Advertisement

Practical Considerations for High Concentration Protein Formulations

  • Deirdre Murphy Piedmonte
  • Jian Hua Gu
  • Stephen R. Brych
  • Monica M. Goss
Chapter
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 38)

Abstract

Practical issues that arise for high concentration protein formulations can complicate manufacturing and affect injectability/device compatibility. High concentration protein formulations have an increased tendency for high solution viscosity, physical stability sensitivities (aggregation/particulation), and non-Newtonian solution behavior (shear thinning) due to high shear rates. Process unit operations can be negatively impacted by these factors, and it is critical to understand how they influence process performance. Device compatibility can be affected by changes in protein concentration and temperature that will impact product viscosity and injectability. Complete characterization of the solution physical properties (viscosity and shear thinning profile) as well as the stability profile must be understood to ensure efficient processing, delivery, and efficacy of the therapeutic product. If potential candidates with impeding viscosity values are not identified early in development, subsequent mitigation efforts to reduce viscosity likely pivot from a protein engineering approach to changes in formulation.

Keywords

High protein concentration formulation Viscosity Shear thinning Device compatibility Injectability Syringeability 

Notes

Acknowledgements

The authors wish to acknowledge the work of Drs. Nitin Rathore and Joseph Bernacki, particularly their data visualization, as Fig. 7.1 was adapted from their work. Thanks to Dr. Nicholas Clark for generating breakloose extrusion data. We would also like to thank Dr. Sugunakar Patro for his critical review and support.

References

  1. 1.
    Shire SJ, Shahrokh Z, Liu J. Challenges in the development of high protein concentration formulations. J Pharm Sci. 2004;93(6):1390–402.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Liu J, Nguyen MD, Andya JD, Shire SJ. Reversible self-association increases the viscosity of a concentrated monoclonal antibody in aqueous solution. J Pharm Sci. 2005;94(9):1928–40.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Jezek J, Rides M, Derham B, Moore J, Cerasoli E, Simler R, Perez-Ramirez B. Viscosity of concentrated therapeutic protein compositions. Adv Drug Deliv Rev. 2011;63(13):1107–17.PubMedCrossRefGoogle Scholar
  4. 4.
    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. 2016;8(2):216–28.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    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(3):998–1011.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    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(10):4219–27.CrossRefGoogle Scholar
  7. 7.
    Berg JC. An introduction to interfaces and colloids: the bridge to nanoscience. Singapore: World Scientific; 2009.Google Scholar
  8. 8.
    Pathak JA, Sologuren RR, Narwal R. Do clustering monoclonal antibody solutions really have a concentration dependence of viscosity? Biophys J. 2013;104(4):913–23.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    French DL, Collins JJ. Advances in parenteral injection devices and aids. In Sandeep Nema JDL, editors. Pharmaceutical dosage forms. London: Informa Healthcare; 2010. pp.71–85.CrossRefGoogle Scholar
  10. 10.
    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(5):1101–7.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Doughty DV, Clawson CZ, Lambert W, Subramony JA. Understanding subcutaneous tissue pressure for engineering injection devices for large-volume protein delivery. J Pharm Sci. 2016;105(7):2105–13.PubMedCrossRefGoogle Scholar
  12. 12.
    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. Medical devices. 2015;8:473–84.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Mahler HC, Friess W, Grauschopf U, Kiese S. Protein aggregation: pathways, induction factors and analysis. J Pharm Sci. 2009;98(9):2909–34.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Wang W. Instability, stabilization, and formulation of liquid protein pharmaceuticals. Int J Pharm. 1999;185(2):129–88.PubMedCrossRefGoogle Scholar
  15. 15.
    Bird B, Stewart W, Lightfoot E. Transport phenomena. New York: John Wiley and Sons; 1960. pp. 1–780.Google Scholar
  16. 16.
    Zarraga IE, Taing R, Zarzar J, Luoma J, Hsiung J, Patel A, Lim F. High shear rheology and anisotropy in concentrated solutions of monoclonal antibodies. J Pharm Sci. 2013;102(8):2538–49.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Allmendinger A, Fischer S, Huwyler J, Mahler H-C, Schwarb E, Zarraga IE, Mueller R. Rheological characterization and injection forces of concentrated protein formulations: an alternative predictive model for non-Newtonian solutions. Eur J Pharm Biopharm. 2014;87(2):318–28.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Viswanath DS, Ghosh T, Prasad DHL, Dutt NVK, Rani KY. Viscosity of liquid—theory, estimation, experiment, and data. Berlin: Springer; 2010.Google Scholar
  19. 19.
    Anderson AM, Bruno BA, Smith LS. Viscosity Measurment part IV. Handbook of measurment in science and engineering. Published Online. Hoboken: John Wiley & Sins, Inc.;2013.Google Scholar
  20. 20.
    Jezek J, Rides M, Derham B, Moore J, Cerasoli E, Simler R, Perez-Ramirez B. Viscosity of concentrated therapeutic protein compositions. Adv Drug Delivery Rev. 2011;63(13):1107–17.CrossRefGoogle Scholar
  21. 21.
    Bee JS, Stevenson JL, Mehta B, Svitel J, Pollastrini J, Platz R, Freund E, Carpenter JF, Randolph TW. Response of a concentrated monoclonal antibody formulation to high shear. Biotechnol Bioeng. 2009;103(5):936–43.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Mahler H-C, Fischer S, Randolph TW, Carpenter JF. Protein aggregation and particle formation: effects of formulation, interfaces, and drug product manufacturing operations. In: Wei Wang CJR, editors. Aggregation of therapeutic proteins; 2010. pp. 301–5.CrossRefGoogle Scholar
  23. 23.
    Neumaier R. Hermetic pumps: the latest innovations and industrial applications of sealless pumps. Houston, TX: Gulf Publishing Company; 1997.CrossRefGoogle Scholar
  24. 24.
    Bechtold-Peters K. Development challenges and validation of fill and finish processes for biotherapeutics in Pharmaceutical Dosage forms-parenteral medications. In: Nema S, Ludwig JD, editors. Pharmaceutical dosage forms—parenteral medications, third edition: volume 3: regulations, validation and the future. Boca Raton: CRC Press; 2010. pp. 25–51.CrossRefGoogle Scholar
  25. 25.
    Grigoriev DO, Derkatch S, Kraegel J, Miller R. Relationship between structure and rheological properties of mixed BSA/Tween 80 adsorption layers at the air/water interface. Food Hydrocolloids. 2007;21(5–6):823–30.CrossRefGoogle Scholar
  26. 26.
    Swindellsr JF, Coe RJ, Godfrey TB. Absolute viscosity of water at 20 °C. J Res Nat Bur Stand 1952; 48(1):2279.Google Scholar
  27. 27.
    Kestin J, Sokolov M, Wakeham WA. Viscosity of liquid water in the range −8° to 150 °C. J Phys Chem Ref Data. 1978;7(3):941–8.CrossRefGoogle Scholar
  28. 28.
    Shire SJ, Liu J, Friess W, Jorg S, Mahler H-C. High-concentration antibody formulations. In: Feroz Jameel SH, editors. Formulation and process development strategies for manufacturing biopharmaceuticals. Hoboken, NJ: Wiley; 2010. pp. 349–81.CrossRefGoogle Scholar
  29. 29.
    Dani B, Platz R, Tzannis ST. High concentration formulation feasibility of human immunoglubulin G for subcutaneous administration. J Pharm Sci. 2007;96(6):1504–17.PubMedCrossRefGoogle Scholar
  30. 30.
    Rao S, Gefroh E, Kaltenbrunner O. Recovery modeling of tangential flow systems. Biotechnol Bioeng. 2012;109(12):3084–92.PubMedCrossRefGoogle Scholar
  31. 31.
    Gefroh E, Lutz H. An alternate diafiltration strategy to mitigate protein precipitation for low solubility proteins. Biotechnol Prog. 2014;30(3):646–55.PubMedCrossRefGoogle Scholar
  32. 32.
    Jaffrin M, Charrier J. Optimization of ultrafiltration and diafiltration processes for albumin production. J Membr Sci. 1994;97:71–81.CrossRefGoogle Scholar
  33. 33.
    Zeman LJ ZA. Microfiltration and ultrafiltration—principles and applications. New York: Marcel Dekker, Inc.; 1996. pp. 618.Google Scholar
  34. 34.
    Mitra GL, J. Ultrafiltration of immune serum globulin and human serum albumin: regression analysis studies. Sep Sci Technol. 1978; 13:89–94.CrossRefGoogle Scholar
  35. 35.
    Porter MC. Concentration polarization with membrane ultrafiltration. Ind Eng Chem Prod Res Dev. 1972;11(3):234–48.CrossRefGoogle Scholar
  36. 36.
    van Reis R, Zydney A. Bioprocess membrane technology. J Membr Sci. 2007;297(1–2):16–50.CrossRefGoogle Scholar
  37. 37.
    Hung JJ, Borwankar AU, Dear BJ, Truskett TM, Johnston KP. High concentration tangential flow ultrafiltration of stable monoclonal antibody solutions with low viscosities. J Membr Sci. 2016;508:113–26.CrossRefGoogle Scholar
  38. 38.
    Jaspe J, Hagen SJ. Do protein molecules unfold in a simple shear flow? Biophys J. 2006;91(9):3415–24.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Stoner MR, Fischer N, Nixon L, Buckel S, Benke M, Austin F, Randolph TW, Kendrick BS. Protein-solute interactions affect the outcome of ultrafiltration/diafiltration operations. J Pharm Sci. 2004;93(9):2332–42.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Arakawa T, Timasheff SN. Preferential interactions of proteins with solvent components in aqueous amino-acid solutions. Arch Biochem Biophys. 1983;224(1):169–77.PubMedCrossRefGoogle Scholar
  41. 41.
    Miao F, Velayudhan A, DiBella E, Shervin J, Felo M, Teeters M, Alred P. Theoretical analysis of excipient concentrations during the final ultrafiltration/diafiltration step of therapeutic antibody. Biotechnol Prog. 2009;25(4):964–72.PubMedCrossRefGoogle Scholar
  42. 42.
    Teeters M, Bezila D, Benner T, Alfonso P, Alred P. Predicting diafiltration solution compositions for final ultrafiltration/diafiltration steps of monoclonal antibodies. Biotechnol Bioeng. 2011;108(6):1338–46.PubMedCrossRefGoogle Scholar
  43. 43.
    Singh S, Nema S. Freezing and thawing of protein solultions. In: Hershenson FJaS, editors. Formulation and process development strategies for manufacturing biopharmaceuticals. Hoboken, NJ: John Wiley & Sons, Inc.; 2010. pp. 624–75. http://www.biopharminternational.com/large-scale-freezing-biologics-understandingprotein-and-solute-concentration-changes-cryovessel-p-0?id=&sk=&date=&pageID=7.CrossRefGoogle Scholar
  44. 44.
    Kolhe P, Badkar A. Protein and solute distribution in drug substance containers during frozen storage and post-thawing: a tool to understand and define freezing-thawing parameters in biotechnology process development. Biotechnol Prog. 2011;27(2):494–504.PubMedCrossRefGoogle Scholar
  45. 45.
    Kolhe P, Holding E, Lary A, Chico S, Singh S. Large-scale freezing of biologics: understanding protein and solute concentration changes in a cryovessel–part I. BioPharm Internat. 2010;23(6):53–60.Google Scholar
  46. 46.
    Singh S, Chico S, Lary A, Kolhe P, Holding E. Large-scale freezing of biologics: understanding protein and solute concentration changes in a cryovessel—Part 2. BioPharm Internat. 2010; 23(7).Google Scholar
  47. 47.
    Shire SJ. Formulation and manufacturability of biologics. Curr Opin Biotechnol. 2009;20(6):708–14.PubMedCrossRefGoogle Scholar
  48. 48.
    Xiao NJ, Medley CD, Shieh IC, Downing G, Pizarro S, Liu J, Patel AR. A small-scale model to assess the risk of leachables from single-use bioprocess containers through protein quality characterization. PDA J Pharm Sci Technol. 2016;70(6):533–46.PubMedCrossRefGoogle Scholar
  49. 49.
    Kolhe P, Amend E, Singh SK. Impact of freezing on pH of buffered solutions and consequences for monoclonal antibody aggregation. Biotechnol Prog. 2010;26(3):727–33.PubMedCrossRefGoogle Scholar
  50. 50.
    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(1):136–46.PubMedCrossRefGoogle Scholar
  51. 51.
    Sundaramurthi P, Patapoff TW, Suryanarayanan R. Crystallization of trehalose in frozen solutions and its phase behavior during drying. Pharm Res. 2010;27(11):2374–83.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Connolly B, Patapoff TW, Wang YJ, Moore JM, Kamerzell TJ. Vibrational spectroscopy and chemometrics to characterize and quantitate trehalose crystallization. Anal Biochem. 2010;399(1):48–57.PubMedCrossRefGoogle Scholar
  53. 53.
    Connolly BD, Le L, Patapoff TW, Cromwell ME, Moore JM, Lam P. Protein aggregation in frozen trehalose formulations: effects of composition, cooling rate, and storage temperature. J Pharm Sci. 2015;104(12):4170–84.PubMedCrossRefGoogle Scholar
  54. 54.
    Piedmonte DM, Hair A, Baker P, Brych L, Nagapudi K, Lin H, Cao W, Hershenson S, Ratnaswamy G. Sorbitol crystallization-induced aggregation in frozen mAb formulations. J Pharm Sci. 2015;104(2):686–97.PubMedCrossRefGoogle Scholar
  55. 55.
    Martin-Moe S, Lim FJ, Wong RL, Sreedhara A, Sundaram J, Sane SU. A new roadmap for biopharmaceutical drug product development: integrating development, validation, and quality by design. J Pharm Sci. 2011;100(8):3031–43.PubMedCrossRefGoogle Scholar
  56. 56.
    Nail S, Akers M. Pharmaceutical biotechnology. In: Hershenson FJaS, editors. Development and manufacture of protein pharmaceuticals. Hoboken: Wiley; 2010.Google Scholar
  57. 57.
    Jiang G, Thummala A, Wadhwa MV. Applications of statistical regression and modeling in fill-finish process development of structurally related proteins. J Pharm Sci. 2011;100(2):464–81.PubMedCrossRefGoogle Scholar
  58. 58.
    Gikanga B, Roshan-Eisner D, Ovadia R, Day ES, Stauch OB, Maa YF. Processing impact on monoclonal antibody drug products: protein subvisible particulate formation induced by grinding stress. PDA J Pharm Sci Technol 2016.Google Scholar
  59. 59.
    Gikanga B, Eisner DR, Ovadia R, Day ES, Stauch OB, Maa YF. Processing impact on monoclonal antibody drug products: protein subvisible particulate formation induced by grinding stress. PDA J Pharm Sci Technol. 2017;71(3):172–88.PubMedCrossRefGoogle Scholar
  60. 60.
    Brose D. Membrane filtration. In: Nail SL, Akers, MJ, editors. Development and manufacture of protein pharmaceuticals. Berlin, US: Springer; 2002. pp. 213–79.Google Scholar
  61. 61.
    Sethuraman APX, Mehta B, Radhakrishnan V. High-concentration antibody formulations. In: Jameel F HS, editors. Formulation and process development strategies for manufacturing biopharmaceuticals. Hoboken: John Wiley & Sons; 2010. pp. 839–56.CrossRefGoogle Scholar
  62. 62.
    Cornell Manning M, Evans G, Payne R. Protein stability during bioprocessing. In: Jameel F, Hershenson S, editors. Formulation and process development strategies for manufacturing biopharmaceuticals. Hoboken, NJ: John Wiley & Sons Inc.; 2010. pp. 605–23.CrossRefGoogle Scholar
  63. 63.
    Allmendinger A, Mueller R, Huwyler J, Mahler HC, Fischer S. Sterile filtration of highly concentrated protein formulations: impact of protein concentration, formulation composition, and filter material. J Pharm Sci. 2015;104(10):3319–29.PubMedCrossRefGoogle Scholar
  64. 64.
    Mahler HC, Huber F, Kishore RS, Reindl J, Ruckert P, Muller R. Adsorption behavior of a surfactant and a monoclonal antibody to sterilizing-grade filters. J Pharm Sci. 2010;99(6):2620–7.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Fink A. Protein aggregation: folding aggregates, inclusion bodies and amyloid. Fold Des. 1998;3(1):R9–23.PubMedCrossRefGoogle Scholar
  66. 66.
    Maa YF, Hsu CC. Investigation on fouling mechanisms for recombinant human growth hormone sterile filtration. J Pharm Sci. 1998;87(7):808–12.PubMedCrossRefGoogle Scholar
  67. 67.
    Lilyestrom WG, Yadav S, Shire SJ, Scherer TM. Monoclonal antibody self-association, cluster formation, and rheology at high concentrations. J Phys Chem B. 2013;117(21):6373–84.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Liu L, Qi W, Schwartz DK, Randolph TW, Carpenter JF. The effects of excipients on protein aggregation during agitation: an interfacial shear rheology study. J Pharm Sci. 2013;102(8):2460–70.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Shieu W, Torhan SA, Chan E, Hubbard A, Gikanga B, Stauch OB, Maa YF. Filling of high-concentration monoclonal antibody formulations into pre-filled syringes: filling parameter investigation and optimization. PDA J Pharm Sci Technol. 2014;68(2):153–63.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Shieu W, Lamar D, Stauch OB, Maa YF. Filling of high-concentration monoclonal antibody formulations: investigating underlying mechanisms that affect precision of low-volume fill by peristaltic pump. PDA J Pharm Sci Technol. 2016;70(2):143–56.PubMedCrossRefGoogle Scholar
  71. 71.
    Shieu W, Stauch OB, Maa YF. Filling of high-concentration monoclonal antibody formulations into pre-filled syringes: investigating formulation-nozzle interactions to minimize nozzle clogging. PDA J Pharm Sci Technol. 2015;69(3):417–26.PubMedCrossRefGoogle Scholar
  72. 72.
    Kiese S, Papppenberger A, Friess W, Mahler HC. Shaken, not stirred: mechanical stress testing of an IgG1 antibody. J Pharm Sci. 2008;97(10):4347–66.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Rathore N, Chen C, Gonzalez O, Ji W. Challenges and strategies for implementing automated visual inspection for biopharmaceuticals. Pharm Technol. 2009;2009(6).Google Scholar
  74. 74.
    Sharnez R, Lathia J, Kahlenberg D, Prabhu S, Dekleva M. In situ monitoring of soil dissolution dynamics: a rapid and simple method for determining worst-case soils for cleaning validation. PDA J Pharm Sci Technol. 2004;58(4):203–14.PubMedGoogle Scholar
  75. 75.
    Rathore N, Qi W, Ji WC. Cleaning characterization of protein drug products using UV-vis spectroscopy. Biotechnol Prog. 2008;24(3):684–90.PubMedCrossRefGoogle Scholar
  76. 76.
    Eu B, Cairns A, Ding G, Cao X, Wen ZQ. Direct visualization of protein adsorption to primary containers by gold nanoparticles. J Pharm Sci. 2011;100(5):1663–70.PubMedCrossRefGoogle Scholar
  77. 77.
    Makwana S, Basu B, Makasana Y, Dharamsi A. Prefilled syringes: an innovation in parenteral packaging. Int J Pharm Invest. 2011;1(4):200–6.CrossRefGoogle Scholar
  78. 78.
    Breitsamer M, Winter G. Needle-free injection of vesicular phospholipid gels—a novel approach to overcome an administration hurdle for semisolid depot systems. J Pharm Sci. 2016;106(4):968–72.PubMedCrossRefGoogle Scholar
  79. 79.
    Cilurzo F, Selmin F, Minghetti P, Adami M, Bertoni E, Lauria S, Montanari L. Injectability evaluation: an open issue. AAPS PharmSciTech. 2011;12(2):604–9.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Rathore N, Pranay P, Bernacki J, Eu B, Ji W, Walls E. Characterization of protein rheology and delivery forces for combination products. J Pharm Sci. 2012;101(12):4472–80.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Jenke DR. Extractables and leachables considerations for prefilled syringes. Expert Opin Drug Deliv. 2014;11(10):1591–600.PubMedCrossRefGoogle Scholar
  82. 82.
    Wen ZQ, Vance A, Vega F, Cao X, Eu B, Schulthesis R. Distribution of silicone oil in prefilled glass syringes probed with optical and spectroscopic methods. PDA J Pharm Sci Technol. 2009;63(2):149–58.PubMedGoogle Scholar
  83. 83.
    Rathore N, Pranay P, Eu B, Ji W, Walls E. Variability in syringe components and its impact on functionality of delivery systems. PDA J Pharm Sci Technol. 2011;65(5):468–80.PubMedCrossRefGoogle Scholar
  84. 84.
    Allmendinger A, Mueller R, Schwarb E, Chipperfield M, Huwyler J, Mahler HC, Fischer S. Measuring tissue back-pressure–in vivo injection forces during subcutaneous injection. Pharm Res. 2015;32(7):2229–40.PubMedCrossRefGoogle Scholar
  85. 85.
    Kang DW, Oh DA, Fu GY, Anderson JM, Zepeda ML. Porcine model to evaluate local tissue tolerability associated with subcutaneous delivery of protein. J Pharmacol Toxicol Method. 2013;67(3):140–7.CrossRefGoogle Scholar
  86. 86.
    Patte C, Pleus S, Wiegel C, Schiltges G, Jendrike N, Haug C, Freckmann G. Effect of infusion rate and indwelling time on tissue resistance pressure in small-volume subcutaneous infusion like in continuous subcutaneous insulin infusion. Diabetes Technol Therapeutics. 2013;15(4):289–94.CrossRefGoogle Scholar
  87. 87.
    Thyagarajapuram N. Presented at the PDA Europe The universe of pre-filled syringes and injection devices, Basel, Switzerland, November 7–11 2011.Google Scholar
  88. 88.
    Adler M. Challenges in the development of pre-filled syringes for biologics for a formulation scientist’s point of view. Am Pharm Rev. 2012;2/1/2012 ed. p 9.Google Scholar
  89. 89.
    Kaestner A, Roth J, Grunzweig C. Real-time neutron imaging to detect origin of blocking in drug injection devices. PDA J Pharm Sci Technol. 2016;70(4):353–60.PubMedCrossRefGoogle Scholar
  90. 90.
    Yearley EJ, Zarraga IE, Shire SJ, Scherer TM, Gokarn Y, Wagner NJ, Liu Y. Small-angle neutron scattering characterization of monoclonal antibody conformations and interactions at high concentrations. Biophys J. 2013;105(3):720–31.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Connolly BD, Petry C, Yadav S, Demeule B, Ciaccio N, Moore JM, Shire SJ, Gokarn YR. Weak interactions govern the viscosity of concentrated antibody solutions: high-throughput analysis using the diffusion interaction parameter. Biophys J. 2012;103(1):69–78.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Li L, Kumar S, Buck PM, Burns C, Lavoie J, Singh SK, Warne NW, Nichols P, Luksha N, Boardman D. Concentration dependent viscosity of monoclonal antibody solutions: explaining experimental behavior in terms of molecular properties. Pharm Res. 2014;31(11):3161–78.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Nichols P, Li L, Kumar S, Buck PM, Singh SK, Goswami S, Balthazor B, Conley TR, Sek D, Allen MJ. Rational design of viscosity reducing mutants of a monoclonal antibody: hydrophobic versus electrostatic inter-molecular interactions. mAbs. 2015; 7(1):212–30.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Shiraki K, Kudou M, Fujiwara S, Imanaka T, Takagi M. Biophysical effect of amino acids on the prevention of protein aggregation. J Biochem. 2002;132(4):591–5.PubMedCrossRefGoogle Scholar
  95. 95.
    Tsumoto K, Umetsu M, Kumagai I, Ejima D, Philo JS, Arakawa T. Role of arginine in protein refolding, solubilization, and purification. Biotechnol Prog. 2004;20(5):1301–8.PubMedCrossRefGoogle Scholar
  96. 96.
    Arakawa T, Ejima D, Tsumoto K, Obeyama N, Tanaka Y, Kita Y, Timasheff SN. Suppression of protein interactions by arginine: a proposed mechanism of the arginine effects. Biophys Chem. 2007;127(1–2):1–8.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Deirdre Murphy Piedmonte
    • 1
  • Jian Hua Gu
    • 1
  • Stephen R. Brych
    • 1
  • Monica M. Goss
    • 1
  1. 1.Amgen, Inc., Process DevelopmentOne Amgen Center DriveThousand OaksUSA

Personalised recommendations