Oxidation of polysorbates – An underestimated degradation pathway?

• Published in: International journal of pharmaceutics: X Vol. 6; p. 100202
• Main Authors: Weber, Johanna, Buske, Julia, Mäder, Karsten, Garidel, Patrick, Diederichs, Tim
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 15.12.2023; Elsevier
• Subjects: Autoxidation; Biologicals; Biotherapeutic formulations; Oxidative degradation; Polysorbate stability; Polysorbates; Review Paper; Surfactants; Tweens; FFA; mM; PS; AcOH; AAPH; EPR; HRP; HP; Polysorbates; Na-AcOH; μM; DSC; MC; CMC; ELSD; Ph. Eur; Tweens; Cys; Polysorbate stability; PS80; SBSE-GC-MS; CID; DTPA; UV; DNPH; PS20; MS; CAD; POE; CMR; HOO; i.m; s.c; AL; Surfactants; AO; FOX; TGA; EU; GC-MS; i.v; Fe2; ROO; HCP; Fe3; Arg; ROS; NaCl; BHA; FA; ICP-MS; Met; RO; Biologicals; HLB; FDA; RT; JP; CO2; t-BuOH; O2-; NPN; BP; PPO; BHT; Autoxidation; R; Oxidative degradation; OH; FMA; Biotherapeutic formulations; SR; ppb; d; KOH; HPßCD; ChP; EDTA; ppm; m; ICH; mAb; RP-HPLC; LC-MS; His; HMW; PEG; USP; 1H-NMR; UPLC; mEq; C12E9
• ISSN: 2590-1567; 2590-1567
• DOI: 10.1016/j.ijpx.2023.100202

To ensure the stability of biologicals over their entire shelf-life, non-ionic surface-active compounds (surfactants) are added to protect biologics from denaturation and particle formation. In this context, polysorbate 20 and 80 are the most used detergents. Despite their benefits of low toxicity and high biocompatibility, specific factors are influencing the intrinsic stability of polysorbates, leading to degradation, loss in efficacy, or even particle formation. Polysorbate degradation can be categorized into chemical or enzymatic hydrolysis and oxidation. Under pharmaceutical relevant conditions, hydrolysis is commonly originated from host cell proteins, whereas oxidative degradation may be caused by multiple factors such as light, residual metal traces, peroxides, or temperature, which can be introduced upon manufacturing or could be found in the raw materials. In this review, we provide an overview of the current knowledge on polysorbates with a focus on oxidation. Subsequently, degradation products and key characteristics of oxidative-mediated polysorbate degradation in respect of different types and grades are summarized, followed by an extensive comparison between polysorbate 20 and 80. A better understanding of the radical-induced oxidative PS degradation pathway could support mitigation. Finally, buffer conditions, various stressors, as well as appropriate mitigation strategies, reagents, and alternative stabilizers are discussed. Prior manufacturing, careful consideration and a meticulous risk-benefit analysis are highly recommended in terms of polysorbate qualities, buffers, storage conditions, as well as mitigation strategies. [Display omitted]