(T1030-08-53) Impact of Microcrystalline Cellulose Grade and Vibrational Feeding Assistance on Loss-in-Weight Continuous Feeding

Purpose: Continuous manufacturing (CM) of pharmaceutical products can potentially improve drug product quality and reduce manufacturing footprint and costs. Continuous feeding of materials with high accuracy and low variability is a critical step in manufacturing drug products using CM technologies. Excipients and excipient selection may impact the robustness of CM operations, like feeding. This study investigated the impact of excipient selection, specifically the grade of microcrystalline cellulose (MCC), and vibrational feeding assistance on the feeding rate variability of a loss-in-weight twins screw continuous feeder.

Methods: Four grades of Avicel® PH MCC (1 different lot per grade) were supplied from IFF Pharma Solutions and used as received. Nominal average particle sizes for each grade were 50 µm for Avicel® PH-101, 100 µm for Avicel® PH-102 and 200 µm for PH-200 (all with bulk powder density < 0.4 g/cc). Avicel® PH-302 has a nominal particle size of 100 µm and a density of < 0.4 g/cc. A Coperion K-Tron loss-in-weight twin screw feeder (K3-PH-ML-D4-QT20, 20 mm auger coarse screws) was set to one of 3 different target feeding rates: 3.75 kg/h, 10 kg/h and 25 kg/h. For certain grades, runs with and without ActiFlow™ vibration flow aid were implemented. The standard deviation of the feed (based on 30 sec increments) is reported in a percentage basis to better compare variability across different feeding rates.

Results: Without the addition of the ActiFlow™ vibration flow aid, the feed rate had the largest impact on the variability (% standard deviation) of the feed rate across all MCC grades. In all cases, feed rates had an inverse relationship with variability (higher feed rate resulted in lower variability). For example, the variability of the PH-102 MCC grade was highest at the 3.75 kg/h target feed rate (1.45%). The variability was reduced to 0.91% with a 3x increase in target feed rate (10 kg/h). Increasing the feed rate to 25 kg/h further decreased the variability to 0.34%. Similar trends were seen for the PH-101 and PH-200 MCC grades and the higher bulk density grade, PH-302 (Figure 1). The high bulk density grade, PH-302, demonstrated the lowest RSD at 3.75 and 10 kg/h compared to the other MCC grades. However, it had feeding accuracy issues due to ratholing and bridging when the feeding rate was increased to 25 kg/h, likely due to its high cohesiveness. ActiFlow™ vibration flow aid technology was tested with the high-density grade and two standard-density grades to determine if it could help reduce feeding RSD. At 3.75 kg/h, the addition of vibration flow aid reduced the variability of feeding by ~10% for the standard-density grades PH-101 and PH-200 (Figure 2). However, it had negative impact on the feeding variability of the high-density grade, PH-302: variability increased from 0.49 % without vibration to 0.70% with light vibration to 1.02 with medium vibration. In contrast, the vibrational feeding helped cut in half the variability of PH-302 at 25 kg/h, where ratholing was observed without the flow aid (Figure 3). The variability reduced from 0.54% without vibration to 0.22% and 0.20% with light and medium vibration, respectively. Addition of vibrational flow aid also helped reduce the feeding variability for Avicel® PH-101 and PH-200 at 25 kg/h.

Conclusion: Feeding of MCC in a continuous twin screw feeder is significantly dependent on the target flow rate, with higher flow rates tending to reduce variability. However, feeding issues like ratholing and bridging in the hopper can cause high variability in the output rate, even at high feed rates. The use of vibrational assistance can significantly reduce variability in these cases.

RSD of feed rate for different grades of Avicel® PH MCC at three different target flow rates (3.75, 10 and 25 kg/hr) without ActiFlow™

RSD of the 3.75 kg/hr feed rate for various grades of Avicel® PH MCC with and without ActiFlow™

RSD of the 25 kg/hr feed rate for various grades of Avicel® PH MCC with and without ActiFlow™