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Vpliv kakovosti polisorbata 80 na fizikalno stabilnost monoklonskega protitelesa = The impact of polysorbate 80 quality on the physical stability of a monoclonal antibody ; enoviti magistrski študijski program FarmacijaBožič, UlaComplex three-dimensional structure of therapeutic proteins and their tendency for aggregate formation, is a challenge for biopharmaceutical companies, since such aggregates can evoke an immune ... response upon administration, cause blood vessel occlusion and lead to loss of effective monomeric proteins. Polysorbates (PS) are surface active ingredients, which are commonly supplemented to biopharmaceutical formulations with intention of preventing aggregation. They are heterogenous mixtures of a PEGylated sorbitan core with one or multiple esterified fatty acids. Although PS molecular mechanism of action is well investigated, it is to this date still not clear how different quality grades compare in stabilizing proteins. Moreover, impact of (partly) degraded PS on protein stability is not fully understood. In this thesis, a monoclonal antibody (IgG) was subjected to pumping, stirring and dropping stress, which mimic applied mechanical stresses to a proteinaceous drug product during manufacturing, transportation and administration. Protein was formulated with two PS 80 quality grades, one compliant with Ph.Eur., USP and JP, and the other in line with stricter ChP. Furthermore, the antibody was supplemented with (partly) hydrolyzed PS 80. LC-CAD was performed to confirm successful degradation and to assess PS 80 concentrations used in this study. Surfactant functionality was assessed by measuring the extent of protein aggregation. Particles in nano- and micro-meter size range were characterized by using particle characterization techniques, such as micro-flow imaging (MFI), backgrounded membrane imaging (BMI) and dynamic light scattering (DLS). Additionally, turbidity and soluble protein aggregates were analyzed by using UV spectroscopy and ultra-high performance size exclusion chromatography (UP-SEC), respectively. We noticed a concentration range, where PS 80 is effective. No discrepancy in functionality was observed for two quality grades. Fully degraded PS 80 does not possess any stabilizing properties. When a portion (more than ~10 %) of neat PS is degraded, this results in poorer protection of the antibody under mechanical stress. Similarly, presence of extra degradants at the same intact PS 80 concentration was found to be destabilizing. More studies should be carried out with focus on development of repeatable stress methods and examination of oxidized PS functionality.Type of material - master's thesis ; adult, seriousPublication and manufacture - Ljubljana : [U. Božič], 2019Language - englishCOBISS.SI-ID - 4767345
Link(s):
https://repozitorij.uni-lj.si/IzpisGradiva.php?id=109087&lang=slvNaloga nedostopna do 20. 8. 2020
Author
Božič, Ula
Other authors
Ahlin Grabnar, Pegi |
Hawe, Andrea
Topics
Famacevtska tehnologija |
polisorbat 80 |
razgradnja polisorbatov |
stabilnost protitelesa IgG |
agregacija |
preizkus na mehansko obremenitev |
analiza delcev
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Library/institution |
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Faculty of Pharmacy, Ljubljana | Ljubljana | FFALJ |
reading room 1 cop.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Božič, Ula | ![]() |
Ahlin Grabnar, Pegi | 15490 |
Hawe, Andrea | ![]() |
Source: Personal bibliographies
and: SICRIS
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