Protein aggregation in the frozen state induced by dropping stress

Torisu, Tetsuo; Maeda, Ayuko; Ito, Shuhei et al.

European Journal of Pharmaceutical Sciences, 2025, 205, 106996

Number of Access:459（2025-08-14 02:27 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/100995

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Title
Protein aggregation in the frozen state induced by dropping stress
Creator
NRID
1000010730492 1000010730492
ORCID
0000-0002-8269-7803 0000-0002-8269-7803
researchmap permalink
torisutetsuo torisutetsuo
Scopus Author ID
57361287600 57361287600
CreatorName
Torisu, Tetsuo
CreatorName
Maeda, Ayuko
CreatorName
Ito, Shuhei
NRID
1000090335381 1000090335381
ORCID
0000-0002-5181-179X 0000-0002-5181-179X
researchmap permalink
read0090387 read0090387
Scopus Author ID
35429790100 35429790100
CreatorName
Uchiyama, Susumu
Subject
Drop
Freeze-thaw
Freezing
Interface
Mechanical stress
Protein aggregation
Description
Torisu T., Maeda A., Ito S., et al. Protein aggregation in the frozen state induced by dropping stress. European Journal of Pharmaceutical Sciences 205, 106996 (2025); https://doi.org/10.1016/j.ejps.2024.106996.
Abstract
The formation of protein aggregates, which can be immunogenic and lower the efficacy and safety of protein drugs, has been an issue in biopharmaceutical development for more than a decade. Although protein drugs are often shipped as frozen material, the effect of the accidental dropping of frozen proteins, which can occur during shipping and handling, on the physical stability has not been studied. Here, a frozen Fc fusion protein was subjected to dropping stress and the increase in the aggregate concentration was evaluated. Significant increases in micron-sized aggregates were observed at –30 °C (p ≤ 0.01), but not at –60 °C. Proteins adsorbed on the vial surfaces were not remarkably detached by the action of dropping and were not the primary cause of the increase in micron-sized aggregates. When the vials were dropped, local heat generation occurred and this led to local freeze-thaw stress that induced protein aggregation. Poloxamer-188, which is known to mitigate aggregation caused by freeze-thaw stress, effectively prevented the aggregation caused by the dropping stress in the frozen state at –30 °C. In addition, rapid freezing could suppress the aggregation caused by the dropping stress. The results demonstrated that dropping stress reduced the stability of proteins even in the frozen state, and they provide new insights into the formulation and freezing processes to prevent protein aggregation caused by dropping stress in the frozen state.
Publisher
Elsevier B.V.
Source Title
European Journal of Pharmaceutical Sciences
Volume (Issue)
205
Page
106996
Date of Issued
2025-02-01
Language
English
Handle URL
https://hdl.handle.net/11094/100995
PISSN
09280987
eISSN
18790720
Relation.isIdenticalTo
DOI (Publisher Version)
https://doi.org/10.1016/j.ejps.2024.106996
Access Rights
open access
CopyRight
This article is licensed under a Creative Commons Attribution 4.0 International License.
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Version of Record
Category
学術雑誌論文 Journal Article