Toward full noninvasive monitoring of a freeze-drying process

In pharmaceutical industry, freeze-drying is often used to produce stable solid products. The process encompasses three operations, which have their own requirements. This study focuses on primary drying, as it is the most risky phase of the process. The critical quality attributes for primary drying are the moisture and the temperature of the product. The former variable gives information about the state of progress of solvent sublimation and thus is useful to establish when the secondary drying can be started. The latter variable, instead, has to accurately be controlled in order to prevent product damage. In fact, temperature of the product has to be maintained below a limit value, beyond which the product collapses. Therefore, monitoring of these parameters is of the utmost importance. These variables can hardly be measured through traditional monitoring tools, but their measurement is possible by using advanced systems. The authors developed a new, full noninvasive method for the monitoring of the mass flow rate of vapor during primary drying. This information combined with a mathematical model of the process allows also the estimation of the other key variables, without the need to insert a probe into the product (e.g. thermocouples), to introduce a disturbance on the process (e.g. pressure rise test technique), or the use of expensive hardware. This paper outlines the operating principle, validation and application, as well as the strengths and the weakness of the method. For this purpose, examples of freeze-drying cycle are given, where the above method is used to monitor the temperature and the position of the interface of sublimation for products with a different structure. The estimation of product temperature is compared with thermocouple measurements and estimations of the pressure rise test technique. On the other hand, the suitability of the above strategy for monitoring the residual water content was demonstrated by comparison with the measurement of water composition inside the drying chamber.