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This paper is focused on the methods based on the Pressure Rise Test (PRT) used to monitor the primary drying of a lyophilisation process. Details about the model-based algorithms proposed to interpret the PRT, namely the Manometric Temperature Measurement (MTM), the Pressure Rise Analysis (PRA), and the 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 of radiation on the thermal balance of the system, are investigated. The optimal selection of the sampling frequency and of 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 illconditioning 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.

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The use of mathematical modeling is demonstrated to be very effective not only for cycle development, but also for solving problem of process transfer. This study showed that inter-vial variability remains significant when vials are loaded on plastic trays, and how inter-vial variability can be taken into account during process design.