The Impact of Inadequate Temperature Storage Conditions on Aggregate and Particle Formation in Drugs Containing Tumor Necrosis Factor-Alpha Inhibitors

N. D. Vlieland, M. R. Nejadnik, H. Gardarsdottir*, S. Romeijn, A. S. Sediq, M. L. Bouvy, A. C. G. Egberts, B. J. F. van den Bemt, W. Jiskoot

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

12 Citations (Web of Science)

Abstract

Purpose To measure aggregate and particle formation in tumor necrosis factor-alpha (TNF-alpha) inhibitors etanercept, adalimumab and certolizumab pegol product samples after exposure to freezing temperature conditions similar to storage conditions previously observed in patients' homes. Methods TNF-alpha inhibitors in their original primary and secondary packaging were exposed to 32 freeze-thaw cycles (-10 degrees C for 120min/5 degrees C for 60 min) or continuous low storage temperature (-20 degrees C for 96 h) before thawing at 2-8 degrees C. Non-stressed products were used as controls. The products were analyzed by high pressure size exclusion chromatography (HP-SEC), dynamic light scattering (DLS), nanoparticle tracking analysis (NTA), micro-flow imaging (MFI) and second derivative ultraviolet (UV) spectroscopy. Results Ten out of twenty-one stressed product samples (47.6%) showed increased particle numbers in the submicron and micron size range when compared to controls. For each product, DLS, MFI and NTA detected an increase in particle level in at least one stressed syringe (both continuous freezing and freeze-thaw), whereas HP-SEC and UV spectroscopy showed no differences between stressed and non-stressed products. Conclusion TNF-alpha inhibitors are relatively resistant to freezing temperatures similar to storage conditions previously observed in patients' homes. However, almost half of the stressed product samples showed formation of particles in the submicron and micron size range.
Original languageEnglish
Article number42
Number of pages11
JournalPharmaceutical Research
Volume35
Issue number2
DOIs
Publication statusPublished - 1 Feb 2018

Keywords

  • aggregation of antibodies
  • drug product characterization
  • freezing stress conditions
  • home storage
  • TNF-alpha inhibitors
  • MONOCLONAL-ANTIBODY
  • IMMUNOGENICITY
  • PROTEINS
  • PRODUCT

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