In continuous granulation, it can be important to control granules particle size distribution (PSD), as it may affect final product quality. Near infrared spectroscopy (NIRS) is already a routine analytical procedure within pharmaceutical continuous manufacturing for the in-line analysis of chemical material-characteristics. Consequently, the extraction of additional information related to granules' physical properties like particle size distribution is tempting, as it would enhance process knowledge without the need for new capital investments. Three in-line NIRS methods were developed via partial least squares regression, to predict dried granules PSD-fractions X10, X50, and X90 within a GMP-qualified continuous twin-screw wet granulation and fluid-bed drying process. Methods were developed for the size range of 20-234 mu m (X10), 98-1017 mu m (X50), and 748-2297 mu m(X90) and assessed with one internal and three external validation datasets in agreement with current guidelines on NIBS. Internal validation indicated root mean square error of predictions (RMSEPs) of 17 mu m, 97 mu m, and 174 mu m, for PSD X10, X50, and X90 respectively, with acceptable linearity, slope, and bias. Furthermore, the ratio of prediction to deviation (RPD), the ratio of prediction error to laboratory error (PRL), and the range error ratio (RER) were evaluated, with all values within the acceptance range for adequate to good NIR methods (1.75 > RPD < 3, PRL <= 2, RER >= 10). Methods applicability to in-line processes and their robustness towards water content and active pharmaceutical ingredient content was further demonstrated with three independent in-line datasets in real-time, showing good agreement between predicted and reference values. In summary, methods demonstrated to be sufficient for their intended purpose to monitor trends and sudden changes in dried granules PSD during continuous granulation and drying. Because of their fast response time, they are unique tools to characterize the dynamic behavior and navigate the agglomeration state of the material in static and transient process conditions during continuous granulation and drying.

• Heinrich Heine University
• Novartis AG

• API
• PAT
• Oral solid dose

1. API
2. Continuous granulation and drying
3. continuous manufacturing
4. Near-infrared spectroscopy
5. oral solid dose
6. particle size distribution
7. pat
8. process control
9. Research Article