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.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Rader RA. (Re)defining biopharmaceutical. Nat Biotechnol. 2008;26(7):743–51.
Chen H. Biocompatible polymer materials: role of protein–surface interactions. Prog Polym Sci. 2008;33:1059–87.
Food and Drug Administration (FDA). Guidance for industry- container closure systems for packaging human drugs and biologics. 1999.
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.
Tavernise S. “FDA makes it official: BPA can’t be used in baby bottles and cups.” New York Times (2012).
Wang W. Instability, stabilization, and formulation of liquid protein pharmaceutical. Int J Pharm. 1999;185:129–88.
Ruiz L, Influence of packaging material on the liquid stability of interferon-α2b. Journal of Pharm Pharmaceut Sci, 2005: p. 207–216.
Hendrick JP, Hartl FU. The role of molecular chaperones in protein folding. FASEB J. 1995;9(15):1559–69.
Golbik R, Zahn R, Harding SE, Fersht AR. Thermodynamic stability and folding of GroEL minichaperones. J Mol Biol. 1998;276(2):505–15.
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.
Jaenicke R. Protein stability and molecular adaptation to extreme conditions. Eur J Biochem. 1991;202(3):715–28.
Kristjansson MM, Kinsella JE. Protein and enzyme stability: structural, thermodynamic, and experimental aspects. Adv Food Nutr Res. 1991;35:237–316.
The four most common glass types, in Department of Chemistry and Biochemistry, University of Delaware. 2006.
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.
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.
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.
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.
Sofia SJ, Merrill EW. Grafting of PEO to polymer surfaces using electron beam irradiation. J Biomed Mater Res. 1998;40(1):153–63.
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.
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.
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.
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.
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.
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.
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.
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.
Directorate C, Medical devices containing DEHP plasticised PVC; neonates and other groups possibly at risk from DEHP toxicity. 2002.
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.
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.
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.
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.
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.
Kiminami H. Impact of sterilization method on protein aggregation and particle formation in polymer-based syringes. J Pharm Sci. 2017;106:1001–7.
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.
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.
Rosenberg AS. Effects of protein aggregates: an immunologic perspective. AAPS J. 2006;8(3):E501–7.
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.
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.
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.
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.
Thurow H, Geisen K. Stabilisation of dissolved proteins against denaturation at hydrophobic interfaces. Diabetologia. 1984;27(2):212–8.
About this article
Cite this article
Wang, M., Li, Y., Srinivasan, P. et al. Interactions Between Biological Products and Product Packaging and Potential Approaches to Overcome Them. AAPS PharmSciTech 19, 3681–3686 (2018). https://doi.org/10.1208/s12249-018-1184-z