AAPS PharmSciTech

, Volume 19, Issue 8, pp 3681–3686 | Cite as

Interactions Between Biological Products and Product Packaging and Potential Approaches to Overcome Them

  • Minjia Wang
  • Yusheng Li
  • Priyanka Srinivasan
  • Zhiqing Hu
  • Rui Wang
  • Anggrida Saragih
  • M. A. Repka
  • S. N. Murthy


Biological products such as protein-based biopharmaceuticals are playing an important role in the healthcare and pharmaceutical industry. The interaction between biological products and packaging materials has become the focus of many studies since it can reduce the effectiveness of biological products. These interactions are heavily influenced by the surface properties and physicochemical nature of the therapeutic agents and the packaging materials. Therefore, it is critical to understand the interactions between packaging materials and biological products in order to design biocompatible packaging materials and develop approaches to minimize adverse interactions. We describe the interactions that occur when using several common packaging materials, including glass and polymer. We discuss the interaction between these materials and biological products such as blood, blood derivatives, recombinant proteins, monoclonal antibodies, and gene therapeutics. We also summarize approaches for overcoming these interactions. Understanding the interactions between biological materials and packaging materials is critical for the development of novel packaging materials that improve the safety of pharmaceutical products.

Key Words

biological interaction packaging stability incompatibility 


  1. 1.
    Rader RA. (Re)defining biopharmaceutical. Nat Biotechnol. 2008;26(7):743–51.CrossRefPubMedGoogle Scholar
  2. 2.
    Chen H. Biocompatible polymer materials: role of protein–surface interactions. Prog Polym Sci. 2008;33:1059–87.CrossRefGoogle Scholar
  3. 3.
    Food and Drug Administration (FDA). Guidance for industry- container closure systems for packaging human drugs and biologics. 1999.Google Scholar
  4. 4.
    Feenstra P, Brunsteiner M, Khinast J. Investigation of migrant-polymer interaction in pharmaceutical packaging material using the linear interaction energy algorithm. J Pharm Sci. 2014;103(10):3197–204.CrossRefPubMedGoogle Scholar
  5. 5.
    Tavernise S. “FDA makes it official: BPA can’t be used in baby bottles and cups.” New York Times (2012).Google Scholar
  6. 6.
    Wang W. Instability, stabilization, and formulation of liquid protein pharmaceutical. Int J Pharm. 1999;185:129–88.CrossRefPubMedGoogle Scholar
  7. 7.
    Ruiz L, Influence of packaging material on the liquid stability of interferon-α2b. Journal of Pharm Pharmaceut Sci, 2005: p. 207–216.Google Scholar
  8. 8.
    Hendrick JP, Hartl FU. The role of molecular chaperones in protein folding. FASEB J. 1995;9(15):1559–69.CrossRefPubMedGoogle Scholar
  9. 9.
    Golbik R, Zahn R, Harding SE, Fersht AR. Thermodynamic stability and folding of GroEL minichaperones. J Mol Biol. 1998;276(2):505–15.CrossRefPubMedGoogle Scholar
  10. 10.
    Thomson JA, Shirley BA, Grimsley GR, Pace CN. Conformational stability and mechanism of folding of ribonuclease T1. J Biol Chem. 1989;264(20):11614–20.PubMedGoogle Scholar
  11. 11.
    Jaenicke R. Protein stability and molecular adaptation to extreme conditions. Eur J Biochem. 1991;202(3):715–28.CrossRefPubMedGoogle Scholar
  12. 12.
    Kristjansson MM, Kinsella JE. Protein and enzyme stability: structural, thermodynamic, and experimental aspects. Adv Food Nutr Res. 1991;35:237–316.CrossRefPubMedGoogle Scholar
  13. 13.
    The four most common glass types, in Department of Chemistry and Biochemistry, University of Delaware. 2006.Google Scholar
  14. 14.
    Chen BL, Arakawa T, Morris CF, Kenney WC, Wells CM, Pitt CG. Aggregation pathway of recombinant human keratinocyte growth factor and its stabilization. Pharm Res. 1994;11(11):1581–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Chapman RG, Ostuni E, Takayama S, Holmlin RE, Yan L, Whitesides GM. Surveying for surfaces that resist the adsorption of proteins. J Am Chem Soc. 2000;122(34):8303–4.CrossRefGoogle Scholar
  16. 16.
    Ostuni E, Chapman RG, Holmlin RE, Takayama S, Whitesides GM. A survey of structure−property relationships of surfaces that resist the adsorption of protein. Langmuir. 2001;17(18):5605–20.CrossRefGoogle Scholar
  17. 17.
    Tsukagoshi T, Kondo Y, Yoshino N. Protein adsorption and stability of poly(ethylene oxide)-modified surfaces having hydrophobic layer between substrate and polymer. Colloids Surf B: Biointerfaces. 2007;54(1):82–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Sofia SJ, Merrill EW. Grafting of PEO to polymer surfaces using electron beam irradiation. J Biomed Mater Res. 1998;40(1):153–63.CrossRefPubMedGoogle Scholar
  19. 19.
    Li ZF, Ruckenstein E. Grafting of poly(ethylene oxide) to the surface of polyaniline films through a chlorosulfonation method and the biocompatibility of the modified films. J Colloid Interface Sci. 2004;269(1):62–71.CrossRefPubMedGoogle Scholar
  20. 20.
    Park JH, Bae YH. Hydrogels based on poly(ethylene oxide) and poly(tetramethylene oxide) or poly(dimethyl siloxane): synthesis, characterization, in vitro protein adsorption and platelet adhesion. Biomaterials. 2002;23(8):1797–808.CrossRefPubMedGoogle Scholar
  21. 21.
    Leckband D, Sheth S, Halperin A. Grafted poly(ethylene oxide) brushes as nonfouling surface coatings. J Biomater Sci Polym Ed. 1999;10(10):1125–47.CrossRefPubMedGoogle Scholar
  22. 22.
    Sanchez J, et al. Inhibition of the plasma contact activation system of immobilized heparin: relation to surface density of functional antithrombin binding sites. J Biomed Mater Res. 1997;37(1):37–42.CrossRefPubMedGoogle Scholar
  23. 23.
    Norde W, Gage D. Interaction of bovine serum albumin and human blood plasma with PEO-tethered surfaces: influence of PEO chain length, grafting density, and temperature. Langmuir. 2004;20(10):4162–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Prowse CV, de Korte D, Hess JR, van der Meer PF, the Biomedical Excellence for Safer Transfusion (BEST) Collaborative. Commercially available blood storage containers. Vox Sang. 2014;106(1):1–13.CrossRefPubMedGoogle Scholar
  25. 25.
    Zhang Y. Detection and identification of leachables in vaccine from plastic packaging materials using UPLC-QTOF MS with self-built polymer additives library. Anal Chem. 2016;88:6749–57.CrossRefPubMedGoogle Scholar
  26. 26.
    Simmchen J, Ventura R, Segura J. Progress in the removal of di-[2-ethylhexyl]-phthalate as plasticizer in blood bags. Transfus Med Rev. 2012;26(1):27–37.CrossRefPubMedGoogle Scholar
  27. 27.
    Directorate C, Medical devices containing DEHP plasticised PVC; neonates and other groups possibly at risk from DEHP toxicity. 2002.Google Scholar
  28. 28.
    Teska BM, Brake JM, Tronto GS, Carpenter JF. Aggregation and particle formation of therapeutic proteins in contact with a novel fluoropolymer surface versus siliconized surfaces: effects of agitation in vials and in prefilled syringes. J Pharm Sci. 2016;105(7):2053–65.CrossRefPubMedGoogle Scholar
  29. 29.
    Carpenter JF, Silicone oil microdroplets and protein aggregates in repackaged bevacizumab and ranibizumab: effects of long-term storage and product mishandling. IOVS, 2011: p. 1023–1034.Google Scholar
  30. 30.
    Nayef L, Khan MF, Brook MA. The stability of insulin solutions in syringes is improved by ensuring lower molecular weight silicone lubricants are absent. Heliyon. 2017;3(3):e00264.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Basu P, Sampathkumarkrishnan, Thirumangalathu R, Randolph TW, Carpenter JF. 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.CrossRefPubMedGoogle Scholar
  32. 32.
    Basu P, Blake-Haskins AW, O’Berry KB, Randolph TW, Carpenter JF. Albinterferon alpha2b adsorption to silicone oil-water interfaces: effects on protein conformation, aggregation, and subvisible particle formation. J Pharm Sci. 2014;103(2):427–36.CrossRefPubMedGoogle Scholar
  33. 33.
    Kiminami H. Impact of sterilization method on protein aggregation and particle formation in polymer-based syringes. J Pharm Sci. 2017;106:1001–7.CrossRefPubMedGoogle Scholar
  34. 34.
    Casadevall N, Nataf J, Viron B, Kolta A, Kiladjian JJ, Martin-Dupont P, et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med. 2002;346(7):469–75.CrossRefPubMedGoogle Scholar
  35. 35.
    Boven K, Stryker S, Knight J, Thomas A, van Regenmortel M, Kemeny DM, et al. The increased incidence of pure red cell aplasia with an Eprex formulation in uncoated rubber stopper syringes. Kidney Int. 2005;67(6):2346–53.CrossRefPubMedGoogle Scholar
  36. 36.
    Rosenberg AS. Effects of protein aggregates: an immunologic perspective. AAPS J. 2006;8(3):E501–7.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Seidl A, Hainzl O, Richter M, Fischer R, Böhm S, Deutel B, et al. Tungsten-induced denaturation and aggregation of epoetin alfa during primary packaging as a cause of immunogenicity. Pharm Res. 2012;29(6):1454–67.CrossRefPubMedGoogle Scholar
  38. 38.
    Kumru OS, Liu J, Ji JA, Cheng W, Wang YJ, Wang T, et al. Compatibility, physical stability, and characterization of an IgG4 monoclonal antibody after dilution into different intravenous administration bags. J Pharm Sci. 2012;101(10):3636–50.CrossRefPubMedGoogle Scholar
  39. 39.
    Parti R, Mankarious S. Stability assessment of lyophilized intravenous immunoglobulin after reconstitution in glass containers and poly(vinyl chloride) bags. Biotechnol Appl Biochem. 1997;25(Pt 1):13–8.CrossRefPubMedGoogle Scholar
  40. 40.
    Ikesue H, Vermeulen LC, Hoke R, Kolesar JM. Stability of cetuximab and panitumumab in glass vials and polyvinyl chloride bags. Am J Health Syst Pharm. 2010;67(3):223–6.CrossRefPubMedGoogle Scholar
  41. 41.
    Thurow H, Geisen K. Stabilisation of dissolved proteins against denaturation at hydrophobic interfaces. Diabetologia. 1984;27(2):212–8.PubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Minjia Wang
    • 1
  • Yusheng Li
    • 1
  • Priyanka Srinivasan
    • 1
  • Zhiqing Hu
    • 1
  • Rui Wang
    • 1
  • Anggrida Saragih
    • 1
  • M. A. Repka
    • 1
  • S. N. Murthy
    • 1
  1. 1.Department of Pharmaceutics & Drug DeliveryThe University of MississippiUniversityUSA

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