Authors: Peyman Aminpour, PhD^*; Sanjay Konagurthu, PhD

Thermo Fisher Scientific,

Purpose

To illustrate the practical application of compaction simulation in drug product development, two case studies are presented. In the first case, it was necessary to optimize a Mini-Tabs manufacturing process for a Phase II oncology drug with limited API. The use of compaction simulation allowed for rapid identification of the critical process parameters (CPPs) in a material sparing manner using minimal API. In the second case, roller compaction and tableting processes were simulated to troubleshoot tableting issues for a Phase III compound during a technology transfer. The approach allowed for rapid process development during tech-transfer and scale-up. In both cases, knowledge gained from the compaction simulation studies were directly translated into clinical manufacturing and resulted in accelerated timelines.

Methods

For both cases, the intra-granular blend was first 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 and gap size. Ribbons were generated at target solid fractions and milled using a small scale Gerteis hand mill. Post-granulation material characterizations included powder flowability, density measurements and particle size distribution (PSD) analysis. Final blends were then compressed into tablets using selected tooling and rotary tablet press profile planned for GMP manufacturing. Compaction behavior of the final blends was evaluated by the analysis of compactibility, tabletability, and compressibility.

Results

In the first case study for Mini-Tabs, processability data including density and flowability revealed low risk of flow issues during the roller compaction process. The Gerteis MINI-PACTOR® simulation on the compaction simulator predicted the required roll forces (kN/cm) for each target solid fraction. The tablet press simulations characterized compaction behavior of six (6) final blends by evaluating compactibility, tabletability, and compressibility profiles and 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 (Fig. 1).

In the second case study, The Gerteis MINI-PACTOR® profile was simulated on the compaction simulator and predicted the risk for loss of tabletability after dry granulation process. Simulation of a Fette 1200i tablet press (Fette Compacting GmbH, Schwarzenbek, Germany) at 20 rpm press speed revealed loss of tabletability by increasing the solid fraction of ribbons (Fig 2.a). Additionally, the risk of over-lubrication during tech-transfer and scale-up was investigated by comparing the lubrication length for different scales of the blenders and the mean residence time of the blend in the rotary tablet press feed-frame. These analyses resulted in recommendations for the reduction of lubrication level/time for the clinical manufacturing campaign (Fig 2.b).

Conclusion

These case studies successfully demonstrated the practical application of compaction simulation in drug product development. The rapid development and troubleshooting during tech-transfer and scale-up were achieved by simulating the roller compaction and the high-speed tableting processes. These studies helped to identify and de-risk the optimal process parameters for the clinical manufacturing campaign using minimal API (< 100 g), and shortened timelines for tech transfer and scale-up (< 1-month).

Figure 1. Manufacturability summary of the final blends (powder and Mini-Tabs).

Figure 2. (a) Tabletability profiles of the final blends based on the simulated Fette 1200i compression profile at 30 RPM. (b) Effect of lubrication level and mixing time (blender and feed-frame-driven lubrication) on tablet mechanical strength.