The effect of mAb and excipient cryoconcentration on long-term frozen storage stability - part 2: Aggregate formation and oxidation.

Autor: Bluemel O; Pharmaceutical Technology and Biopharmaceutics, Department of Pharmacy, Ludwig-Maximilians-Universitaet Muenchen, 81377 Munich, Germany., Buecheler JW; Technical Research and Development, Novartis Pharma AG, 4002 Basel, Switzerland., Hauptmann A; Sandoz GmbH, 6336 Langkampfen, Austria., Hoelzl G; Sandoz GmbH, 6336 Langkampfen, Austria., Bechtold-Peters K; Technical Research and Development, Novartis Pharma AG, 4002 Basel, Switzerland., Friess W; Pharmaceutical Technology and Biopharmaceutics, Department of Pharmacy, Ludwig-Maximilians-Universitaet Muenchen, 81377 Munich, Germany.
Jazyk: angličtina
Zdroj: International journal of pharmaceutics: X [Int J Pharm X] 2021 Dec 25; Vol. 4, pp. 100109. Date of Electronic Publication: 2021 Dec 25 (Print Publication: 2022).
DOI: 10.1016/j.ijpx.2021.100109
Abstrakt: We examined the impact of monoclonal antibody (mAb) and buffer concentration, mimicking the cryoconcentration found upon freezing in a 2 L bottle, on mAb stability during frozen storage. Upon cryoconcentration, larger protein molecules and small excipient molecules freeze-concentrate differently, resulting in different protein to stabiliser ratios within a container. Understanding the impact of these shifted ratios on protein stability is essential. For two mAbs a set of samples with constant mAb (5 mg/mL) or buffer concentration (medium histidine/adipic acid) was prepared and stored for 6 months at -10 °C. Stability was evaluated via size-exclusion chromatography, flow imaging microscopy, UV/Vis spectroscopy at 350 nm, and protein A chromatography. Dynamic light scattering was used to determine k D values. Soluble aggregate levels were unaffected by mAb concentration, but increased with histidine concentration. No trend in optical density could be identified. In contrast, increasing mAb or buffer concentration facilitated the formation of subvisible particles. A trend towards attractive protein-protein interactions was seen with higher ionic strength. MAb oxidation levels were negatively affected by increasing histidine concentration, but became less with higher mAb concentration. Small changes in mAb and buffer composition had a significant impact on stability during six-month frozen storage. Thus, preventing cryoconcentration effects in larger freezing containers may improve long-term stability.
Competing Interests: 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.
(© 2021 The Authors. Published by Elsevier B.V.)
Databáze: MEDLINE
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