Determination of the dried product resistance variability and its influence on the product temperature in pharmaceutical freeze-drying.

During the primary drying step of the freeze-drying process, mass transfer resistance strongly affects the product temperature, and consequently the final product quality. The main objective of this study was to evaluate the variability of the mass transfer resistance resulting from the dried product layer (R) in a manufacturing batch of vials, and its potential effect on the product temperature, from data obtained in a pilot scale freeze-dryer. Sublimation experiments were run at -25 °C and 10 Pa using two different freezing protocols: with spontaneous or controlled ice nucleation. Five repetitions of each condition were performed. Global (pressure rise test) and local (gravimetric) methods were applied as complementary approaches to estimate R. The global method allowed to assess variability of the evolution of R with the dried layer thickness between different experiments whereas the local method informed about R variability at a fixed time within the vial batch. A product temperature variability of approximately ±4.4 °C was defined for a product dried layer thickness of 5 mm. The present approach can be used to estimate the risk of failure of the process due to mass transfer variability when designing freeze-drying cycle.