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The first industrial doctorate project between Reig Jofré, UAB and CSIC has been succesfully completed

Development of a stable pharmaceutical formulation for adenoviral vectors

ABSTRACT

Adenoviral vectors are far from being commonly established in clinic use because of the complexity to preserve their activity at optimal conditions of transport and administration. Currently, the stabilization of adenovirus for long-term storage requires the presence of glycerol at -80ºC. This ultra-low temperature creates significant inconvenient for storage, transport and practical clinic use. In the other hand, the presence of glycerol requires an extensive dilution before administration to reduce toxic effects. So, enhancing the thermostability has long been recognized as the target for improving the impact of viral vectors on world health.

The goal of this study was the identification of a combination of excipients which allows the storage of Adenovirus type 5 vector at higher temperatures and the maintenance of infectivity at an acceptable level. At the same time, it was necessary a design of a lyophilization process that enhanced stability by limiting the loss of infectivity with a more controllable and reproducible behavior.

This goal requires a global approach that starts by analyzing the factors that influence stability of viral preparations prior to and during freeze-drying, and the major mechanisms responsible for inactivation during storage. Among the factors that affect stability highlight virus concentration, pH, aggregation and residual water. It is crucial to control the previous factors during the process by Dynamic Light Scattering (DLS) and coulometric Karl Fischer titration, as well as verify the physical and functional titer at different points of the process to assure well-design.

A battery of formulations has been developed to test its effectiveness in terms of liquid stability at 4ºC, freeze-dry impact and stability of lyophilized powder during storage. A formulation stable until 8 hours in liquid at room temperature has been identified what it is suitable for industrial scale. The designed lyophilization process with the selected formulation avoid the loss of activity during lyophilization at the stablished lot size. The titer is maintained at the analytical point of stability study of 6 months at 5°C and -20°C. This formulation is being submitted to a 2-years stability program at -20°C, 5°C and 25°C.

Image 1. Lluna Lopez during her PhD defense.

Image 2. Núria Carbajal, Lluna López, Elisabet Rosell, Gemma Lahuerta, Sandra Saiz (industrial PhD candidate) y Carlos Berrio (industrial PhD candidate)

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