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

Abstract

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.

An Experimental-Based Approach to Construct the Process Design Space of a Freeze-Drying Process: An Effective Tool to Design an Optimum and Robust Freeze-Drying Process for Pharmaceuticals

“…It is well-known that dried product resistance and product temperature increase when product dried layer thickness increases. 19,22,36 Therefore, to include the maximum effect of the dried product resistance during the determination of the sublimation rate, the sublimation experiments were stopped once the dried layer of the front edge vials was close to the vial bottom. This was performed by visually observing the dried layer of the front edge vials.…”

Use of a temperature ramp approach (TRA) to design an optimum and robust freeze-drying process for pharmaceutical formulations

“…It has been reported that the resistance of the dried product increases as the length of the dried layer of the product increases (Fissore et al, 2011;Kodama et al, 2014;Kuu et al, 2006;Scutellà et al, 2018b). This implies that the sublimation rate decreases by increasing the product dried layer.…”

Use of a multi-vial mathematical model to design freeze-drying cycles for pharmaceuticals at known risk of failure

“…where is the the mass transfer resistance of the dried layer, which depends linearly on the dried layer thickness for the considered product: [7] = 0 + 1 (5) can be calculated from the Clausius Clapeyron equation from the sublimation interface temperature, [6] and is defined as in Trelea et al [8] assuming ideal gas law for water vapour in the drying chamber:…”

“…This phenomenon is known as edge vial effect. In the present study, the additional radiation heat flow rates from the wall and rail to the edge vials were calculated for edge vials using the Stefan-Boltzmann equation, as proposed in the 3D simplified radiation model developed by Scutellà et al [10]  Mass transfer resistance: The product resistance variability in a large batch of vials was previously quantified as normal distributions of 0 and 1 in Scutellà et al [7]  Desorption kinetics: The variability of the desorption kinetics was previously quantified as normal distributions of characteristics desorption times in Scutellà et al [11]…”