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Microfluidic Stress Device to Decouple the Synergistic Effect of Shear and Interfaces on Antibody Aggregation

Gerlt, Michael S. LU orcid ; Meier, Eduard M. ; Dingfelder, Fabian ; Zürcher, Dominik ; Müller, Marius and Arosio, Paolo (2024) In Journal of Pharmaceutical Sciences
Abstract

Protein denaturation and aggregation resulting from the effects of interfacial stress that can be enhanced by flow and shear stress pose significant challenges in the production of therapeutic proteins such as monoclonal antibodies. The influence of flow on protein stability is closely intertwined with interfacial effects. In this study, we have developed a microfluidic device capable of exposing low volume (< 320 μL) protein solutions to highly uniform shear. To disentangle the synergistic impact of flow and interfaces on protein aggregation, we fabricated two devices composed of different materials, namely poly(methyl methacrylate) (PMMA) and stainless steel. Upon application of shear, we observed formation of protein particles in... (More)

Protein denaturation and aggregation resulting from the effects of interfacial stress that can be enhanced by flow and shear stress pose significant challenges in the production of therapeutic proteins such as monoclonal antibodies. The influence of flow on protein stability is closely intertwined with interfacial effects. In this study, we have developed a microfluidic device capable of exposing low volume (< 320 μL) protein solutions to highly uniform shear. To disentangle the synergistic impact of flow and interfaces on protein aggregation, we fabricated two devices composed of different materials, namely poly(methyl methacrylate) (PMMA) and stainless steel. Upon application of shear, we observed formation of protein particles in the micron-size range. Notably, The number of particles generated in the steel devices was ∼ 3.5 fold lower than in the PMMA device, hinting at an interface-mediated effect. With increasing the protein concentration from 1 to 50 mg/mL we observed a saturation in the amount of aggregates, further confirming the key role of solid-liquid interfaces in inducing particle formation. Introduction of non-ionic surfactants prevented protein aggregation, even at the highest tested protein concentration and low surfactant concentrations of 0.05 mg/mL. Overall, our findings corroborate the synergistic impact of shear and interface effects on protein aggregation. The device developed in this study offers a small-scale platform for assessing the stability of antibody formulations throughout various stages of the development and manufacturing process.

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author
; ; ; ; and
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
Interfaces, Microfluidics, Monoclonal antibodies, Protein aggregation, Scale down, Shear stress, Stress test, Surfactant
in
Journal of Pharmaceutical Sciences
publisher
Elsevier
external identifiers
  • pmid:38801973
  • scopus:85195483742
  • pmid:38801973
ISSN
0022-3549
DOI
10.1016/j.xphs.2024.05.024
language
English
LU publication?
no
id
03ef7d2c-5d73-4200-ac02-10cfb7d7da8a
date added to LUP
2024-06-06 23:06:59
date last changed
2024-09-24 18:10:38
@article{03ef7d2c-5d73-4200-ac02-10cfb7d7da8a,
  abstract     = {{<p>Protein denaturation and aggregation resulting from the effects of interfacial stress that can be enhanced by flow and shear stress pose significant challenges in the production of therapeutic proteins such as monoclonal antibodies. The influence of flow on protein stability is closely intertwined with interfacial effects. In this study, we have developed a microfluidic device capable of exposing low volume (&lt; 320 μL) protein solutions to highly uniform shear. To disentangle the synergistic impact of flow and interfaces on protein aggregation, we fabricated two devices composed of different materials, namely poly(methyl methacrylate) (PMMA) and stainless steel. Upon application of shear, we observed formation of protein particles in the micron-size range. Notably, The number of particles generated in the steel devices was ∼ 3.5 fold lower than in the PMMA device, hinting at an interface-mediated effect. With increasing the protein concentration from 1 to 50 mg/mL we observed a saturation in the amount of aggregates, further confirming the key role of solid-liquid interfaces in inducing particle formation. Introduction of non-ionic surfactants prevented protein aggregation, even at the highest tested protein concentration and low surfactant concentrations of 0.05 mg/mL. Overall, our findings corroborate the synergistic impact of shear and interface effects on protein aggregation. The device developed in this study offers a small-scale platform for assessing the stability of antibody formulations throughout various stages of the development and manufacturing process.</p>}},
  author       = {{Gerlt, Michael S. and Meier, Eduard M. and Dingfelder, Fabian and Zürcher, Dominik and Müller, Marius and Arosio, Paolo}},
  issn         = {{0022-3549}},
  keywords     = {{Interfaces; Microfluidics; Monoclonal antibodies; Protein aggregation; Scale down; Shear stress; Stress test; Surfactant}},
  language     = {{eng}},
  month        = {{05}},
  publisher    = {{Elsevier}},
  series       = {{Journal of Pharmaceutical Sciences}},
  title        = {{Microfluidic Stress Device to Decouple the Synergistic Effect of Shear and Interfaces on Antibody Aggregation}},
  url          = {{http://dx.doi.org/10.1016/j.xphs.2024.05.024}},
  doi          = {{10.1016/j.xphs.2024.05.024}},
  year         = {{2024}},
}