(509e) Optimization of Batch High Shear Granulation and Transfer to a Continuous Granulation Process: A Case Study of Metoprolol Succinate ER Tablets

Authors: 
Zidan, A., U.S. Food and Drug Administration
Alayoubi, A., U.S. Food and Drug Administration
O'Connor, T., U.S. Food and Drug Administration
Ashraf, M., Office of Testing and Research, U.S. Food and Drug Administration
Cruz, C. N., U.S. Food and Drug Administration
Feng, X., FDA
While the most common implementation of continuous manufacturing (CM) has been for continuous direct compression, continuous wet granulation has been successfully established as a processing alternative in the continuous tableting lines. To date, no extended release products have yet been approved using CM technology. Continuous twin screw granulation utilizes a different mechanism than traditional batch granulation (e.g. high shear or planetary) and forms granules in a very short time (seconds). Twin screw granulation has the potential to produce granules with a broader size distribution compared to other wet granulation processes and may have different physical properties. Formulation properties, process parameters, and screw configuration have a complex influence on granule properties in twin screw granulation. This presentation will then highlight the critical material and process parameters to be controlled in high shear granulation process for the transfer to the continuous granulation process. A surrogate extended release formulation of metoprolol succinate was developed in house for this purpose. OFAT optimization of the formulation ingredients was done in a batch-mode. Optimization of the process parameters, namely impeller speed, granulation time, and spray rate, of the high shear granulator was done using a central composite design. Particle size distribution and bulk and flow properties of the granules and dissolution characteristics of the ER tablets were evaluated. The interactions among the effects of the input and intermediate factors on the in vitro performance of the finished product will be also discussed.

The identified critical process parameters of the batch high shear granulation were then translated into those of the twin screw granulation. The product transfer was done based on the granulation model developed from multivariate experiments, prior process knowledge, and a rational classification of formulation characteristics. Four external runs were performed on the twin screw granulator as a function of screw speed and shearing rate. Various variables of the granulation process will be also discussed in the presentation with an emphasis on their importance for “translating” a process between a batch process and continuous manufacturing line.

DISCLAIMER

This presentation reflects the views of the presenter and should not be construed to represent FDA’s views or policies.