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Eur J Pharm Biopharm. 2019 Sep;142:334-343. doi: 10.1016/j.ejpb.2019.07.008. Epub 2019 Jul 12.

A spray freeze dried micropellet based formulation proof-of-concept for a yellow fever vaccine candidate.

Author information

1
Bioprocess R&D Department, Sanofi Pasteur, Marcy l'Etoile, France. Electronic address: didier.clenet@sanofi.com.
2
MTech Department, Sanofi Pasteur, Marcy l'Etoile, France.
3
Analytical Sciences BIEM, Sanofi Pasteur, Neuville s/Saône, France.
4
R&D Global Projects Strategy and Execution, Sanofi Pasteur, Marcy l'Etoile, France.

Abstract

The stability of live-attenuated viruses is very challenging due to thermal sensitivity; therefore, solid form is usually required (often freeze-dried products). Micropellet technology is a lyophilization technology that has the potential to provide greater flexibility in the presentation of a given vaccine particularly in multi-dose format or in combination of different vaccines. As a novel vaccine alternative process, this spray freeze-dried (SFD) micropellet technology was evaluated using as a model a yellow fever virus produced in Vero cells (vYF). Screening of excipients was performed in order to optimize physico-chemical properties of the micropellets. Sugar/polymer-based formulations induced high glass transition temperature (Tg), adequate breaking force and attrition resistance of the SFD micropellets. These mechanical parameters and their stability are of considerable importance for the storage, the transport but also the filling process of the SFD micropellets. By adding excipients required to best preserve virus infectivity, an optimal sugar/polymer-based formulation was selected to build micropellets containing vYF. Monodisperse and dried micropellets with a diameter of about 530 µm were obtained, exhibiting similar potency to conventional freeze-dried product in terms of vYF infectious titer when both solid forms were kept under refrigerated conditions (2-8 °C). Comparable kinetics of degradation were observed for vYF formulated in micropellets or as conventional freeze-dried product during an accelerated stability study using incubations at 25 °C and 37 °C over several weeks. The results from this investigation demonstrate the ability to formulate live-attenuated viruses in micropellets. Pharmaceutical applications of this novel vaccine solid form are discussed.

KEYWORDS:

Formulation screening; Freeze-drying; Live-attenuated vaccine stability; Micropellets

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