Do we worry too much about polysorbate degradation? An industry-wide perspective with real-life case studies

Abstract

Polysorbates are commonly used in biotherapeutic drug formulations, but their stability over the course of the product’s shelf life is a matter of concern. An industry-wide survey involving 15 biopharmaceutical companies found that 23 biotherapeutic drug products (DPs) in clinical development exhibited significant reductions in polysorbate (PS) content during long-term storage at 2–8 °C. In all cases, this decline did not impact critical quality attributes (CQAs), except for the formation of fatty acid (FA)-related sub-visible particles (SVP) in 7 DPs and FA-visible particles (VP) in 1 DP. Particle formation predominantly resulted from enzymatic or uncharacterized degradation mechanisms, not oxidative pathways. Corrective measures, such as optimization of downstream purification or reformulation, were undertaken only when SVP levels exceeded acceptable thresholds.

For PS20 and PS80, the levels of FAs generated were estimated and translated into predicted SVP levels based on theoretical assumptions. Additionally, the current understanding of PS degradation in biopharmaceuticals, based on the latest literature, is summarized, with consideration of safety and immunogenicity aspects related to the primary PS degradation products. Overall, PS degradation is considered manageable and not problematic under practical conditions. Enzymatic hydrolysis of PS is generally deemed acceptable, provided that all CQAs are maintained within specified limits. If FA-related particles are formed it is recommended that the PS degradation pathway is well characterized, and an appropriate control strategy be implemented.

Introduction

Polysorbates (PS), specifically PS20 and PS80, are essential surfactants in the biopharmaceutical industry due to their ability to effectively stabilize therapeutic proteins and protect them from interfacial stresses encountered during manufacturing, storage, and usage. In earlier publications.1,2 we provided a comprehensive industry view of the handling and characterization of polysorbates, detailing common degradation pathways and offering best practice recommendations for effective control and mitigation strategies.

Recent reviews have delved into various aspects of polysorbate degradation, including enzymatic.3 and oxidative pathways.4 and alternative excipients for protein stabilization.5, 6, 7 However, a notable gap remains in understanding the consequences of polysorbate degradation on critical quality attributes (CQAs) beyond PS content itself, particle formation and protein oxidation. Specifically, there has not been an extensive examination of the extent to which such degradation of polysorbates may be deemed acceptable.

To address this, members of a European Federation of Pharmaceutical Industries and Associations (EFPIA) industry working group focusing on the role of polysorbates as protein stabilizers collected real-world cases of biopharmaceutical products that exhibited a significant decrease in polysorbate content under typical long-term storage conditions (2–8°C). In total, 23 cases, collected under blinded conditions, were identified in which marked reductions in polysorbate levels occurred in drug products (DP) under development. Within the participating companies, the survey evaluated if reduced PS content affects key CQAs of biotherapeutic products manufactured under GMP for clinical studies. Additional cases indicated that polysorbate degradation proceeded more rapidly under accelerated or stressed temperature conditions, yet these cases were not elaborated upon in this manuscript. In the evaluation of the 23 identified cases, the impact of the observed decrease in polysorbate content on critical DP quality attributes, such as purity, potency, general characteristics, and particle formation was

Additionally, this paper provides a brief overview of the most recent published findings related to polysorbate degradation pathways. It discusses some critical considerations regarding the formation of fatty acids and the associated particle formation that can result from hydrolytic cleavage of polysorbates. Lastly, potential safety risks for patients resulting from enzymatic breakdown, and release of fatty acids (FA), the most pertinent PS degradation pathway for protein-based biotherapeutics, are also briefly addressed.

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Klaus Wuchner, Felix Nikels, Patrick Garidel, Karoline Bechtold-Peters, Sanjay Gupta, Pierre Guibal, Linda Yi, Neil Steinmeyer, Cyrille Chery, Sebastian Peuker, Ryan E Mould, Shousong Jason Zhang, Charlie Bupp, Felix Wiggers, Yogita Krishnamachari, Indira Prajapati, Stefan Bleher, Do we worry too much about polysorbate degradation? An industry-wide perspective with real-life case studies, Journal of Pharmaceutical Sciences, 2026, 104169, ISSN 0022-3549, https://doi.org/10.1016/j.xphs.2026.104169.