Model-Based Framework for the Analysis of Failure Consequences in a Freeze-Drying Process

This paper shows how mathematical modeling can be used to assess the effect of process failures on product quality during the freeze-drying of pharmaceutical and biotech products. In particular, the model is used to calculate the product temperature response after an unexpected variation in the temperature of the heat transfer fluid and/or in the chamber pressure. Here a monodimensional model is used as it requires a limited number of parameters, which are the heat transfer coefficient and the product resistance to vapor flow. In this paper, the problem of determination of model parameters is addressed, with emphasis on the nonuniformity of the batch and on the uncertainty of the method of measurement used. The heat transfer coefficient was determined by gravimetric method, while the product resistance to vapor flow was measured by a weighing device placed directly in the chamber. Results obtained by the above devices agreed with the values estimated by the pressure rise test technique. This paper also shows how mathematical modeling can be used to calculate the probability that product temperature is maintained below its limit value, as well as to estimate the new duration for the primary drying.