A multifaceted approach to understanding protein-buffer interactions in biopharmaceuticals.

Autor: Lebar B; University of Ljubljana, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Aškerčeva 7, SI-1000 Ljubljana, Slovenia; Novartis Pharmaceutical Manufacturing LLC, Kolodvorska 27, SI-1234 Menges, Slovenia., Orehova M; National Institute of Chemistry, Slovenian NMR Centre, Hajdrihova ulica 19, SI-1000 Ljubljana, Slovenia., Japelj B; Novartis Pharmaceutical Manufacturing LLC, Kolodvorska 27, SI-1234 Menges, Slovenia., Šprager E; Novartis Pharmaceutical Manufacturing LLC, Kolodvorska 27, SI-1234 Menges, Slovenia., Podlipec R; Jožef Stefan Institute, Laboratory of Biophysics & Quantum Materials Group, Jamova cesta 39, SI-1000 Ljubljana, Slovenia., Knaflič T; Jožef Stefan Institute, Laboratory of Biophysics & Quantum Materials Group, Jamova cesta 39, SI-1000 Ljubljana, Slovenia., Urbančič I; Jožef Stefan Institute, Laboratory of Biophysics & Quantum Materials Group, Jamova cesta 39, SI-1000 Ljubljana, Slovenia., Knez B; Novartis Pharmaceutical Manufacturing LLC, Kolodvorska 27, SI-1234 Menges, Slovenia., Zidar M; Novartis Pharmaceutical Manufacturing LLC, Kolodvorska 27, SI-1234 Menges, Slovenia., Cerar J; Novartis Pharmaceutical Manufacturing LLC, Kolodvorska 27, SI-1234 Menges, Slovenia., Mravljak J; University of Ljubljana, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Aškerčeva 7, SI-1000 Ljubljana, Slovenia., Žula A; Novartis Pharmaceutical Manufacturing LLC, Kolodvorska 27, SI-1234 Menges, Slovenia., Arčon D; Jožef Stefan Institute, Laboratory of Biophysics & Quantum Materials Group, Jamova cesta 39, SI-1000 Ljubljana, Slovenia., Plavec J; National Institute of Chemistry, Slovenian NMR Centre, Hajdrihova ulica 19, SI-1000 Ljubljana, Slovenia., Pajk S; University of Ljubljana, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Aškerčeva 7, SI-1000 Ljubljana, Slovenia. Electronic address: stane.pajk@ffa.uni-lj.si.
Jazyk: angličtina
Zdroj: European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V [Eur J Pharm Biopharm] 2024 Nov 19, pp. 114582. Date of Electronic Publication: 2024 Nov 19.
DOI: 10.1016/j.ejpb.2024.114582
Abstrakt: The excipient selection process plays a crucial role in biopharmaceutical formulation development to ensure the long-term stability of the drug product. Though there are numerous options approved by regulatory authorities, only a subset is commonly utilized. Previous research has proposed various stabilization mechanisms, including protein-excipient interactions. However, identifying these interactions remains challenging due to their weak and transient nature. In this study, we present a comprehensive approach to identify such interactions. Using the 1 HT 2 CPMG (Carr-Purcel-Meiboom-Gill) filter experiment we identified interactions of rituximab with certain buffers and amino acids, shedding light on its Fc fragment instability that manifested during the enzymatic cleavage of the antibody. Moreover, chemometric analyses of 2D NMR fingerprints revealed interactions of selected excipients with antibody fragments. Furthermore, molecular dynamics simulations revealed potential interacting hotspots without NMR spectra assignment. Our results highlight the importance of an orthogonal methods approach to uncovering these critical interactions, advancing our understanding of excipient stabilization mechanisms and rational formulation design in biopharmaceutics.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024. Published by Elsevier B.V.)
Databáze: MEDLINE
Externí odkaz: