Novel markers to track oxidative polysorbate degradation in pharmaceutical formulations

Dahotre, Sanket N.; Tomlinson, A. A. G.; Lin, Baiwei; Yadav, Sandeep

doi:10.1016/j.jpba.2018.05.031

Cited by 28 publications

(19 citation statements)

References 27 publications

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“…Therefore, PS hydrolysis was classified as the predominant degradation pathway. 9,33 Additionally, PS degradation in mAb-1 purified material correlated with mAb-1 product concentration as well as storage temperature (data not shown), and was inhibited by the addition of tetrahydrolipstatin (Orlistat), a common lipase inhibitor (Fig. 1).…”

Section: Identification Of Hcps After Enrichmentmentioning

confidence: 93%

“…The mechanisms of chemically induced instability of PS (i.e., autooxidation and acid-or base-catalyzed hydrolysis of the fatty acid esters) have been widely investigated. 3,9 In particular, the chemical hydrolysis rate for PS has been previously shown to be negligible under relevant formulation conditions. 7,10,11 Therefore, PS degradation concomitant with the accumulation of free fatty acids (FFAs)-which can give rise to visible and subvisible particles -is usually attributed to enzyme-catalyzed hydrolysis of the carboxylic ester bond.…”

Section: Introductionmentioning

confidence: 99%

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Identification and Characterization of Polysorbate-Degrading Enzymes in a Monoclonal Antibody Formulation

Graf

Tomlinson²,

Yuk³

et al. 2021

Journal of Pharmaceutical Sciences

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Section: Identification Of Hcps After Enrichmentmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Identification and Characterization of Polysorbate-Degrading Enzymes in a Monoclonal Antibody Formulation

Graf

Tomlinson²,

Yuk³

et al. 2021

Journal of Pharmaceutical Sciences

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“…This is particularly relevant to the oxidation of polysorbates. These represent one of the most commonly used excipients in such biopharmaceutical formulations, which can result in the production of an array of potentially damaging products [25][26][27][28][29]. Ha et al reported that polysorbate 80 (PS80) can increase oxidation products in an interleukin-2 formulation.…”

Section: Introductionmentioning

confidence: 99%

“…Low molecular weight aldehydes and ketones show low ionisation efficiencies in mass spectrometry (MS) analysis due to their low proton affinities. Therefore, their chemical derivatisation is usually carried out with hydrazides, hydrazines, hydroxylamines or coumarines [29,34,35].…”

Section: Introductionmentioning

confidence: 99%

Protein Formulations Containing Polysorbates: Are Metal Chelators Needed at All?

Brovč

Pajk

Šink³

et al. 2020

Antioxidants

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Proteins are prone to post-translational modifications at specific sites, which can affect their physicochemical properties, and consequently also their safety and efficacy. Sources of post-translational modifications include oxygen and reactive oxygen species. Additionally, catalytic amounts of Fe(II) or Cu(I) can promote increased activities of reactive oxygen species, and thus catalyse the production of particularly reactive hydroxyl radicals. When oxidative post-translational modifications are detected in the biopharmaceutical industry, it is common practice to add chelators to the formulation. However, the resultant complexes with metals can be even more damaging. Indeed, this is supported here using an ascorbate redox system assay and peptide mapping. Ethylenediaminetetraacetic acid (EDTA) addition strongly accelerated the formation of hydroxyl radicals in an iron-ascorbate system, while diethylenetriaminepentaacetic acid (DTPA) addition did not. When Fe(III) was substituted with Cu(II), EDTA addition almost stopped hydroxyl radical production, whereas DTPA addition showed continued production, but at a reduced rate. Further, EDTA accelerated metal-catalysed oxidation of proteins, and thus did not protect them from Fe-mediated oxidative damage. As every formulation is unique, justification for EDTA or DTPA addition should be based on experimental data and not common practice.

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“…These include chemical modifications, for example, the potential reactions of peroxides and aldehydes and ketones with proteins, and physical alterations, for example, the generation of protein aggregates and particles. [1][2][3][5][6][7][8][9][10][11]39,40 In this article, we show that light exposure of PS80-containing formulations leads to cis/trans isomerization of unsaturated FA components of PS80 when an mAb is present, but not in its absence. This pathway likely involves the reductive cleavage of disulfide bonds by photoinduced electron transfer from Trp, generating thiyl radicals (reactions 1-4).…”

Section: Discussionmentioning

confidence: 77%

Cis/Trans Isomerization of Unsaturated Fatty Acids in Polysorbate 80 During Light Exposure of a Monoclonal Antibody–Containing Formulation

Prajapati

Peters

Larson

et al. 2020

Journal of Pharmaceutical Sciences

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Light exposure of a monoclonal antibody formulation containing polysorbate 80 (PS80) leads to cis/trans isomerization of monounsaturated and polyunsaturated fatty acids. This cis/trans isomerization was monitored by positive electrospray ionization mass spectrometry of intact PS80 components as well as by negative ion electrospray ionization mass spectrometry analysis of free fatty acids generated via esterase-catalyzed hydrolysis. The light-induced cis/trans isomerization of unsaturated fatty acids in PS80 required the presence of the monoclonal antibody, or, at a minimum (for mechanistic studies), a combination of N-acetyltryptophan amide and glutathione disulfide, suggesting the involvement of thiyl radicals generated by photoinduced electron transfer from Trp to the disulfide. Product analysis confirmed the conversion of PS80-bound oleic acid to elaidic acid; furthermore, together with linoleic acid, we detected conjugated linoleic acids in PS80, which underwent light-induced cis/trans isomerization.

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Novel markers to track oxidative polysorbate degradation in pharmaceutical formulations

Cited by 28 publications

References 27 publications

Identification and Characterization of Polysorbate-Degrading Enzymes in a Monoclonal Antibody Formulation

Identification and Characterization of Polysorbate-Degrading Enzymes in a Monoclonal Antibody Formulation

Protein Formulations Containing Polysorbates: Are Metal Chelators Needed at All?

Cis/Trans Isomerization of Unsaturated Fatty Acids in Polysorbate 80 During Light Exposure of a Monoclonal Antibody–Containing Formulation

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