: MAbs: Taylor & Francis; 2014. p. 483–92.Google Scholar
  50. 50.
    He F, Woods CE, Litowski JR, Roschen LA, Gadgil HS, Razinkov VI, et al. Effect of sugar molecules on the viscosity of high concentration monoclonal antibody solutions. Pharm Res. 2011;28:1552–60.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Wang S, Zhang N, Hu T, Dai W, Feng X, Zhang X, et al. Viscosity-lowering effect of amino acids and salts on highly concentrated solutions of two IgG1 monoclonal antibodies. Mol Pharm. 2015;12:4478–87.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Bolli R, Woodtli K, Bärtschi M, Höfferer L, Lerch P. L-Proline reduces IgG dimer content and enhances the stability of intravenous immunoglobulin (IVIG) solutions. Biologicals. 2010;38:150–7.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Hung JJ, Dear BJ, Dinin AK, Borwankar AU, Mehta SK, Truskett TT, et al. Improving viscosity and stability of a highly concentrated monoclonal antibody solution with concentrated proline. Pharm Res. 2018;35:133.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Du W, Klibanov AM. Hydrophobic salts markedly diminish viscosity of concentrated protein solutions. Biotechnol Bioeng. 2011;108:632–6.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Kumar A, Klibanov AM. Viscosity-reducing bulky-salt excipients prevent gelation of protein, but not carbohydrate, solutions. Appl Biochem Biotechnol. 2017;182:1491–6.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Dear BJ, Hung JJ, Truskett TM, Johnston KP. Contrasting the influence of cationic amino acids on the viscosity and stability of a highly concentrated monoclonal antibody. Pharm Res. 2017;34:193–207.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Huang HZ, Liu D, Sloey CJ, Gleason C. Reducing viscosity of pharmaceutical formulations. US Patent App. 13/582,357, 2013.Google Scholar
  58. 58.
    Berteau C, Filipe-Santos O, Wang T, Rojas HE, Granger C, Schwarzenbach F. Evaluation of the impact of viscosity, injection volume, and injection flow rate on subcutaneous injection tolerance. Med Devices (Auckland, NZ). 2015;8:473.Google Scholar
  59. 59.
    Dias C, Abosaleem B, Crispino C, Gao B, Shaywitz A. Tolerability of high-volume subcutaneous injections of a viscous placebo buffer: a randomized, crossover study in healthy subjects. AAPS PharmSciTech. 2015;16:1101–7.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Beddoes C. Understanding the market for wearable large volume injectors. Health. 2016;44:928045.Google Scholar
  61. 61.
    Frost GI. Recombinant human hyaluronidase (rHuPH20): an enabling platform for subcutaneous drug and fluid administration. Expert Opin Drug Deliv. 2007;4:427–40.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Srinivasan C, Weight AK, Bussemer T, Klibanov AM. Non-aqueous suspensions of antibodies are much less viscous than equally concentrated aqueous solutions. Pharm Res. 2013;30:1749–57.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Bowen M, Armstrong N, Y-f M. Investigating high-concentration monoclonal antibody powder suspension in nonaqueous suspension vehicles for subcutaneous injection. J Pharm Sci. 2012;101:4433–43.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Yang MX, Shenoy B, Disttler M, Patel R, McGrath M, Pechenov S, et al. Crystalline monoclonal antibodies for subcutaneous delivery. Proc Natl Acad Sci. 2003;100:6934–9.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Basu SK, Govardhan CP, Jung CW, Margolin AL. Protein crystals for the delivery of biopharmaceuticals. Expert Opin Biol Ther. 2004;4:301–17.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Aboulaich N, Chung WK, Thompson JH, Larkin C, Robbins D, Zhu M. A novel approach to monitor clearance of host cell proteins associated with monoclonal antibodies. Biotechnol Prog. 2014;30:1114–24.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Labrenz SR. Ester hydrolysis of polysorbate 80 in mAb drug product: evidence in support of the hypothesized risk after the observation of visible particulate in mAb formulations. J Pharm Sci. 2014;103:2268–77.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Chiu J, Valente KN, Levy NE, Min L, Lenhoff AM, Lee KH. Knockout of a difficult-to-remove CHO host cell protein, lipoprotein lipase, for improved polysorbate stability in monoclonal antibody formulations. Biotechnol Bioeng. 2017;114:1006–15.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Dixit N, Salamat-Miller N, Salinas PA, Taylor KD, Basu SK. Residual host cell protein promotes polysorbate 20 degradation in a sulfatase drug product leading to free fatty acid particles. J Pharm Sci. 2016;105:1657–66.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    McShan AC, Kei P, Ji JA, Kim DC, Wang YJ. Hydrolysis of polysorbate 20 and 80 by a range of carboxylester hydrolases. PDA J Pharm Sci Technol. 2016;70:332–45.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Mihara K, Ito Y, Hatano Y, Komurasaki Y, Sugimura A, Jones M, et al. Host cell proteins: the hidden side of biosimilarity assessment. J Pharm Sci. 2015;104:3991–6.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Park JH, Jin JH, Lim MS, An HJ, Kim JW, Lee GM. Proteomic analysis of host cell protein dynamics in the culture supernatants of antibody-producing CHO cells. Sci Rep. 2017;7:44246.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Hanne B, Mattila J, Li N, Tang X, Dix D, Li C, et al. Process for reducing subvisible particles in a pharmaceutical formulation. Google Patents; 2016.Google Scholar
  74. 74.
    Bak H, Mattila J, LI N, Tang X, Dix D, LI C, et al. Process for reducing subvisible particles in a pharmaceutical formulation. US Patent App 14/878,079, 2016.Google Scholar
  75. 75.
    Waddell WJ. A simple ultraviolet spectrophotometric method for the determination of protein. J Lab Clin Med. 1956;48:311–4.PubMedGoogle Scholar
  76. 76.
    Watson L, Veeraragavan K. Dilution-free protein concentration measurement for high protein concentration samples. BioPharm Int. 2014;27:26–37.Google Scholar
  77. 77.
    Huffman S, Soni K, Ferraiolo J. UV-Vis based determination of protein concentration. BioProcess Int. 2014;12:8.Google Scholar
  78. 78.
    Demeule B, Messick S, Shire SJ, Liu J. Characterization of particles in protein solutions: reaching the limits of current technologies. AAPS J. 2010;12:708–15.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Sharma DK, King D, Oma P, Merchant C. Micro-flow imaging: flow microscopy applied to sub-visible particulate analysis in protein formulations. AAPS J. 2010;12:455–64.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2020

Authors and Affiliations

  • Qingyan Hu
    • 1
  • Bowen Jiang
    • 1
  • Dingjiang (Dean) Liu
    • 1
    Email author
  • Xiaolin (Charlie) Tang
    • 1
  • Thomas Daly
    • 1
  • Mohammed Shameem
    • 1
  1. 1.Regeneron Phamraceuticals Inc.TarrytownUSA

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