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Polysorbate Degradation and Quality

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Challenges in Protein Product Development

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 38))

Abstract

Among many other applications, polysorbates (PSs) are used as the most common surfactants in biopharmaceutical products in particular to protect proteins against interfacial stress. Structural heterogeneity, presence of degradants and other impurities, and tendency for degradation are interrelated features found in commercial PSs with a direct impact on their functional properties in biopharmaceutical products. These pose a challenge for the analytical characterization of PSs at different stages of product development. This review article focuses on methods and strategies reported in the recent years for the analytical characterization of PSs, their degradants and other impurities within neat PS (i.e., PS raw materials), diluted PS solutions, as well as in biopharmaceutical formulations. The use of versatile and complementary methods applied in a systematic approach is crucial to understand the impact of the concentration, composition, and degradation of PSs on the quality of biopharmaceutical products.

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Abbreviations

CMC:

Critical micelle concentration

HSA:

Human serum albumin

FFA:

Free fatty acids

FID:

Flame ionization detector

ICH:

International Conference for Harmonization

MALDI-TOF:

Matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry

PS:

Polysorbates

PS20:

Polysorbate 20

PS80:

Polysorbate 80

References

  1. Frokjaer S, Otzen DE. Protein drug stability: a formulation challenge. Nat Rev Drug Discov. 2005;4(4):298–306.

    Article  PubMed  CAS  Google Scholar 

  2. Kamerzell TJ, et al. Protein–excipient interactions: mechanisms and biophysical characterization applied to protein formulation development. Adv Drug Deliv Rev. 2011;63(13):1118–59.

    Article  PubMed  CAS  Google Scholar 

  3. Lee HJ, et al. Molecular origins of surfactant-mediated stabilization of protein drugs. Adv Drug Deliv Rev. 2011;63(13):1160–71.

    Article  PubMed  CAS  Google Scholar 

  4. Cleland JL, Powell MF, Shire SJ. The development of stable protein formulations: a close look at protein aggregation, deamidation, and oxidation. Crit Rev Ther Drug Carrier Syst. 1993;10(4):307–77.

    PubMed  CAS  Google Scholar 

  5. Hillgren A, Lindgren J, Alden M. Protection mechanism of Tween 80 during freeze-thawing of a model protein. LDH. Int J Pharm. 2002;237(1–2):57–69.

    Article  PubMed  CAS  Google Scholar 

  6. Kiese S, et al. Shaken, not stirred: mechanical stress testing of an IgG1 antibody. J Pharm Sci. 2008;97(10):4347–66.

    Article  PubMed  CAS  Google Scholar 

  7. Jones LS, Bam NB, Randolph TW. Surfactant-stabilized protein formulations: a review of protein-surfactant interactions and novel analytical methodologies. In: Shahrokh Z, Cleland JL, Shire SJ, editors. Therapeutic proteins and protein formulation and delivery. Washington, DC.; 1997. pp. 206–22.

    Google Scholar 

  8. Kreilgaard L, et al. Effect of Tween 20 on freeze-thawing- and agitation-induced aggregation of recombinant human factor XIII. J Pharm Sci. 1998;87(12):1597–603.

    Article  PubMed  CAS  Google Scholar 

  9. Wang W. Protein aggregation and its inhibition in biopharmaceutics. Int J Pharm. 2005;289(1–2):1–30.

    Article  PubMed  CAS  Google Scholar 

  10. Mahler HC, et al. Protein aggregation: pathways, induction factors and analysis. J Pharm Sci. 2009;98(9):2909–34.

    Article  PubMed  CAS  Google Scholar 

  11. FDA. Approved biologics [Internet]. 2008. Available from: http://www.fda.gov/cder/biologics/biologics_table.htm.

  12. EMEA. European Public Assessment Reports [Internet]. 2009 [cited 2008; Available from: http://www.emea.europa.eu/htms/human/epar.

  13. Mahler H-C, et al. Induction and analysis of aggregates in a liquid IgG1-antibody formulation. Eur J Pharm Biopharm. 2005;59(3):407–17.

    Article  PubMed  CAS  Google Scholar 

  14. Maa Y-F, Hsu CC. Protein denaturation by combined effect of shear and air-liquid interface. Biotechnol Bioeng. 1997;54(6):503–12.

    Article  PubMed  CAS  Google Scholar 

  15. Cromwell MEM, Hilario E, Jacobson F. Protein aggregation and bioprocessing. Aaps Journal. 2006;8(3):E572–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Carpenter JF, et al. Rational design of stable lyophilized protein formulations: theory and practice. Pharm Biotechnol. 2002;13(Rational Design of Stable Protein Formulations):109–33.

    Google Scholar 

  17. Carpenter JF, et al. Rational design of stable lyophilized protein formulations: some practical advice. Pharm Res. 1997;14(8):969–75.

    Article  PubMed  CAS  Google Scholar 

  18. Chang BS, Kendrick BS, Carpenter JF. Surface-induced denaturation of proteins during freezing and its inhibition by surfactants. J Pharm Sci. 1996;85(12):1325–30.

    Article  PubMed  CAS  Google Scholar 

  19. Randolph TW, Jones LS. Surfactant-protein interactions, in rational design of stable protein formulations—theory and practice. In: Carpenter J, Manning MC, editors. New York: Kluwer Academic/Plenum Publishers; 2002. p. 159–175.

    Google Scholar 

  20. Kerwin BA, et al. Effects of Tween 80 and sucrose on acute short-term stability and long-term storage at −20 degrees C of a recombinant hemoglobin. J Pharm Sci. 1998;87(9):1062–8.

    Article  PubMed  CAS  Google Scholar 

  21. Vidanovic D, et al. Effects of nonionic surfactants on the physical stability of immunoglobulin G in aqueous solution during mechanical agitation. Pharmazie. 2003;58(6):399–404.

    PubMed  CAS  Google Scholar 

  22. Chou DK, et al. Effects of Tween 20 and Tween 80 on the stability of Albutropin during agitation. J Pharm Sci. 2005;94(6):1368–81.

    Article  PubMed  CAS  Google Scholar 

  23. Mahler H-C, et al. Induction and analysis of aggregates in a liquid IgG1-antibody formulation. Eur J Pharm Biopharm. 2005;59(3):407–17.

    Article  PubMed  CAS  Google Scholar 

  24. Carpenter JF, Arakawa T, Crowe JH. Interactions of stabilizing additives with proteins during freeze-thawing and freeze-drying. Dev Biol Stand. 1992;74:225–38; discussion 238–9.

    Google Scholar 

  25. Jones LS, et al. The effects of Tween 20 and sucrose on the stability of anti-L-selectin during lyophilization and reconstitution. J Pharm Sci. 2001;90(10):1466–77.

    Article  PubMed  CAS  Google Scholar 

  26. Liu W, Wang DQ, Nail SL. Freeze-drying of proteins from a sucrose-glycine excipient system: effect of formulation composition on the initial recovery of protein activity. AAPS PharmSciTech. 2005;6(2):E150–7.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Mahler HC, et al. Adsorption behavior of a surfactant and a monoclonal antibody to sterilizing-grade filters. J Pharm Sci. 2010;99(6):2620–7.

    Article  PubMed  CAS  Google Scholar 

  28. Charman SA, Mason KL, Charman W.N. Techniques for assessing the effects of pharmaceutical excipients on the aggregation of porcine growth hormone. Pharmaceut Res. 1993; V10(7):954–62.

    Google Scholar 

  29. Bam NB, et al. Tween protects recombinant human growth hormone against agitation-induced damage via hydrophobic interactions. J Pharm Sci. 1998;87(12):1554–9.

    Article  PubMed  CAS  Google Scholar 

  30. Kreilgaard L, et al. Effects of additives on the stability of recombinant human factor XIII during freeze-drying and storage in the dried solid. Arch Biochem Biophys. 1998;360(1):121–34.

    Article  PubMed  CAS  Google Scholar 

  31. Katakam M, Bell LN, Banga AK. Effect of surfactants on the physical stability of recombinant human growth hormone. J Pharm Sci. 1995;84(6):713–6.

    Article  PubMed  CAS  Google Scholar 

  32. Ayorinde FO, et al. Analysis of some commercial polysorbate formulations using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Rapid Commun Mass Spectrom. 2000;14(22):2116–24.

    Article  PubMed  CAS  Google Scholar 

  33. Brandner JD. The composition of NF-defined emulsifiers: sorbitan monolaurate, monopalmitate, monostearate, monooleate, polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. Drug Dev Ind Pharm. 1998;24(11):1049–54.

    Article  PubMed  CAS  Google Scholar 

  34. Frison-Norrie S, Sporns P. Investigating the molecular heterogeneity of polysorbate emulsifiers by MALDI-TOF MS. J Agric Food Chem. 2001;49(7):3335–40.

    Article  PubMed  CAS  Google Scholar 

  35. Smidrkal J, Cervenkova R, Filip V. Two-stage synthesis of sorbitan esters, and physical properties of the products. Eur J Lipid Sci Technol. 2004;106(12):851–5.

    Article  CAS  Google Scholar 

  36. Vu Dang H, et al. Composition analysis of two batches of polysorbate 60 using MS and NMR techniques. J Pharm Biomed Anal. 2006;40(5):1155–65.

    Article  PubMed  CAS  Google Scholar 

  37. Zhang R, et al. Analysis of polysorbate 80 and its related compounds by RP-HPLC with ELSD and MS detection. J Chromatogr Sci. 2012;50(7):598–607.

    Article  PubMed  CAS  Google Scholar 

  38. Bates TR, Nightingale CH, Dixon E. Kinetics of hydrolysis of poly(oxyethylene) (20) sorbitan fatty acid ester surfactants. J Pharm Pharmacol. FIELD Full Journal Title: J Pharm Pharmacol. 1973;25(6):470–7.

    Article  PubMed  CAS  Google Scholar 

  39. Lippold S, et al. Impact of mono- and poly-ester fractions on polysorbate quantitation using mixed-mode HPLC-CAD/ELSD and the fluorescence micelle assay. J Pharm Biomed Anal. 2017;132:24–34.

    Article  PubMed  CAS  Google Scholar 

  40. Tani TH, Moore JM, Patapoff TW. Single step method for the accurate concentration determination of polysorbate 80. J Chromatogr A. 1997;786(1):99–106.

    Article  CAS  Google Scholar 

  41. Hewitt D, Zhang T, Kao Y-H. Quantitation of polysorbate 20 in protein solutions using mixed-mode chromatography and evaporative light scattering detection. J Chromatogr A. 2008;1215(1–2):156–60.

    Article  PubMed  CAS  Google Scholar 

  42. Ilko D, et al. Fatty acid composition analysis in polysorbate 80 with high performance liquid chromatography coupled to charged aerosol detection. Eur J Pharm Biopharm. 2015;94:569–74.

    Article  PubMed  CAS  Google Scholar 

  43. Hewitt D, et al. Mixed-mode and reversed-phase liquid chromatography-tandem mass spectrometry methodologies to study composition and base hydrolysis of polysorbate 20 and 80. J Chromatogr A. 2011;1218(15):2138–45.

    Article  PubMed  CAS  Google Scholar 

  44. Kerwin BA. Polysorbates 20 and 80 used in the formulation of protein biotherapeutics: structure and degradation pathways. J Pharm Sci. 2008;97(8):2924–35.

    Article  PubMed  CAS  Google Scholar 

  45. Ha E, Wang W, Wang YJ. Peroxide formation in polysorbate 80 and protein stability. J Pharm Sci. 2002;91(10):2252–64.

    Article  PubMed  CAS  Google Scholar 

  46. Wasylaschuk WR, et al. Evaluation of hydroperoxides in common pharmaceutical excipients. J Pharm Sci. 2007;96(1):106–16.

    Article  PubMed  CAS  Google Scholar 

  47. Lam X, et al. Site-specific tryptophan oxidation induced by autocatalytic reaction of polysorbate 20 in protein formulation. Pharm Res. 2011:1–13.

    Google Scholar 

  48. Harmon PA, et al. A novel peroxy radical based oxidative stressing system for ranking the oxidizability of drug substances. J Pharm Sci. 2006;95(9):2014–28.

    Article  PubMed  CAS  Google Scholar 

  49. Gerhardt A, et al. Protein aggregation and particle formation in prefilled glass syringes. J Pharm Sci. 2014;103(6):1601–12.

    Article  PubMed  CAS  Google Scholar 

  50. Ludwig DB, et al. Protein adsorption and excipient effects on kinetic stability of silicone oil emulsions. J Pharm Sci. 2010;99(4):1721–33.

    Article  PubMed  CAS  Google Scholar 

  51. Britt KA, et al. Excipient effects on humanized monoclonal antibody interactions with silicone oil emulsions. J Pharm Sci. 2012;101(12):4419–32.

    Article  PubMed  CAS  Google Scholar 

  52. Basu P, et al. IgG1 aggregation and particle formation induced by silicone-water interfaces on siliconized borosilicate glass beads: a model for siliconized primary containers. J Pharm Sci. 2013;102(3):852–65.

    Article  PubMed  CAS  Google Scholar 

  53. Hawe A, Friess W. Formulation development for hydrophobic therapeutic proteins. Pharm Dev Technol. 2007;12(3):223–37.

    Article  PubMed  CAS  Google Scholar 

  54. Khan TA, Mahler HC, Kishore RS. Key interactions of surfactants in therapeutic protein formulations: a review. Eur J Pharm Biopharm. 2015;97(Pt A):60–7.

    Article  PubMed  CAS  Google Scholar 

  55. Bos MA, van Vliet T. Interfacial rheological properties of adsorbed protein layers and surfactants: a review. Adv Colloid Interface Sci. 2001;91(3):437–71.

    Article  PubMed  CAS  Google Scholar 

  56. Bam NB, et al. Tween protects recombinant human growth hormone against agitation-induced damage via hydrophobic interactions. J Pharm Sci. 1998;87(12):1554–9.

    Article  PubMed  CAS  Google Scholar 

  57. Garidel P, Hoffmann C, Blume A. A thermodynamic analysis of the binding interaction between polysorbate 20 and 80 with human serum albumins and immunoglobulins: a contribution to understand colloidal protein stabilisation. Biophys Chem. 2009;143(1–2):70–8.

    Article  PubMed  CAS  Google Scholar 

  58. Jones LS, Bam NB, Randolph TW. Surfactant-stabilized protein formulations: A review of protein-surfactants interactions and novel analytical methodologies. Ther Protein Pept Formulation Deliv. 1997;675:206–22.

    Article  CAS  Google Scholar 

  59. Perez-Gramatges A, et al. Physico-chemical studies of molecular interactions between non-ionic surfactants and bovine serum albumin. Colloids Surf B-Biointerfaces. 2010;75(1):282–9.

    Article  PubMed  CAS  Google Scholar 

  60. Nielsen AD, Borch K, Westh P. Thermochemistry of the specific binding of C12 surfactants to bovine serum albumin. Biochim Biophys Acta. 2000;1479(1–2):321–31.

    Article  PubMed  CAS  Google Scholar 

  61. Hoffmann C, et al. Insights into protein-polysorbate interactions analysed by means of isothermal titration and differential scanning calorimetry. Eur Biophys J Biophys Lett. 2009;38(5):557–68.

    Article  CAS  Google Scholar 

  62. Wu J, et al. Binding characteristics between polyethylene glycol (PEG) and proteins in aqueous solution. J Mater Chem B. 2014;2(20):2983–92.

    Article  CAS  PubMed  Google Scholar 

  63. Delgado-Magnero KH, et al. Unraveling the binding mechanism of polyoxyethylene sorbitan esters with bovine serum albumin: a novel theoretical model based on molecular dynamic simulations. Colloids Surf B-Biointerfaces. 2014;116:720–6.

    Article  PubMed  CAS  Google Scholar 

  64. McAuley WJ, Jones DS, Kett VL. Characterisation of the interaction of lactate dehydrogenase with tween-20 using isothermal titration calorimetry, interfacial rheometry and surface tension measurements. J Pharm Sci. 2009;98(8):2659–69.

    Article  PubMed  CAS  Google Scholar 

  65. Chou DK, et al. Effects of tween 20 (R) and tween 80 (R) on the stability of albutropin during agitation. J Pharm Sci. 2005;94(6):1368–81.

    Article  PubMed  CAS  Google Scholar 

  66. Tandon S, Horowitz PM. Detergent-assisted refolding of guanidinium chloride-denatured rhodanese the effects of the concentration and type of detergent. J Biol Chem. 1987;262:4486–91.

    PubMed  CAS  Google Scholar 

  67. Bam NB, Cleland JL, Randolph TW. Molten globule intermediate of recombinant human growth hormone: stabilization with surfactants. Biotechnol Prog. 1996;12(6):801–9.

    Article  PubMed  CAS  Google Scholar 

  68. Kim HL, et al. Modulation of protein adsorption by poloxamer 188 in relation to polysorbates 80 and 20 at solid surfaces. J Pharm Sci. 2014;103(4):1043–9.

    Article  PubMed  CAS  Google Scholar 

  69. Bam NB, Randolph TW, Cleland JL. Stability of protein formulations—investigation of surfactant effects by a novel EPR Spectroscopic technique. Pharm Res. 1995;12(1):2–11.

    Article  PubMed  CAS  Google Scholar 

  70. Xu RJ, Vidal-Madjar C, Sebille B. Capillary electrophoretic behavior of milk proteins in the presence of non-ionic surfactants. J Chromatogr B. 1998;706(1):3–11.

    Article  CAS  Google Scholar 

  71. Jones LS, et al. Investigation of protein-surfactant interactions by analytical ultracentrifugation and electron paramagnetic resonance: the use of recombinant human tissue factor as an example. Pharm Res. 1999;16(6):808–12.

    Article  PubMed  CAS  Google Scholar 

  72. Hillgren A, Lindgren J, Alden M. Protection mechanism of tween 80 during freeze-thawing of a model protein, LDH. Int J Pharm. 2002;237(1–2):57–69.

    Article  PubMed  CAS  Google Scholar 

  73. Kett VL, Mcauley WJ, Jones DS. Characterisation of the interaction of lactate dehydrogenase with tween-20 using isothermal titration calorimetry, interfacial rheometry and surface tension measurements. J Pharm Sci. 2009;98(8):2659–69.

    Article  PubMed  CAS  Google Scholar 

  74. Kotsmar C, et al. Thermodynamics, adsorption kinetics and rheology of mixed protein-surfactant interfacial layers. Adv Colloid Interface Sci. 2009;150(1):41–54.

    Article  PubMed  CAS  Google Scholar 

  75. Chauhan S, Jyoti J, Kumar G. Non-ionic surfactant interactions in aqueous gelatin solution: a physico-chemical investigation. J Mol Liq. 2011;159(3):196–200.

    Article  CAS  Google Scholar 

  76. McGuire J, Joshi O. Adsorption behavior of lysozyme and tween 80 at hydrophilic and hydrophobic silica-water interfaces. Appl Biochem Biotechnol. 2009;152(2):235–48.

    Article  PubMed  CAS  Google Scholar 

  77. McGuire J, et al. Adsorption and function of recombinant factor VIII at the air-water interface in the presence of tween 80. J Pharm Sci. 2009;98(9):3099–107.

    Article  PubMed  CAS  Google Scholar 

  78. Zhu XY, Shen L, Guo A. Tween surfactants: adsorption, self-organization, and protein resistance. Surf Sci. 2011;605(5–6):494–9.

    Google Scholar 

  79. Arakawa T, Kita Y. Protection of bovine serum albumin from aggregation by tween 80. J Pharm Sci. 2000;89(5):646–51.

    Article  PubMed  CAS  Google Scholar 

  80. Kim HL, Mcauley A, Mcguire J. Protein effects on surfactant adsorption suggest the dominant mode of surfactant-mediated stabilization of protein. J Pharm Sci. 2014;103(5):1337–45.

    Article  PubMed  CAS  Google Scholar 

  81. Lin SY, Lu TL, Hwang WB. Adsorption-kinetics of decanol at the air-water-interface. Langmuir. 1995;11(2):555–62.

    Article  CAS  Google Scholar 

  82. Wustneck R, et al. Dynamic surface tension and adsorption properties of beta-casein and beta-lactoglobulin. Food Hydrocolloids. 1996;10(4):395–405.

    Article  Google Scholar 

  83. Gunning PA, et al. Effect of surfactant type on surfactant-protein interactions at the air-water interface. Biomacromol. 2004;5(3):984–91.

    Article  CAS  Google Scholar 

  84. Elwing H, et al. A wettability gradient method for studies of macromolecular interactions at the liquid/solid interface. J Colloid Interface Sci. 1987;119(1):203–10.

    Article  CAS  Google Scholar 

  85. Joshi O, McGuire J. Adsorption behavior of lysozyme and tween 80 at hydrophilic and hydrophobic silica-water interfaces. Appl Biochem Biotechnol. 2009;152(2):235–48.

    Article  PubMed  CAS  Google Scholar 

  86. Rabe M, Verdes D, Seeger S. Understanding protein adsorption phenomena at solid surfaces. Adv Coll Interface Sci. 2011;162(1–2):87–106.

    Article  CAS  Google Scholar 

  87. Sammond DW, et al. Predicting enzyme adsorption to lignin films by calculating enzyme surface hydrophobicity. J Biol Chem. 2014;289(30):20960–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Absolom DR, Zingg W, Neumann AW. Protein adsorption to polymer particles—role of surface-properties. J Biomed Mater Res. 1987;21(2):161–71.

    Article  PubMed  CAS  Google Scholar 

  89. Rampon V, et al. Evidence that homogenization of BSA-stabilized hexadecane-in-water emulsions induces structure modification of the nonadsorbed protein. J Agric Food Chem. 2003;51(20):5900–5.

    Article  PubMed  CAS  Google Scholar 

  90. Rampon V, et al. Front-face fluorescence spectroscopy study of globular proteins in emulsions: displacement of BSA by a nonionic surfactant. J Agric Food Chem. 2003;51(9):2482–9.

    Article  PubMed  CAS  Google Scholar 

  91. Rampon V, et al. Front-face fluorescence spectroscopy study of globular proteins in emulsions: influence of droplet flocculation. J Agric Food Chem. 2003;51(9):2490–5.

    Article  PubMed  CAS  Google Scholar 

  92. Li JJ, et al. Mechanistic understanding of protein-silicone oil interactions. Pharm Res. 2012;29(6):1689–97.

    Article  PubMed  CAS  Google Scholar 

  93. Dixit N, Maloney KM, Kalonia DS. Protein-silicone oil interactions: comparative effect of nonionic surfactants on the interfacial behavior of a fusion protein. Pharm Res. 2013;30(7):1848–59.

    Article  PubMed  CAS  Google Scholar 

  94. Wan LSC, Lee PFS. CMC of polysorbates. J Pharm Sci. 1974;63(1):136–7.

    Article  PubMed  CAS  Google Scholar 

  95. Mahler HC, et al. Surface activity of a monoclonal antibody. J Pharm Sci. 2009;98(12):4525–33.

    Article  PubMed  CAS  Google Scholar 

  96. Dixit N, Zeng DL, Kalonia DS. Application of maximum bubble pressure surface tensiometer to study protein-surfactant interactions. Int J Pharm. 2012;439(1–2):317–23.

    Article  PubMed  CAS  Google Scholar 

  97. Mackie AR, et al. Orogenic displacement of protein from the air/water interface by competitive adsorption. J Colloid Interface Sci. 1999;210(1):157–66.

    Article  PubMed  CAS  Google Scholar 

  98. Gibbs JW. On the equilibrium of heterogeneous substances. Am J Sci. 1878; Series 3 Vol. 16(96):441–58.

    Article  Google Scholar 

  99. Mackie AR, et al. Orogenic displacement of protein from the oil/water interface. Langmuir. 2000;16(5):2242–7.

    Article  CAS  Google Scholar 

  100. Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2008;84(5):548–58.

    Article  PubMed  CAS  Google Scholar 

  101. Loos WJ, et al. Clinical pharmacokinetics of unbound docetaxel: role of polysorbate 80 and serum proteins. Clin Pharmacol Ther. 2003;74(4):364–71.

    Article  PubMed  CAS  Google Scholar 

  102. ten Tije A, et al. Pharmacological effects of formulation vehicles. Clin Pharmacokinet. 2003;42(7):665–85.

    Article  PubMed  Google Scholar 

  103. Levine HL, et al. The use of surface tension measurements in the design of antibody-based product formulations. J Parenter Sci Technol. 1991;45(3):160.

    PubMed  CAS  Google Scholar 

  104. Dickinson E. Proteins at interfaces and in emulsions—stability, rheology and interactions. J Chem Soc—Faraday Trans. 1998;94(12):1657–69.

    Article  CAS  Google Scholar 

  105. Pugnaloni LA, et al. Competitive adsorption of proteins and low-molecular-weight surfactants: computer simulation and microscopic imaging. Adv Coll Interface Sci. 2004;107(1):27–49.

    Article  CAS  Google Scholar 

  106. Wang Y-CJ, Hanson MA. Parenteral formulations of proteins and peptides: stability and stabilizers. PDA J Pharm Sci Technol. 1988;42:S1–25.

    Google Scholar 

  107. Timasheff N. The control of protein stability and association by weak interactions with water: how do solvents affect these processes? Annu Rev Biophys Biomol Struct. 1993;22:67–97.

    Article  PubMed  CAS  Google Scholar 

  108. Mahler HC. Stabilisierung und Analyse pharmazeutischer Proteinformulierungen. In: Fachbereich Chemische und Pharmazeutische Wissenschaften. Frankfurt: Johann Wolfgang Goethe-Universität; 2009.

    Google Scholar 

  109. Zimmerman SB, Minton AP. Macromolecular crowding: biochemical, biophysical, and physiological consequences. Annu Rev Biophys Biomol Struct. 1993;22:27–65.

    Article  PubMed  CAS  Google Scholar 

  110. Hall D, Minton AP. Macromolecular crowding: qualitative and semiquantitative successes, quantitative challenges. Biochim Biophys Acta. 2003;1649(2):127–39.

    Article  PubMed  CAS  Google Scholar 

  111. Kiese S, et al. Equilibrium studies of protein aggregates and homogeneous nucleation in protein formulation. J Pharm Sci. 2010;99(2):632–44.

    Article  PubMed  CAS  Google Scholar 

  112. Kishore RSK, et al. The degradation of polysorbate 20 and 80 and its potential impact on the stability of biotherapeutics. Pharm Res. 2011;28(5):1194–210.

    Article  PubMed  CAS  Google Scholar 

  113. Rosenberg AS. Effects of protein aggregates: an immunologic perspective. AAPS J. 2006;8(3):E501–7.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Saggu M, Liu J, Patel A. Identification of subvisible particles in biopharmaceutical formulations using raman spectroscopy provides insight into polysorbate 20 degradation pathway. Pharm Res. 2015;32(9):2877–88.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Dixit N, et al. Residual host cell protein promotes polysorbate 20 degradation in a sulfatase drug product leading to free fatty acid particles. J Pharm Sci. 2016;105(5):1657–66.

    Article  PubMed  CAS  Google Scholar 

  116. 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(8):2268–77.

    Article  PubMed  CAS  Google Scholar 

  117. Hall T, et al. Polysorbates 20 and 80 degradation by group XV lysosomal phospholipase A2 isomer X1 in monoclonal antibody formulations. J Pharm Sci. 2016;105(5):1633–42.

    Article  PubMed  CAS  Google Scholar 

  118. Borisov OV, Ji JA, Wang YJ. Oxidative degradation of polysorbate surfactants studied by liquid chromatography-mass spectrometry. J Pharm Sci. 2015;104(3):1005–18.

    Article  PubMed  CAS  Google Scholar 

  119. Kishore RSK, et al. Degradation of polysorbates 20 and 80: studies on thermal autoxidation and hydrolysis. J Pharm Sci. 2011;100(2):721–31.

    Article  PubMed  CAS  Google Scholar 

  120. Zhang L, et al. Degradation mechanisms of polysorbate 20 differentiated by 18O-labeling and mass spectrometry. Pharm Res. 2017;34(1):84–100.

    Article  PubMed  CAS  Google Scholar 

  121. Donbrow M, Azaz E, Pillersdorf A. Autoxidation of polysorbates. J. Pharm. Sci. FIELD Full Journal Title: J Pharm Sci. 1978;67(12):1676–81.

    Article  PubMed  CAS  Google Scholar 

  122. Mueller R, et al. Evaluation of the immuno-stimulatory potential of stopper extractables and leachables by using dendritic cells as readout. 2009;98(10):3548–61.

    CAS  Google Scholar 

  123. Yao J, et al. A quantitative kinetic study of polysorbate autoxidation: the role of unsaturated fatty acid ester substituents. Pharm Res. 2009;26(10):2303–13.

    Article  PubMed  CAS  Google Scholar 

  124. Li S, Schöneich C, Borchardt RT. Chemical instability of protein pharmaceuticals: mechanisms of oxidation and strategies for stabilization. Wiley; 2004, pp. 490–500.

    Article  PubMed  CAS  Google Scholar 

  125. Donbrow M, Hamburger R, Azaz E. Surface tension and cloud point changes of polyoxyethylenic nonionic surfactants during autoxidation. J Pharm Pharmacol. FIELD Full Journal Title: J Pharmacy and Pharmacology. 1975;27(3):160–6.

    Article  PubMed  CAS  Google Scholar 

  126. Donbrow M, et al. Development of acidity in nonionic surfactants: formic and acetic acid. Analyst (London) FIELD Full Journal Title: Analyst (Cambridge, United Kingdom). 1978;103(1225):400–2.

    Google Scholar 

  127. Ha E, Wang W, Wang YJ. Peroxide formation in polysorbate 80 and protein stability. J. Pharm. Sci. FIELD Full Journal Title: J Pharm Sci. 2002;91(10):2252–64.

    Article  PubMed  CAS  Google Scholar 

  128. Hamburger R, Azaz E, Donbrow M. Autoxidation of polyoxyethylenic nonionic surfactants and of polyethylene glycols. Pharm Acta Helv. FIELD Full Journal Title: Pharmaceutica Acta Helvetiae. 1975;50(1–2):10–17.

    Google Scholar 

  129. Kerwin BA. Polysorbates 20 and 80 used in the formulation of protein biotherapeutics: structure and degradation pathways. J Pharm Sci. 2008;97(8):2924–35.

    Article  PubMed  CAS  Google Scholar 

  130. Magill A, Becker AR. Spectrophotometric method for quantitation of peroxides in sorbitan monooleate and monostearate. J Pharm Sci. FIELD Full Journal Title: J Pharm Sci. 1984;73(11):1663–4.

    Article  PubMed  CAS  Google Scholar 

  131. Segal R, Azaz E, Donbrow M. Peroxide removal from nonionic surfactants. J Pharm Pharmacol. FIELD Full Journal Title: J Pharm Pharmacol. 1979;31(1):39–40.

    Article  PubMed  CAS  Google Scholar 

  132. Wasylaschuk WR, et al. Evaluation of hydroperoxides in common pharmaceutical excipients. J Pharm Sci. 2007;96(1):106–16.

    Article  PubMed  CAS  Google Scholar 

  133. Li S, Schoneich C, Borchardt RT. Chemical instability of protein pharmaceuticals: mechanism of oxidation and strategies for stabilization. Biotechnol Bioeng. 1995;48(5):490–500.

    Article  PubMed  CAS  Google Scholar 

  134. Decker C, Marchal J. Autoxydation radio-induite du poly (oxyéthylène) en solution aqueuse, 7. Cinétique de la consommation d’oxygène, pp. 3531–40.

    Google Scholar 

  135. Dulog VL, Storck G. Die oxydation von polyepoxiden mit molekularem sauerstoff. 1966:50–73.

    Article  CAS  Google Scholar 

  136. Kishore RSK, Pappenberger A, Dauphin IB, Ross A, Buergi B, Staempfli A, Mahler H-C. An assessment of degradation of polysorbate 20 and 80: studies on thermal auto-oxidation in bulk and hydrolysis in formulations. J Pharm Sci. 2010.

    Google Scholar 

  137. Donbrow M. Stability of polyoxyethylene chain in non ionic surfactants. In: Schick MJ, editor. Nonionic surfactants: physical chemistry. New york: CRC Press; 1987. p. 1135.

    Google Scholar 

  138. Zhou Y, Woo LK, Angelici RJ. Solid acid catalysis of tandem isomerization-lactonization of olefinic acids. Elsevier; 2007.

    Article  CAS  Google Scholar 

  139. Shepherd IS, Showell JS. The mechanism of the aqueous perchloric acid isomerization of oleic acid to -stearolactone. Springer; 1969. p. 479–81.

    Article  CAS  Google Scholar 

  140. Arudi RL, Sutherland MW, Bielski BH. Purification of oleic acid and linoleic acid. 1983. p. 485.

    Google Scholar 

  141. Tomita M, Irie M, Ukita T. Sensitized photooxidation of histidine and its derivatives. Products and mechanism of the reaction. Am Chem Soc. 1969:5149–5160.

    Article  PubMed  CAS  Google Scholar 

  142. Carey FA, Sundberg RJ. Advanced organic chemistry. Springer Verlag; 2007.

    Google Scholar 

  143. Tomlinson A, et al. Polysorbate 20 degradation in biopharmaceutical formulations: quantification of free fatty acids, characterization of particulates, and insights into the degradation mechanism. Mol Pharm. 2015;12(11):3805–15.

    Article  PubMed  CAS  Google Scholar 

  144. Hvattum E, et al. Characterization of polysorbate 80 with liquid chromatography mass spectrometry and nuclear magnetic resonance spectroscopy: specific determination of oxidation products of thermally oxidized polysorbate 80. J Pharm Biomed Anal. 2012;62:7–16.

    Article  PubMed  CAS  Google Scholar 

  145. Nimura N, et al. 1-Pyrenyldiazomethane as a fluorescent labeling reagent for liquid chromatographic determination of carboxylic acids. Anal Chem. 1988;60(19):2067–70.

    Article  PubMed  CAS  Google Scholar 

  146. Khossravi M, et al. Analysis methods of polysorbate 20: a new method to assess the stability of polysorbate 20 and established methods that may overlook degraded polysorbate 20. Pharm Res. 2002;19(5):634–9.

    Article  PubMed  CAS  Google Scholar 

  147. Adamo M, et al. A simple reversed phaseHPLCaphy method for polysorbate 80 quantitation in monoclonal antibody drug products. J Chromatogr B: Anal Technol Biomed Life Sci. 2010; 878(21):1865–70.

    Google Scholar 

  148. Siska CC, et al. Free fatty acid particles in protein formulations. Part 2: contribution of polysorbate raw material. J Pharm Sci. 2015;104(2):447–56.

    Article  PubMed  CAS  Google Scholar 

  149. Daniels DH, Warner CR, Selim S. Determination of polysorbate 60 in salad dressings by colorimetric and thin layer chromatographic techniques. J Assoc Off Anal Chem. 1982;65(1):162–5.

    CAS  Google Scholar 

  150. Savjani N, et al. Use of ferric thiocyanate derivatization for quantification of polysorbate 80 in high concentration protein formulations. Talanta. 2014;130:542–6.

    Article  PubMed  CAS  Google Scholar 

  151. Wasylaschuk WR, et al. Evaluation of hydroperoxides in common pharmaceutical excipients. J Pharm Sci. 2006;96(1):106–16.

    Article  CAS  Google Scholar 

  152. Nair LM, et al. Determination of polysorbate 80 in parenteral formulations by high-performance liquid chromatography and evaporative light scattering detection. J Chromatogr A. 2003;1012(1):81–6.

    Article  PubMed  CAS  Google Scholar 

  153. Nayak VS, et al. Evaporative light scattering detection based HPLC method for the determination of polysorbate 80 in therapeutic protein formulations. J Chromatogr Sci. 2012;50(1):21–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Fekete S, Ganzler K, Fekete J. Fast and sensitive determination of Polysorbate 80 in solutions containing proteins. J Pharm Biomed Anal. 2010;52(5):672–9.

    Article  PubMed  CAS  Google Scholar 

  155. Verbrugghe M, et al. Quantification of hydrophilic ethoxylates in polysorbate surfactants using diffusion 1H NMR spectroscopy. J Pharm Biomed Anal. 2010;51(3):583–9.

    Article  PubMed  CAS  Google Scholar 

  156. Lei M, et al. The effects of membrane filters used in biopharmaceutical processes on the concentration and composition of polysorbate 20. Biotechnol Prog. 2013;29(6):1503–11.

    Article  PubMed  CAS  Google Scholar 

  157. Zhang Q, et al. NMR method for accurate quantification of polysorbate 80 copolymer composition. Anal Chem (Washington, DC, U. S.). 2015;87(19):9810–16.

    Article  PubMed  CAS  Google Scholar 

  158. Doshi N, Demeule B, Yadav S. Understanding particle formation: solubility of free fatty acids as polysorbate 20 degradation byproducts in therapeutic monoclonal antibody formulations. Mol. Pharmaceutics. 2015;12(11):3792–804.

    Article  CAS  Google Scholar 

  159. Mahler H-C, et al. Behaviour of polysorbate 20 during dialysis, concentration and filtration using membrane separation techniques. J Pharm Sci. 2007;97(2):764–74.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Pharmaceutical Development, F. Hoffmann-La Roche, Ltd., 4070, Basel, Switzerland

    Kishore S. K. Ravuri

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Correspondence to Kishore S. K. Ravuri .

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  1. BioTherapeutics Research and Development Pharmaceutics Research and Development, Pfizer Inc., Andover, Massachusetts, USA

    Nicholas W. Warne

  2. Lonza AG, Drug Product Services, Basel, Basel Stadt, Switzerland

    Hanns-Christian Mahler

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Ravuri, K.S.K. (2018). Polysorbate Degradation and Quality. In: Warne, N., Mahler, HC. (eds) Challenges in Protein Product Development. AAPS Advances in the Pharmaceutical Sciences Series, vol 38. Springer, Cham. https://doi.org/10.1007/978-3-319-90603-4_2

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