Sensitivity Study to Assess the Robustness of Primary Drying Process in Pharmaceutical Lyophilization

The objective of this work is to apply a sensitivity study to assess the robustness of the primary drying step of pharmaceutical lyophilization with respect to deviations in process parameters. The sensitivity study can provide valuable information regarding the effect of process input parameters on the product quality that can aid in designing robust lyophilization processes. In this study, the output response is related to its inputs using Smolyak sparse grid generalized polynomial chaos method, and the sensitivity was calculated using elementary effects method. Sensitivity of chamber pressure and shelf temperature on product temperature of 2 sucrose-based and one mannitol-based formulation was studied, and the results were analyzed in terms of risk of adverse effects due to process deviations on the product quality. The study revealed that the sensitivity varies among formulations, and preliminary information regarding the possible impact of process deviations can be obtained from the process cycle diagram. The product temperature showed greater sensitivity toward the change in the shelf temperature than toward change in the chamber pressure for the greater part of the primary drying stage. An aggressive process-deviation scenario at the late stage of primary drying was also studied for different formulations, and the results were consistent with the sensitivity study.