Robust freeze-drying process re-design of a legacy product based on risk analysis and design of experiments.

In this study, a QbD freeze-drying process re-design applied to a lyophilized injectable drug product is presented. The main objective was to assess the freeze-drying process robustness using risk analysis and a proper experimental design. First, the product's thermal fingerprint was characterized by thermal analysis and freeze-drying microscopy. Then, according to the output of the risk analysis, primary drying temperature and pressure were studied by a Doehlert DoE design with four responses; primary drying time, appearance, residual moisture content, and reconstitution time. Statistically significant MLR models were obtained for residual moisture content and primary drying time. In the latter, the temperature factor was the predominant factor to predict the duration of the primary drying stage. Two additional lab-scale batches were run to confirm the mathematical model predictions. Finally, optimal primary drying conditions (30 °C, 0.400 mbar) were selected to minimize the duration of the primary drying stage, while preserving the quality of the product. It was possible to set high temperature and pressure values because no collapse temperature was found during the thermal characterization of the product. Secondary drying temperature and time were defined based on the residual moisture content results. It was shown that secondary drying is robust between 30 °C and 50 °C and from 3 to 16 h. In conclusion, we were able to define a robust freeze-drying process which was further validated at an industrial scale with satisfactory results and approved by the health authorities in different countries around Europe.