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Gregoritza K, Cai SK, Siketanc M, et al. Metal-Induced Fatty Acid Particle Formation Resulting from Hydrolytic Polysorbate Degradation. J Pharm Sci. 2021;doi: 10.1016/j.xphs.2021.09.044.
Gregoritza, K., Cai, S. K., Siketanc, M., Woehr, A., Lebouc, V., Kishore, R. S. K., Nicoulin, V., Bleher, S., & Allmendinger, A. (2021). Metal-Induced Fatty Acid Particle Formation Resulting from Hydrolytic Polysorbate Degradation. Journal of pharmaceutical sciences, . https://doi.org/10.1016/j.xphs.2021.09.044
Gregoritza, Kathrin, et al. "Metal-Induced Fatty Acid Particle Formation Resulting from Hydrolytic Polysorbate Degradation." Journal of pharmaceutical sciences vol. (2021). doi: https://doi.org/10.1016/j.xphs.2021.09.044
Gregoritza K, Cai SK, Siketanc M, Woehr A, Lebouc V, Kishore RSK, Nicoulin V, Bleher S, Allmendinger A. Metal-Induced Fatty Acid Particle Formation Resulting from Hydrolytic Polysorbate Degradation. J Pharm Sci. 2021 Oct 01; doi: 10.1016/j.xphs.2021.09.044. Epub 2021 Oct 01. PMID: 34600939.
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J Pharm Sci. 2021 Oct 01; doi: 10.1016/j.xphs.2021.09.044. Epub 2021 Oct 01.

Metal-Induced Fatty Acid Particle Formation Resulting from Hydrolytic Polysorbate Degradation.

Journal of pharmaceutical sciences

Kathrin Gregoritza, Si Kai Cai, Matej Siketanc, Anne Woehr, Vanessa Lebouc, Ravuri S K Kishore, Victor Nicoulin, Stefan Bleher, Andrea Allmendinger

Affiliations

  1. Pharma Technical Development Biologics, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, Basel 4070, Switzerland. Electronic address: [email protected].
  2. Pharma Technical Development Biologics, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, Basel 4070, Switzerland.

PMID: 34600939 DOI: 10.1016/j.xphs.2021.09.044

Abstract

The occurrence of visible particles over the shelf-life of biopharmaceuticals is considered a potential safety risk for parenteral administration. In many cases, particle formation resulted from the accumulation of fatty acids released by the enzymatic hydrolysis of the polysorbate surfactant by co-purified host cell proteins. However, particle formation can occur before the accumulated fatty acids exceed their expected solubility limit. This early onset of particle formation is driven by nucleation phenomena e.g. the presence of metal cations that promote the formation and growth of fatty acid particles. To further characterize and understand this phenomenon, we assessed the potential of different metal cations to induce fatty acid particle formation using a dynamic light scattering assay. We demonstrated that the presence of trace amounts of multivalent cations, in particular trivalent cations such as aluminum and iron, may act as nucleation seed in the process of particle formation. Finally, we developed a mitigation strategy for metal-induced fatty acid particles that deploys a chelator to reduce the risk of particle formation in biopharmaceutical formulations.

Copyright © 2021 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.

Keywords: Degradation; Dynamic light scattering; Fatty acids; Hydrolysis; Metal impurities; Nucleation; Polysorbate; Surfactant; Visible particles

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