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

doi:10.1007/s11095-017-2341-x

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

Journal article

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Peer reviewed

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 and W Jiskoot

Pharmaceutical research, Vol.35(2), pp.42-11

02/01/2018

DOI: 10.1007/s11095-017-2341-x

PMCID: PMC5799349

PMID: 29404710

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Abstract

To measure aggregate and particle formation in tumor necrosis factor-alpha (TNF-α) inhibitors etanercept, adalimumab and certolizumab pegol product samples after exposure to freezing temperature conditions similar to storage conditions previously observed in patients' homes. TNF-α inhibitors in their original primary and secondary packaging were exposed to 32 freeze-thaw cycles (-10°C for 120min/5°C for 60 min) or continuous low storage temperature (-20°C for 96 h) before thawing at 2-8°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. 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. TNF-α 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.

Adalimumab - chemistry

Adalimumab - pharmacology

Anti-Inflammatory Agents - chemistry

Anti-Inflammatory Agents - pharmacology

Biological Factors - chemistry

Biological Factors - pharmacology

Certolizumab Pegol - chemistry

Certolizumab Pegol - pharmacology

Chemistry, Pharmaceutical

Drug Storage - standards

Etanercept - chemistry

Etanercept - pharmacology

Freezing - adverse effects

Particle Size

Protein Aggregates

Tumor Necrosis Factor-alpha - antagonists & inhibitors

Details

Title: Subtitle: The Impact of Inadequate Temperature Storage Conditions on Aggregate and Particle Formation in Drugs Containing Tumor Necrosis Factor-Alpha Inhibitors
Creators: N D Vlieland - University Medical Center Utrecht
M R Nejadnik - Centre for Human Drug Research
H Gardarsdottir - University Medical Center Utrecht
S Romeijn - Centre for Human Drug Research
A S Sediq - Centre for Human Drug Research
M L Bouvy - Utrecht University
A C G Egberts - University Medical Center Utrecht
B J F van den Bemt - Sint Maartenskliniek
W Jiskoot - Centre for Human Drug Research
Resource Type: Journal article
Publication Details: Pharmaceutical research, Vol.35(2), pp.42-11
DOI: 10.1007/s11095-017-2341-x
PMID: 29404710
PMCID: PMC5799349
NLM abbreviation: Pharm Res
ISSN: 0724-8741
eISSN: 1573-904X
Grant note: name: University Medical Center Utrecht
Language: English
Date published: 02/01/2018
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Pharmaceutical Sciences and Experimental Therapeutics
Record Identifier: 9984420839502771

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