Purpose: Quantitative tools were developed to characterize the cake appearance and compressive strength of lyophilized drug products. Application of these tools will be presented during lyophilization cycle development of a protein drug product formulation.
Methods: An imaging technique was developed to quantify the cake shrinkage and surface cracking in lyophilized products. To image the cake, an in-house digital camera and black box system was built, and further data processing was done using commercially available software such as Photoshop and Matlab. To assess the compressive strength of the lyophilized cake, we used the Instron Model 5543 Testing System. Specifically, the Instron load cell was placed in contact with the cake surface and moved at the rate of 3 mm/min until complete collapse of cake structure was visually observed. The compressive force measured as a function of the cake height was correlated to the cake structural strength and batch homogeneity.
Results: The accuracy and reproducibility of the cake appearance and compressive strength tests was established. For a low concentration high fill protein formulation (amorphous matrix, fill depth of 1.5cm), the lyophilized cake appearance was highly variable across the batch. Specifically, up to 29% cake shrinkage was observed for 15% of the vials. Lyophilization cycle development studies indicated that optimization of the freezing step was important. When the cooling rate was reduced from 1°C/min to 0.2°C/min (annealing at -10°C for 5hrs), no cake shrinkage was apparent across the batch. Furthermore, the compressive force profile at 0.2°C/min was significantly altered, reflecting a more homogeneous batch with structurally stronger product.
Conclusion: Quantitative tools to assess cake appearance and compressive strength test were successfully developed for lyophilized product characterization. These tools can be useful for assessing batch homogeneity during lyophilization process development and scale-up.