Monitoring of the Primary Drying

After freezing the product, most of the solvent is removed by sublimation during the primary drying. In this stage it is necessary to monitor product temperature and the residual water content in such a manner that the control system can both optimize 

Despite the various drawbacks listed above, thermocouples have been proposed to monitor the primary drying and to detect the endpoint of this stage. When the primary drying ends, an increase in the product temperature is measured at the bottom of the vials due to the loss of thermal contact between the sensor and the ice. Moreover, the product temperature increases as there is no longer an endothermic sublimation process that uses the heat supplied by the heating shelf 

The product temperature can be used to detect the end of primary drying also using a completely different procedure, by regularly and drastically reducing the pressure in the chamber if no decrease in the product temperature is observed as a consequence of the pressure reduction, that in the presence of residual ice would cause an increase in water flux by endothermic sublimation, then the primary drying can be considered complete (Thompson, 1988). 

Finally, by coupling a mathematical model of the process to the measurement of the product temperature in the vial (or of the wall temperature of the vial) it is possible to build a soft-sensor that allows estimation in-line of the whole product temperature profile and the mass/heat transfer coefficients this has been called the smart-vial concept (Barresi et al., 2007, 2009a, b, c) 

Non-invasive monitoring techniques have been proposed as valuable alternatives to the use of thermocouples. Most of them are based on the results obtained from the 

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Barresi, A. A Pisano, R Fissore, D Rasetto, V., Velardi, S. A Vallan, A Parvis, M., Galan, M., 2009a. Monitoring of the primary drying of a lyophilization process in vials. Chem. Eng. Process. 48 408-423. 

In-line monitoring of the primary drying phase of the freeze-drying process in vial by means of a Kalman filter based observer. 

Further revealing information is obtained from individual monitoring of the polarization evolution profiles of the separate components of the CIDEP spectrum. These are given in Figure 4b. The results clearly indicate that the "new" radical is the primary intermediate, formed before the phenacyl radical. Furthermore, the relative relaxation rate of the spin polarization of the phenacyl radical is faster than that of the "new" radical. A final critical experiment is that when very dry acetonitrile was used as solvent, no CIDEP observations could be obtained for any radicals. From all these observations we are now ready to formulate the primary phototriplet reactions mechanism to account for all these facts. 

The monitoring of the soil plant available water (PAW) between 0 and 8 m depth in the soil has shown that during the dry season, in active B. brizantha pastures areas, a considerable use of water reserves occurs primarily in the top 2 m of soil. This is similar to observations made in primary and secondary forest areas. However, below 2 m, the depletion of the soil water reserves was greater in the forest ecosystem (Jipp et al. 1998). In general, active pasture ecosystems have a greater proportion of fine roots in soil layers between 0-2 meters, and the water in these layers is depleted more quickly, while a major part of the water reserve in the soil is stored in deeper layers. As the pasture... 

The various techniques available to monitor the primary drying can be roughly divided into three groups as they can be used to monitor single vials, a group of vials or the whole batch (Barresi et al, 2009a) these techniques will be discussed and compared in the following sections. 

Fig. 4.6 Example of results obtained during a freeze-drying cycle using the special balance with the embedded wireless temperature measurement in order to monitor the primary drying stage of a mannitol-dextran solution (6-14% by weight) in a pilot-scale freeze-dryer. The freezing stage was run at 223 K for about 5 h, while the main drying was carried out setting the fluid temperature at 293 l< and the chamber pressure at 10 Pa (Nv = 98 on tray, dv= 14.2 X 10 m, Lp = 7.2 x 10 m).

The main drawback of all these model-based algorithms is that they require that the model describes perfectly the dynamics of the process and that all the parameters and all the variables of the process are known. As this seldom happens, it is necessary to use one of the techniques described in Section 4.3 to monitor the primary drying in order to know the value of the temperature of the product, that is the controlled variable, and, thus, to calculate the control action. 

During the ongoing assessment, the nurse monitors the patient for relief of pain. If pain recurs it is important to assess its severity, location, and intensity. The nurse monitors the vital signs every 4 hours or more frequently if necessary. Hot, dry, flushed skin and a decrease in urinary output may develop if temperature elevation is prolonged and dehydration occurs. The nurse assesses the joints for a decrease in inflammation and greater mobility. The nurse reports adverse reactions, such as unusual or prolonged bleeding or dark-colored stools, to the primary health care provider. 

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