(W0930-03-18) Impact of Formulation Composition, Lyophilization Processing Parameters and Freeze Dryer Configuration on Appearance of Lyophilized Finished Product

Purpose: To evaluate the impact of critical lyophilization processing variables on the appearance of bottom hexagonal shrinkage in lyophilized finished product.

Methods: Low temperature thermal analysis was performed on two isotonic and buffered sucrose model formulations. Processing of two model formulations with variation in processing parameters and fill depth was completed in both a pilot 8-square foot and 24-square foot internal condenser lyophilizer. Lyophilization was completed in 6R, 10cc, and 20cc vials with a 3.10 mL fill volume using conditions as described in Table 1. The thermocouples were precisely placed in vials at the edge and center of the tray to measure product temperatures during processing. The product was evaluated for physical appearance using typical finished product evaluation that included visual inspection and cake dissection techniques.

Results: Low temperature thermal analysis was completed for both formulations. The bulk solution for Rx1 exhibited a collapse temperature of -33°C while the collapse temperature for Rx2 was -38°C. In the first study, even though the temperature of the product was below the lowest collapse temperature of -38°C (Rx 2), all 6R vials experienced hexagonal shrinkage (Figure 1, Table 2). In the second study, the vial size was increased while maintaining the same fill volume. During this study, a few 10 cc and 20 cc product vials were kept outside the nested ring of vials for observation during primary drying. It was observed that the shrinkage occurred only during the beginning to middle of primary drying and not at either the end of primary drying or the ramp to secondary drying when the product temperature is raised above the Tg’ of the product. While the incidence of hexagonal shrinkage was reduced, the appearance was still readily apparent in those vials that did experience shrinkage. The third study was completed at a lower primary drying temperature, in a larger freeze dryer which has better thermal shielding than the previous freeze dryer. While a significant proportion of vials still exhibited hexagonal shrinkage, the amount of shrinkage from the sides of the vials was greatly reduced and was not as readily apparent (Table 2).

Conclusion: For two typical model formulations consisting of a sugar, buffer, salt, and surfactant, there was an impact of primary drying temperature, cake height and size of the freeze dryer on bottom hexagonal shrinkage. Both formulations were dried under lyophilization conditions that maintained the product temperature below the collapse temperature observed by freeze drying microscopy. A number of factors influenced the final appearance of the cake. In general, for both formulations, fewer 20 cc vials exhibited hexagonal shrinkage compared with 10 cc vials. It was also apparent that the extent of shrinkage from the side of the vials was reduced in the larger dryer which was more thermally insulated. It is important to understand and evaluate the influence of the formulation, process parameters, product configuration as well as lyophilizer design when evaluating the appropriateness a lyophilization cycle.

Processing Parameters for all Studies

Results

Lyophilization Graph