Freeze primary drying

In common with most freeze-drying operations there are three basic stages in the process freezing, primary drying, and secondary drying. 

Therefore, freeze-drying should be carried out at the highest allowable product temperature that maintains the appropriate attributes of a freeze-dried product. This temperature depends on the nature of the formulation. Process development and validation requires characterizing the physical state of the solute, or solutes, that result from the freezing process and identifying a maximum allowable product temperature for the primary drying process [20,21]. 

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. 

The objective of the primary drying stage of the freeze-drying process is to remove the ice as quickly as possible without undue risk of product loss... 

Figure 8 An example of the decreasing heat requirement during primary drying at a chamber pressure of 0.15 torr. 5% mannitol maintained at -20°C during primary drying. Results obtained by computer simulation of freeze drying (see Ref. 3). Heavy curve Shelf Fluid. Light curve Shelf surface. Lightweight dashed curve Product Bottom. Heavy dashed curve Sublimation.

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

As compared with a higher pressure and lower shelf temperature outlined in Table 7, drying rates with the reversed conditions of lower pressure and higher shelf temperature would be expected to be slower than the conditions at target shelf temperature and chamber pressure. Compared with those conditions, freezing would be expected to require more time. Primary drying rates would also be reduced because heat transfer rates would be less, product temperatures lower, and residual moisture higher. 

Since the driving force for freeze drying is the vapor pressure of ice, it is important from the standpoint of process efficiency to keep the product temperature as high as practical during primary drying. However, the... 

Searles, J.A., Carpenter, J.F., Randolph, T.W. Annealing to optimize the primary drying rate, reduce freezing-induced drying heterogeneity, and determine T8g in pharmaceutical lyophilization. J. Pharm. Sci. 90, 872-887, 2001... 

Aliquots of nanoparticulate suspension were frozen at -20 °C in the presence of 0,5,10,15,20,25 and 30 % trehalose. Samples were freeze-dried in a Virtis Co. (model BT 6.6 X L, Gardiner, NJ) system under the following conditions a primary drying step for 24 hours at -30 °C and secondary drying step until the temperature gradually rose to 20 °C. The particles were then resuspended in distilled water (to return to starting trehalose concentration), and their size and charge were measured. 

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