A Newly Identified Impurity in Polysorbate 80, the Long-Chain Ketone 12-Tricosanone, Forms Visible Particles in a Biopharmaceutical Drug Product

Hampl, V.; Guo, Xinghua; Ehrenstrasser, Christian; Viertler, Martin; Rayner, Lucy; Campanelli, Giusy; Schipflinger, Reinhard; Thewes, Karine; Cerreti, Alessandra; Boehm, Stephan; Sonderegger, Corinna

doi:10.1016/j.xphs.2018.02.017

Cited by 18 publications

(7 citation statements)

References 24 publications

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“…Ultrapure PS 80 is a highly purified PS that was prepared to meet the standards of Chinese pharmacopeia for human use [151,152]. Commercial PS 80 contains impurities such as 12-tricosanone, which leads to the occurrence of visible 12-tricosanone particles in drug formulations and decreases the activity of drugs [153]. The impurities of PSs can affect their performance in drug formulations.…”

Section: Discussionmentioning

confidence: 99%

Polysorbate-Based Drug Formulations for Brain-Targeted Drug Delivery and Anticancer Therapy

et al. 2021

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Polysorbates (PSs) are synthetic nonionic surfactants consisting of polyethoxy sorbitan fatty acid esters. PSs have been widely employed as emulsifiers and stabilizers in various drug formulations and food additives. Recently, various PS-based formulations have been developed for safe and efficient drug delivery. This review introduces the general features of PSs and PS-based drug carriers, summarizes recent progress in the development of PS-based drug formulations, and discusses the physicochemical properties, biological safety, P-glycoprotein inhibitory properties, and therapeutic applications of PS-based drug formulations. Additionally, recent advances in brain-targeted drug delivery using PS-based drug formulations have been highlighted. This review will help researchers understand the potential of PSs as effective drug formulation agents.

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Section: Discussionmentioning

confidence: 99%

Polysorbate-Based Drug Formulations for Brain-Targeted Drug Delivery and Anticancer Therapy

et al. 2021

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“…One potential source of fatty acids in the observed particles are the residual FFA that may be present in the polysorbate excipient before it is used to manufacture a drug product (13). FFA can also arise from reaction of polysorbate with therapeutic protein manufacturing process-related impurities or components of the formulation such as buffers, solvents, and residual host cell enzymatic proteins (14)(15)(16)(17). Previous publications have reported observation of visible and sub-visible particles in some formulations and the apparent decreases in polysorbate concentration over time under conditions where enzymatic host cell proteins were identified as the mediator of hydrolysis of the fatty acid ester (14).…”

Section: Introductionmentioning

confidence: 99%

Effect of Fatty Acid Composition in Polysorbate 80 on the Stability of Therapeutic Protein Formulations

et al. 2021

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Purpose Polysorbate excipients are commonly used as surfactants to stabilize therapeutic proteins in formulations. Degradation of polysorbates could lead to particle formation and instability of the drug formulation. We investigated how the fatty acid composition of polysorbate 80 impacts the degradation profile, particle formation, and product stability under stress conditions. Methods Two polysorbate 80-containing therapeutic protein formulations were reformulated with either Polysorbate 80 NF synthesized from a fatty acid mixture that contains mainly oleic acid (≥58%) or a version of polysorbate 80 synthesized with high oleic acid (>98%). Stress conditions, including high temperature and esterase spiking, were applied and changes to both the polysorbate and the therapeutic protein product were investigated for stability, purity, innate immune response and biological activity. Results The addition of esterase and storage at 37°C led to significant hydrolysis of the polysorbate and increases in sub-visible particle formation for both polysorbates tested. The fatty acid composition of polysorbate 80 did not directly alter the stability profile of either therapeutic protein as measured by size exclusion chromatography, or significantly impact innate immune response or biological activity. However, formulations with Polysorbate 80 NF showed greater propensity for sub-visible particle formation under stress conditions. Conclusions These results suggest that composition of fatty acids in polysorbate 80 may be a promoter for sub-visible particulate formation under the stress conditions tested but may not impact protein aggregation or biological activity.

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“…It is poorly soluble in water and therefore forms visible particles in protein formulations. 17 In spiked PS 20 samples, the lauron signal is well separated from the α-methylene group signal for esterified FA and FFAs. Using the 1 H NMR method, lauron can be easily identified (Figure 7).…”

Section: Benefits Of 1 H Nmr Methodsmentioning

confidence: 96%

Comparison of the NMR and the Acid Value Determination Methods for Quality Control of Input Polysorbates

Brovč

Pajk

Šink³

et al. 2019

ACSi

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Polysorbates (PS) are the most common non-ionic surfactants used in protein formulations. Their degradation has been studied intensively in recent years. Ester bond hydrolysis is one of many pathways of PS degradation that can lead to accumulation of free fatty acids (FFAs) and particle formation. The distribution and quantity of FFAs in PSs impacts directly on product quality. Characterization of input PS is highly relevant, because the initial content of FFAs differs greatly between manufacturers. The purpose of this study was to set up a quick and simple analytical method for the quantitative evaluation of FFAs in PS. The content of FFAs was measured for selected PS 20 and 80, using two methods, 1 H nuclear magnetic resonance spectroscopy (1 H NMR) and the European pharmacopoeia method for determining acid value (I A). These methods have been evaluated using the method of standard addition and, based on the results, they are interchangeable. It was concluded that 1 H NMR is a useful tool for quality control of input PS and a rapid method for indicating the rate of PS degradation by hydrolysis and oxidation. Further, a newly discovered impurity in PS raw material, the long chain ketone 12-tricosanone, can be identified using 1 H NMR.

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A Newly Identified Impurity in Polysorbate 80, the Long-Chain Ketone 12-Tricosanone, Forms Visible Particles in a Biopharmaceutical Drug Product

Cited by 18 publications

References 24 publications

Polysorbate-Based Drug Formulations for Brain-Targeted Drug Delivery and Anticancer Therapy

Polysorbate-Based Drug Formulations for Brain-Targeted Drug Delivery and Anticancer Therapy

Effect of Fatty Acid Composition in Polysorbate 80 on the Stability of Therapeutic Protein Formulations

Comparison of the NMR and the Acid Value Determination Methods for Quality Control of Input Polysorbates

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