(T1430-09-57) Driving Timely Clinical Development: Simulation-Based Process Development and Tech-Transfer for Mini-Tablets in Capsules

Purpose: The goal of this study is to facilitate process development and clinical trial material (CTM) manufacture of COMPOUND-X IR Mini-Tablets in capsules. COMPOUND-X is a potent candidate for an oncology indication. The primary manufacturing process consists of pre-blending, roller compaction and milling for the granulation process followed by compression of the final blend into Mini-Tabs. The final dosage forms are 20 mg and 50 mg strength capsules. To establish the critical process parameters (CPPs) in a material sparing and expedited manner, the roller compaction and high-speed tableting processes were simulated leveraging Compaction Simulation. This allowed for rapid process development during the tech-transfer and scale-up. The gained knowledge was successfully translated to clinical manufacturing in a material sparing manner and resulted in accelerated timelines for technology transfer and scale-up.

Methods: The intra-granular blend of COMPOUND-X was prepared and evaluated for the bulk/tapped density, true density (Accupyc gas displacement pycnometer), flow properties (FT4 shear-cell), and compression behavior (elasticity/plasticity via Heckel analysis) on a compaction simulator (Medelpharm Styl’One Evolution). The intra-granular blend was then roller compacted using a simulated Gerteis MINI-PACTOR® (Gerteis Maschinen, Stampfstrasse, Switzerland) profile on the compaction simulator with a constant roll speed of 6 rpm and gap width of 2.0 mm. Ribbons were generated at three target solid fractions (0.62, 0.69 and 0.77) and milled using a small scale Gerteis hand mill equipped with either 0.5 mm Conidur-Screen or 0.8 mm Square-Screen. Combination of three target solid fractions and two milling conditions led to six (6) final blends (C1-C6). Post-granulation material characterization included powder flowability, density measurements and particle size distribution (PSD) analysis. Final blends were then compressed into 8 mg Mini-Tabs using a 10-tip, 2-mm SRC tooling and simulated profile of a Fette 1200i tablet press (Fette Compacting GmbH, Schwarzenbek, Germany) at 20 rpm press speed. Compaction behavior of the final blends were evaluated by the analysis of compactibility, tabletability, and compressibility.

Results: Processability data (bulk density=0.41, Hausner Ratio=1.38, Carr Index=27.7% and shear-cell measured flow function coefficient, FFC=9.54) revealed low risk of flowability issues during the roller compaction process. Heckel analysis of the intra-granular blend demonstrated acceptable strain rate sensitivity of 17% and yield pressure of around 100 MPa with compression behavior in between ductile/brittle (elastic) and moderately hard (plastic) material with no risk of lamination or sticking during high-speed compression. The Gerteis MINI-PACTOR® simulation on the compaction simulator predicted the required roll forces (kN/cm) for each target solid fraction (Fig. 1). The Fette 1200i tablet press simulations (i.e., realistic compression kinetics and dwell-time) characterized compaction behavior of six (6) final blends by evaluating compactibility, tabletability, and compressibility profiles, as shown in Figure 2. These studies revealed sufficient tensile strength of > 2 MPa for all the final blends at 150 MPa main compression pressure with no risk of lamination, capping or punch sticking. Furthermore, processability evaluations of the final blends including density, FT4 flowability, PSD analysis and weight variability measurements demonstrated guidance in identifying the optimum process parameters. The manufacturability summary is shown in Figure 3.

Conclusion: This study successfully demonstrated an accelerated and material sparing approach for process development and clinical trial material (CTM) manufacturing of COMPOUND-X IR Mini-Tablets in capsules. By leveraging compaction simulation, the critical process parameters (CPPs) for roller compaction and high-speed tableting were efficiently identified and transferred. The recommended CPPs for roller compaction included a 2 mm gap width, 6 rpm roll speed, and a solid fraction range of 0.65 – 0.72. The identified compression parameters for the Fette 1200i tablet press included a turret speed of 20 rpm, feeder speed of 10 rpm, main compression force of 7 – 9 kN, and 10% pre-compression force. Material characterization and processability evaluation demonstrated favorable flow properties and compression behavior and minimized manufacturability risks (e.g., flowability, weight variability, capping, punch-sticking) during high-speed compression. These findings contributed to the efficient development and scale-up of COMPOUND-X IR Mini-Tablets, reducing risks and shortening product development timelines associated with tech-transfer and scale-up.

Figure 1. Predicted ribbon solid fraction as a function of actual roll-force on the simulated Gerteis MINI-PACTOR®.

Figure 2. Simulated Fette 1200i compression profiles of the final blends at 20 rpm.

Figure 3. Manufacturability summary of the final blends (powder and Mini-Tabs).