Application of Optical Coherence Tomography Freeze-Drying Microscopy for Designing Lyophilization Process and Its Impact on Process Efficiency and Product Quality.

Optical coherence tomography freeze-drying microscopy (OCT-FDM) is a novel technique that allows the three-dimensional imaging of a drug product during the entire lyophilization process. OCT-FDM consists of a single-vial freeze dryer (SVFD) affixed with an optical coherence tomography (OCT) imaging system. Unlike the conventional techniques, such as modulated differential scanning calorimetry (mDSC) and light transmission freeze-drying microscopy, used for predicting the product collapse temperature (Tc), the OCT-FDM approach seeks to mimic the actual product and process conditions during the lyophilization process. However, there is limited understanding on the application of this emerging technique to the design of the lyophilization process. In this study, we investigated the suitability of OCT-FDM technique in designing a lyophilization process. Moreover, we compared the product quality attributes of the resulting lyophilized product manufactured using Tc, a critical process control parameter, as determined by OCT-FDM versus as estimated by mDSC. OCT-FDM analysis revealed the absence of collapse even for the low protein concentration (5 mg/ml) and low solid content formulation (1%w/v) studied. This was confirmed by lab scale lyophilization. In addition, lyophilization cycles designed using Tc values obtained from OCT-FDM were more efficient with higher sublimation rate and mass flux than the conventional cycles, since drying was conducted at higher shelf temperature. Finally, the quality attributes of the products lyophilized using Tc determined by OCT-FDM and mDSC were similar, and product shrinkage and cracks were observed in all the batches of freeze-dried products irrespective of the technique employed in predicting Tc.