On the Methods Based on the Pressure Rise Test for Monitoring a Freeze-Drying Process

Abstract

This article is focused on the methods based on the pressure rise test (PRT) used to monitor the primary drying of a lyophilization process. Details about the model-based algorithms proposed to interpret the PRT, namely, manometric temperature measurement (MTM), pressure rise analysis (PRA), and dynamic parameters estimation (DPE), are briefly summarized and various features of the models used by these algorithms, in particular the role of the vial wall and radiation on the thermal balance of the system, are investigated. The optimal selection of the sampling frequency and the time interval between two tests is discussed, and the influence of the duration of the test on the results is investigated by means of mathematical simulation: results obtained from the PRT can be significantly improved by optimizing the duration of the test. Moreover, the problem of misleading results obtained at the end of the primary drying is investigated, taking into account the problem of ill-conditioning of the algorithms. An improved version of the DPE algorithm is proposed to cope with this problem; its effectiveness is demonstrated by means of mathematical simulations and experimental runs.