Fatty Acids Can Induce the Formation of Proteinaceous Particles in Monoclonal Antibody Formulations

Zhang, Jingtao; He, Jing; Smith, Katelyn J.

doi:10.1016/j.xphs.2021.10.008

Cited by 9 publications

(3 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent studies have evaluated the fate of polysorbate-derived particles in mAb formulations in the presence of human plasma, serum, or infusion solutions. [18][19][20][21] The findings presented here build upon these previous studies by providing a reasonable mechanism leading to the observed phenomena. The mechanism of particle dissolution in infusion solutions perhaps differs from that in serum, plasma, or in the in vitro conditions described here; despite these differences, a similar end point (reversal of fatty acid particles) was achieved.…”

Section: Discussionsupporting

confidence: 84%

Human Serum Albumin Mitigates Formation of Fatty Acid Particles in Polysorbate-Containing Solutions

Kim¹,

Stansberry-Perkins²,

Marlow³

et al. 2022

Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 84%

Human Serum Albumin Mitigates Formation of Fatty Acid Particles in Polysorbate-Containing Solutions

Kim¹,

Stansberry-Perkins²,

Marlow³

et al. 2022

Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

“… 7 , 8 , 11 , 12 , 14 , 15 The released FFAs can also induce the formation of proteinaceous particles, as suggested in a recent study by Zhang et al . 25 Furthermore, the loss of PS can result in protein aggregation in DPs or during intravenous admixture, thereby negatively affecting DP quality. 7 , 8 …”

Section: Introductionmentioning

confidence: 99%

Prediction of long-term polysorbate degradation according to short-term degradation kinetics

Zhang

Riccardi

Carlson

et al. 2023

mAbs

View full text Add to dashboard Cite

Polysorbates (PSs) are a class of surfactants commonly used in the formulation of protein therapeutic agents to provide protection against denaturation and aggregation. When the PS in these drug formulations degrades, loss of stabilization of the protein therapeutic and formulation may occur, resulting in particulate formation or other undesirable changes in product critical quality attributes. Here, we present a simplified platform to predict long-term PS20 and PS80 degradation for monoclonal antibody drugs containing the PS-degrading enzyme lysosomal acid lipase. The platform was based on a temperature-dependent equation derived from existing PS20 degradation stability data. Accurate prediction of both PS20 and PS80 hydrolysis for as long as 2 years was achieved through short-term kinetics studies performed within 2 weeks. This platform substantially shortens the time required to determine the long-term stability of PS degradation and therefore can be used to guide the purification process and optimization of antibody formulations.

show abstract

“…In recent years, the biopharmaceutical industry has increasingly reported incidences of and investigations into the root cause of polysorbate degradation and associated particle formation in protein formulations, particularly for recombinant monoclonal antibody (mAb) products (Allmendinger et al 2021;Doshi et al 2021;Graf et al 2021;Gregoritza et al 2022;Roy et al 2021;Zhang et al 2022aZhang et al , 2022bZhang et al , 2021Zhang et al , 2020. We hypothesize that this increasing prevalence of particle observations is the unintended consequence of multiple end-to-end aspects of current industry trends: (1) The reliance on intensified upstream processes to increase cell mass and productivity, which increases the HCP load and product recovery burden for downstream processing (Strube et al 2018;Valente et al 2018).…”

Section: Introductionmentioning

confidence: 99%

Formulation mitigations for particle formation induced by enzymatic hydrolysis of polysorbate 20 in protein-based drug products: insights from a full-factorial longitudinal study

Yuk¹,

Koulis²,

Doshi³

et al. 2022

AAPS Open

View full text Add to dashboard Cite

Hydrolytic degradation of the polysorbate 20 (PS20) surfactant in protein-based liquid formulations releases free fatty acids (FFAs), which can accumulate to form particles in drug products during real-time (long-term) storage. To identify formulation conditions that mitigate the risk of particle formation, we conducted a longitudinal study using purified recombinant monoclonal antibody (mAb) formulated in 24 conditions. In this real-time stability study at 5 °C, three key formulation parameters—mAb concentration, initial PS20 concentration, and pH—were varied across representative ranges in a full-factorial design. A longitudinal regression analysis was used to evaluate the effects of these parameters and their interactions on PS20 degradation (via measurements of PS20, FFAs, and PS20 ester distribution) and on particle formation (via visible particle observations and subvisible particle counts). The time-dependent onset of visible particles trended with the rise in subvisible particle counts and FFA levels and fall in PS20 concentration. In the ranges studied here, lower mAb concentration and higher initial PS20 concentration delayed the onset of particles, whereas pH had a negligible effect. These observations were consistent with the general trends predicted by our previously published FFA solubility model. Taken together, these findings highlight the complex relationships between formulation parameters, PS20 degradation, and particle formation.

show abstract

Fatty Acids Can Induce the Formation of Proteinaceous Particles in Monoclonal Antibody Formulations

Cited by 9 publications

References 30 publications

Human Serum Albumin Mitigates Formation of Fatty Acid Particles in Polysorbate-Containing Solutions

Human Serum Albumin Mitigates Formation of Fatty Acid Particles in Polysorbate-Containing Solutions

Prediction of long-term polysorbate degradation according to short-term degradation kinetics

Formulation mitigations for particle formation induced by enzymatic hydrolysis of polysorbate 20 in protein-based drug products: insights from a full-factorial longitudinal study

Contact Info

Product

Resources

About