Freeze secondary drying

M. J. Pikal, S. Shah, M. L. Roy, and R. Putman, The secondary drying stage of freeze drying drying kinetics as a function of shelf temperature and chamber pressure, Int. J. Pharm., 60, 203-217 (1990). 

In addition to the additives used in a formulation to help stabilize the protein to freezing, the residual moisture content of the lyophilized powder needs to be considered. Not only is moisture capable of affecting the physicochemical stability of the protein itself, equally important is the ability of moisture to affect the Tg of the formulation. Water acts as a plasticizer and depresses the Tg of amorphous solids [124,137,138]. During primary drying, as water is gradually removed from the product, the Tg increases accordingly. The duration and temperature of the secondary drying step of the lyophilization process determines how much moisture remains bound to the powder. Usually lower residual moisture in the finished biopharmaceutical product leads to enhanced stability. Typically, moisture content in lyophilized formulations should not exceed 2% [139]. The optimal moisture level for maximum stability of a particular product must be demonstrated on a case-by-case basis. 

Even after all ice has been removed by sublimation, the product phase, or freeze concentrate, contains a large amount of dissolved water that must be removed to produce a stable product. This water is removed by desorption during secondary drying. Secondary drying is usually carried out at elevated product temperature to achieve efficient water removal. 

The storage of a freeze dried product starts with the end of the secondary drying and its transfer into a suitable packing. In the drying plant a certain residual moisture content (RM) is achieved as a function of the product temperature and the drying time (Section 1.2.2). 

During secondary drying, a small RM should be reached, since Tg of the dry product increases with decreasing water content. Tg- of amorphous, freeze dried sucrose increases from 16 °C with 8.5 % RM to 63 °C or 64 °C between 1.0 and 0.7 % RM. It should be taken into account, that RM cannot be taken only at the end of drying, but a possible increase during storage by water desorbed from the stopper has to be considered (see Section 1.3.2 and Pikal et al. [3.7]). 

The outer vials are influenced (if the shelf temperature is uniform) by a different temperature of the walls and door of the chamber. If the chamber walls and the door are not kept at shelf temperature, the outer vials must be shielded or they may be too warm during freezing (e. g. freezing differently) or too cold during secondary drying (see Fig. 1.68), and this may lead to a different residual moisture content, from that in inner vials. 

Gieseler et al. utilized tunable diode laser absorption spectroscopy to detect water vapor concentrations, gas velocities and mass flow during freeze-drying of pure water at different pressure and shelf temperature settings and of a 5%w/w mannitol solution. The analyzer was interfaced to the spool that connected the dryer chamber to the condenser. The reported method was advantageous in that primary and secondary drying end-point control based upon mass flow rate was independent of freeze-dryer size and configuration. ... 

The freezing of a product is a very important step. The structure in the frozen product decides whether the product can be freeze-dried at all and under which conditions it can be done. For this reason, the consequences of the freezing rate, layer thickness of the product and excipients are discussed in some detail. The second main point is the measurement and control of the two drying phases the main and secondary drying and the third concentrates on the residual moisture content, its measurement and the consequences during storage of the dry product. There will be critical opinions that some of the processes are unilaterally represented. aim was to show the, hmrts and the advantages ot certain procedures to enable the reader to decide whether the ideas of the quoted authors, or my own can be applied to his tasks. 

Process condition Product loading Cooling rate Freezing Ramp to primary drying Primary drying Ramp to secondary drying Secondary drying... 

Fig. 1.56.2. Course of a freeze-drying process. 1, Precooling of the shelves 2, freezing of the product 3, evacuation and main drying (MD) 4, secondary drying (SD) 5, changeover from MD to SD sh raised to maximum tolerable product temperature 6, Tjce measurements by BTM 7, temperature sensors RTD in the product 8, temperature sensors Th in the product 9, temperature of the shelves (T h) 10, ice condenser temperature ...

Secondary drying is dominated by the sorption behavior and the strucure of the product. Therefore, the DR plots are not always as straightforward as shown so far. Figure 1.73.2 gives the DR plots of a 10% mannitol solution frozen in 300 vials on a shelf with a freezing rate of 0.3-0.6 °C/min, d = 10 mm. The process data during MD were as follows ... 

Pikal, M.J., Shaw, S. Intravial distribution of moisture during the secondary drying stage of freeze drying. PDA J. 

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