Lebar, Blaz, Zidar, Mitja, Mravljak, Janez, Sink, Roman, Zula, Ales and Pajk, Stane (2024) Alternative buffer systems in biopharmaceutical formulations and their effect on formulation stability. Acta pharmaceutica, 74. ISSN 1846-9558; 1330-0075

Abstract

Formulation of biopharmaceutical drug is supposed to eliminate chemical instabilities, increase conformational and colloidal stability of protein, and optimize interfacial stability. This is achieved by combination of many excipients, among which buffer composition is one of the most important one. However, reference buffer, such as conventionally used histidine and phosphate buffers, may not always be the most optimal choice for all mAbs. In this study we tested seven mAbs with multiple alternative buffer systems, alternating combinations of ionic strengths, main buffer component concentrations, mAb concentration and stress condition. Protein stability was correlated to aggregates formation, which was detected by size exclusion chromatography. At low protein concentration, only bis-TRIS/glucuronate buffer formulation displayed protein instability after temperature stress, while freeze-thaw stress was best mitigated by arginine/citrate buffer. Addition of arginine to histidine buffer systems further stabilized proteins during temperature stress, whereas same was not true for histidine/HCl buffer during freeze thaw. Interestingly, five out of seven reference formulations displayed higher aggregate content after freeze-thaw stress at lower protein concentration, rather than higher. Mechanism of action was proposed.At high protein concentration, histidine/citrate buffer proved to be one of the best choices at temperature and light stress. Former was successfully mitigated by histidine buffers, probably due to histidine molecule light-absorbing capabilities. Our results demonstrate that biopharmaceutical formulation development should not limit itself to conventional buffer systems for many alternatives perform just as good if not even better.

Item Type:	Article
Keywords:	Biopharmaceuticals, buffer, stress, alternative buffers, stability
Date Deposited:	11 Sep 2024 00:45
Last Modified:	11 Sep 2024 00:45
URI:	https://oak.novartis.com/id/eprint/49777