DEHP Nanodroplets Leached From Polyvinyl Chloride IV Bags Promote Aggregation of IVIG and Activate Complement in Human Serum.

Publisher: Elsevier Country of Publication: United States NLM ID: 2985195R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-6017 (Electronic) Linking ISSN: 00223549 NLM ISO Abbreviation: J Pharm Sci Subsets: MEDLINE

Publication: 2016- : New York, NY : Elsevier
Original Publication: Easton, Pa., American Pharmaceutical Assn.

Protein Aggregates*; Complement Activation/*drug effects ; Diethylhexyl Phthalate/*chemistry ; Immunoglobulins, Intravenous/*chemistry ; Immunologic Factors/*blood ; Nanoparticles/*chemistry ; Polyvinyl Chloride/*chemistry; Complement C3a/analysis ; Complement C4a/analysis ; Diethylhexyl Phthalate/toxicity ; Drug Contamination/prevention & control ; Drug Packaging ; Drug Stability ; Gas Chromatography-Mass Spectrometry ; Humans ; Nanoparticles/toxicity ; Particle Size ; Plasticizers/chemistry ; Plasticizers/toxicity ; Protein Stability ; Rheology ; Surface Properties

Concerns regarding the impact of subvisible particulate impurities on the safety and efficacy of therapeutic protein products have led manufacturers to implement strategies to minimize protein aggregation and particle formation during manufacturing, storage, and shipping. However, once these products are released, manufacturers have limited control over product handling. In this work, we investigated the effect of di(2-ethylhexyl) phthalate (DEHP) nanodroplets generated in polyvinyl chloride (PVC) bags of intravenous (IV) saline on the stability and immunogenicity of IV immunoglobulin (IVIG) formulations. We showed that PVC IV bags containing saline can release DEHP droplets into the solution when agitated or transported using a pneumatic tube transportation system in a clinical setting. We next investigated the effects of emulsified DEHP nanodroplets on IVIG stability and immunogenicity. IVIG adsorbed strongly to DEHP nanodroplets, forming a monolayer. In addition, DEHP nanodroplets accelerated IVIG aggregation in agitated samples. The immunogenicity of DEHP nanodroplets and IVIG aggregates generated in these formulations were evaluated using an in vitro assay of complement activation in human serum. The results suggested DEHP nanodroplets shed from PVC IV bags could reduce protein stability and induce activation of the complement system, potentially contributing to adverse immune responses during the administration of therapeutic proteins.
(Copyright © 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

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R01 EB006006 United States EB NIBIB NIH HHS

Keywords: immunogenicity; microparticle(s); nanoparticle(s); protein aggregation; stability

0 (Immunoglobulins, Intravenous)
0 (Immunologic Factors)
0 (Plasticizers)
0 (Protein Aggregates)
80295-42-7 (Complement C3a)
80295-49-4 (Complement C4a)
9002-86-2 (Polyvinyl Chloride)
C42K0PH13C (Diethylhexyl Phthalate)

Date Created: 20190624 Date Completed: 20210322 Latest Revision: 20210322

20240829

PMC6951798

10.1016/j.xphs.2019.06.015

31229435