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Stabilisation of biopharmaceutical products and finished product formulations

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Biopharmaceuticals, an Industrial Perspective

Abstract

This chapter overviews the stabilization of protein-based biopharmaceuticals. Finished biopharmaceutical products must have the required stability from a clinical and regulatory point of view. Furthermore, the stability profile should cover the manufacturing and marketing cycles of the product to minimise costs. The major routes by which proteins may be degraded are outlined. A brief description of biopharmaceutical production processes is provided to acquaint the reader with issues relating to stabilisation during processing. The basic principles of how in-process material and fmished product may be stabilized are presented. Finally, a table of major constituents in approved biopharmaceuticals is included at the end of the chapter to illustrate how stabilisation principles have been put to practice to date.

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References

  1. Federal Register (1996). International conference on harmonisation; fmal guidelines on stability testing of biotechnological/ biological products; availability; notice. 61,36466–36469.

    Google Scholar 

  2. Nguyen, T.H. and Shire, S.J. (1996). Stability and characterization of recombinant human relaxin. In: Pearlman, R. and Wang, Y.J. (Eds.) Formulation, characterization and stability of protein drugs. Plenum. New York.

    Google Scholar 

  3. Hora, M.S. et al. (1992). Lyophilized formulations of recombinant tumor necrosis factor. Pharm. Res., 9, 33–36.

    Google Scholar 

  4. Shire, S.J. Stability, characterization and formulation development of recombinant human deoxyribonuclease I [Pulmozyme® (dornase alpha)] In: Pearlman, R. and Wang, Y.J. (Eds.) Formulation, characterization and stability of protein drugs. Plenum. New York.

    Google Scholar 

  5. Wang, Y.-C. J. and Hanson. M. A. (1988). Parenteral Formulations of proteins and peptides: stability and stabilisers. J. Parenteral Sci. & Tech. 42, S4–S26.

    Google Scholar 

  6. Manning, M. C. et al. (1989). Stability of protein pharmaceuticals. Pharm. Res. 6, 903–918.

    Google Scholar 

  7. Chen, T. (1992). Formulation concerns of protein drugs. Drug Dev. and Industrial Pharmacy. 18, 1311–1354.

    Article  CAS  Google Scholar 

  8. Cleland, J. L. et al. (1993). The development of stable protein formulations: a close look at protein aggregation, deamidation, and oxidation. Critical Reviews in Therapeutic Drug Carrier Systems. 10, 307–377.

    CAS  Google Scholar 

  9. Kunitani, M. et al. (1986). Reversed-phase chromatography of interleukin-2 muteins. J. Chromatogr. 359, 391–402.

    Article  CAS  Google Scholar 

  10. Prescribing information for Nutropin AQ (1997), In: Physician desk reference, Medical Economics Company, Inc., Montville, NJ.

    Google Scholar 

  11. Becktel, W. J. and Schellman, J. A. (1987). Protein stability curves. Biopolymers. 26, 1859–1877.

    Article  CAS  Google Scholar 

  12. Kauzmann, W. (1959). Some factors in the interpretation of protein denaturation. Adv. Protein Chem. 14, 1–64.

    Google Scholar 

  13. Pace, C. N. (1975). The stability of globular proteins. CRC Crit. Rev. Biochem. 5, 1–43.

    Google Scholar 

  14. King, J. (1989). Deciphering the role of protein folding. Chem. Eng. News. 67, 32–54.

    Google Scholar 

  15. Chen, B.-L. et al. (1994). Aggregation pathway of recombinant human keratinocyte growth factor and its stabilisation. Pharm. Res. 11, 1581–1587.

    Google Scholar 

  16. Young, B.R. et al. (1988). Protein adsorption on polymeric biomaterials I. Adsorption isotherms. J. Colloid hit. Sci. 124, 28–43.

    Google Scholar 

  17. Foote, C. S. (1968). Mechanisms of photosensitized oxidation. Science, 162, 963–970.

    Article  CAS  Google Scholar 

  18. Franks, F. (1985). Biophysics and biochemistry at low temperatures. Cambridge University Press, London.

    Google Scholar 

  19. Wisniewski, R. and Wu, V. (1996) Large scale freezing and thawing of biopharmaceutical products. In: Avis, K. and Wu, V. (Eds.) Biotechnology and biopharmaceutical manufacturing, processing and preservation. Interpharm. Buffalo Grove, IL.

    Google Scholar 

  20. Akers, M.J. and Schmidt, D.J. (1997). Cryogranulation: A potential new final process for bulk drug substances. Biopharm, 10, 28–32.

    Google Scholar 

  21. Patton, J. (1998). Breathing life into protein drugs. Nature Biotechnology, 16, 141–143.

    Article  CAS  Google Scholar 

  22. Fransson, J. and Espander-Jansson, A. (1996). Local tolerance of subcutanous injections. J. Pharm. Pharmacol., 48, 1012–1015.

    Google Scholar 

  23. Franken, L.A.M. et al. (1994). Analysis of the efficacy of measures to reduce pain after subcutaneous administration of epotein alpha. Nephrol. Dial. Transplant., 9, 1295–1298.

    Google Scholar 

  24. CPMP working party on quality of medicinal products note for guidance (1994). Excipients in the dossier for application for marketing authorization of medicinal product. Commission of the European Communities, Brussels.

    Google Scholar 

  25. Commission decision on the prohibition of the use of material presenting risks as regards transmissable spongiform encephalopathies (1997). Commission of the European Communities, Brussels.

    Google Scholar 

  26. Schellman, J. A. (1975). Macromolecular binding. Biopolymers. 14, 999–1018.

    Article  CAS  Google Scholar 

  27. Schellman, J. A. (1987). The thermodynamic stability of proteins. Ann. Rev. Biophys. Biophys. Chem. 16, 115–137.

    Google Scholar 

  28. Volkin, D.B. and Middaugh, C.R. (1996). The characterization, stabilization and formulation of acidic fibroblast growth factor. In: Pearlman, R. and Wang, Y.J. (Eds.) Formulation, characterization and stability of protein drugs. Plenum. New York.

    Google Scholar 

  29. Wang, Y.J. et al. (1996). In: Pearlman, R. and Wang, Y.J. (Eds.) Formulation, characterization and stability of protein drugs. Plenum. New York.

    Google Scholar 

  30. Cleary, S. et al. (1989). Purification and characterization of tissue plasminogen activator Kringle-2 domain expressed in Escherichia coli. Biochemistry, 28, 1884–1891.

    Article  Google Scholar 

  31. Chien, Y.-W. (1996). Human insulin: basic sciences to therpeutic uses. Drug Dev. And Industrial Pharmacy. 22, 753–789.

    Google Scholar 

  32. Timasheff, S. N. and Arakawa, T. (1989). Stabilisation of protein structure by solvents. In: Creighton, T. E. (Ed.) Protein Structure, a practical approach. IRI Press, Oxford, pp. 301–345.

    Google Scholar 

  33. Yancey, P. H. et al. (1982). Living with water stress: evolution of osmolyte systems. Science, 217, 1214–1222.

    Article  CAS  Google Scholar 

  34. Santoro, M. M. et al. (1992). Increased thermal stability of proteins in the presence of naturally occurring osmolytes. Biochemistry, 31, 5278–5283.

    Article  CAS  Google Scholar 

  35. Chen, B.-L., and Arakawa, T. (1996). Stabilisation of recombinant human keratinocyte growth factor by osmolytes and salts. J. Pharm. Sci. 85, 419–422.

    Google Scholar 

  36. Katakam, M. et al. (1995). Effect of surfactants on the physical stability of recombinant human growth hormone. J. Pharm. Sci. 84, 713–716.

    Google Scholar 

  37. Johnston, T. P. (1996). Adsorption of recombinant human granulocyte colony stimulating factor (rhG-CSF) to polyvinyl chloride, polypropylene, and glass: effect of solvent additives. PDA J. Pharm. Tech. 50, 238–245.

    Google Scholar 

  38. Chang, B. S. et al. (1996). Surface-induced denaturation of proteins during freezing and its inhibition by surfactants. J. Pharm. Sci. 85, 1325–1330.

    Google Scholar 

  39. Schein, C.H. (1990). Solubility as a function of protein structure and solvent components. Bio/Technology, 8, 308–315.

    Article  CAS  Google Scholar 

  40. Franks, F. (1990). Freeze drying: from empiricism to predictability. Cryo-Letters 11, 93110.

    Google Scholar 

  41. Roser, B. (1991). Trehalose Drying: a novel replacement for freeze-drying. BioPharm. 4, 47–53.

    CAS  Google Scholar 

  42. Wolfe, S.P. et al. (1991). Protein glycation and oxidative stress in diabetes mellitus and ageing. Free Radical Biology & Medicine, 10, 339–352.

    Article  Google Scholar 

  43. Pikal, M. J. et al. (1991). The effects of formulation variables on the stability of freeze-dried human growth hormone. Pharm. Res. 8, 427–436.

    Google Scholar 

  44. Carpenter, J. F. et al. (1990). Comparison of solute-induced protein stabilisation in aqueous solution and in the frozen and dried states. J Dairy Sci. 73, 3627–3636.

    Article  CAS  Google Scholar 

  45. Carpenter, J. F. and Crowe, J. H. (1989). An infrared soectroscopic study of the interactions of carbohydrates with dried proteins. Biochemistry, 28, 3916–3922.

    Article  CAS  Google Scholar 

  46. Pikal, M. J. (1994). Freeze-drying of proteins. In: Cleland, J. L. and Langer, R. (Eds.) Formulation and delivery of proteins and peptides. ACS Symposium Series. 567, 120133.

    Google Scholar 

  47. Bell, L. N. et al. (1995). Thermally induced denaturation of lyophilised bovine somatotropin and lysozyme as impacted by moisture and excipients. J. Pharm. Sci. 84, 707–712.

    Google Scholar 

  48. Rupley, J. A. and Careri, G. (1991). Protein hydration and function. Adv. Prot. Chem. 41, 37–172.

    Google Scholar 

  49. Prestrelski, S.J. et al. (1995) Optimization of lyophilization for recombinant human interleukin-2 by dried-state conformational analysis using Fourier-transform infrared spectroscopy. Pharm. Res. 12, 1250–1259.

    CAS  Google Scholar 

  50. Tzannis, S.T. et al. (1996). Irreversible inactivation of interleukin-2 in a pump-based delivery environment. Proc. Natl. Acad. Sci. USA, 93, 5460–5465.

    Google Scholar 

  51. Hora, M. and Rana R.K. (1991). Delivery of Proleukin from a Deltec CADD pump, Data on file at Chiron Corporation, Emeryville, CA.

    Google Scholar 

  52. Hora, M.S. et al. (1990). Controlled release of interleukin-2 from biodegradable microspheres. Bio/Technology, 8, 755–758.

    Article  CAS  Google Scholar 

  53. Hora, M.S. et al. (1989). Biodegradable polymeric microspheres for controlled release of interleukin-2. Pacific Polymer Preprints of the First Pacific Polymer Conference, Maui, HE, 1, 519–520.

    Google Scholar 

  54. Cleland, J.L. and Jones, A.J.L. (1996). Stable formulations of recombinant human growth hormone and interferon-y for microencapsulation in biodegradable microspheres. Pharm. Res., 13, 1464–1475.

    Google Scholar 

  55. Cleland, J.L. et al. (1997). Recombinant human growth hormone poly(lactic-co-glycolic acid) microsphere formulation development. Adv. Drug Del. Rev., 28, 71–84.

    Google Scholar 

  56. Hunt, J.V. et al. (1988). Hydroperoxide-mediated fragmentation of proteins. Biochem. J., 250, 87–93.

    Google Scholar 

  57. Hora, M.S. et al. (1991) Development of a lyophilized formulation of interleukin-2, In: Develop. Biol. Standard., Karger, Basel.

    Google Scholar 

  58. Nguyen, T.H. et al. (1993). The kinetics of relaxin oxidation by hydrogen peroxide. Pharm. Res., 10, 1563–1571.

    Google Scholar 

  59. Charm, S.E. and Wong, B.L. (1970) Enzyme inactivation with shearing, Biotech. Bioeng., 12, 1103–1109.

    Google Scholar 

  60. Sluzky, V. et al. (1991) Kinetics of insulin aggregation in aqueous solutions upon agitation in the presence of hydrophobic surfaces. Proc. Natl. Acad. Sci. USA, 88, 93779381.

    Google Scholar 

  61. Privalov, P. L. (1990). Cold denaturation of proteins. Crit. Rev. Biochem. Molec. Biol. 25, 281–305.

    Google Scholar 

  62. Strambini, G. B. and Gabellieri, (1996). Proteins in frozen solutions: evidence of ice-induced partial unfolding. Biophys. J. 70, 971–976.

    Google Scholar 

  63. Murase, N. and Franks, F. (1989). Salt precipitation during the freeze-concentration of phosphate buffer solutions. Biophysical Chemistry, 34, 293–300.

    Article  CAS  Google Scholar 

  64. Carpenter, J. F. and Crowe, J. H. (1988). The mechanism of cryoprotection of proteins by solutes. Cryobiology, 25, 244–255.

    Article  CAS  Google Scholar 

  65. Hill, J. P. and Buckley, P. D. (1991). The use of pH indicators to identify suitable environments for freezing samples in aqueous and mixed aqueous/nonaqueous solution. Analytical Biochem. 192, 358–361.

    Article  CAS  Google Scholar 

  66. Horbett, T. A. and Brash, J.L. (1987) Proteins at interfaces: Current issues and future prospects. In: Brash, J.L. and Horbett T.A. (Eds.), Proteins at interfaces: Physicochemical and biochemical studies, American Chemical Society, Washington, D.C.

    Google Scholar 

  67. Burke, C.J. et al. (1992). The adsorption of proteins to pharmaceutical container surfaces. Int. J. Pharm., 86, 89–93.

    Google Scholar 

  68. Hora, M. et al. (1991). Compatibility of macrophage colony stimulating factor (M-CSF) with plastic components of intravenous administration systems. Pharm. Res., 8, S-59.

    Google Scholar 

  69. Physicians’ Desk Reference. (1996). Medical Economics Company, Monvale, NJ.

    Google Scholar 

  70. The Food and Drug Administration. (1998). http://www.fda.gov/cber/efoi/approve.htm

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Author information

Authors and Affiliations

  1. Department of Formulation Development, Chiron Corporation, 4560 Horton Street, Emeryville, Ca, 94608, USA

    Maninder S. Hora & Bao-lu Chen

Authors
  1. Maninder S. Hora
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  2. Bao-lu Chen
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Editor information

Editors and Affiliations

  1. University of Limerick, Limerick, Ireland

    Gary Walsh

  2. Limerick Institute of Technology, Limerick, Ireland

    Brendan Murphy

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Hora, M.S., Chen, Bl. (1999). Stabilisation of biopharmaceutical products and finished product formulations. In: Walsh, G., Murphy, B. (eds) Biopharmaceuticals, an Industrial Perspective. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-0926-2_9

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  • DOI: https://doi.org/10.1007/978-94-017-0926-2_9

  • Publisher Name: Springer, Dordrecht

  • Print ISBN: 978-90-481-5237-7

  • Online ISBN: 978-94-017-0926-2

  • eBook Packages: Springer Book Archive

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