Abstract
Process analytical technology (PAT)-tools were used to monitor freeze-drying of Bacille Calmette-Guérin (BCG) at pilot and production scale. Among the evaluated PAT-tools, there is the novel use of the vacuum valve open/close frequency for determining the endpoint of primary drying at production scale. The duration of primary drying, the BCG survival rate, and the residual moisture content (RMC) were evaluated using two different freeze-drying protocols and were found to be independent of the freeze-dryer scale evidencing functional equivalence. The absence of an effect of the freeze-dryer scale on the process underlines the feasibility of the pilot scale freeze-dryer for further BCG freeze-drying process optimization which may be carried out using a medium without BCG.
Highlights
Lyophilization or freeze-drying is often used for stabilization of biopharmaceuticals such as vaccines [1, 2]
Several in-process parameters, Process analytical technology (PAT)-tools, are available for monitoring Bacille Calmette-Guérin (BCG) primary drying at pilot and production scale of which the pressure rise test (PRT) is available in both freeze-dryers
The PRT is only routinely used to confirm the endpoint after the fixed primary drying time of 228.5 hours
Summary
Lyophilization or freeze-drying is often used for stabilization of biopharmaceuticals such as vaccines [1, 2]. Besides improvement of the stability of vaccines, lyophilization is used to facilitate the production of new dosage forms of vaccines [3, 4], such as bioneedles for intramuscular delivery [5,6,7,8] or powders for pulmonary delivery [9, 10]. The process of freeze-drying includes besides a freezing step two drying steps: primary drying, and secondary drying. During primary drying ice is removed by sublimation and during secondary drying water is removed by desorption [2, 11, 15]
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