(M0930-08-44) Accelerated Technology Transfer for the Development and Commercialization of Fexuprazan Using Compaction Simulation

Purpose: The purpose of this work was to enable initiation of clinical development for Fexuprazan in the U.S. Fexuprazan, an investigational novel potassium-competitive acid blocker (P-CAB) for the treatment of erosive esophagitis (EE), has successfully completed a phase III trial in South Korea and seeks development and commercialization in the U.S. The original manufacturing process for 40 mgA tablets comprised of mixing, dry granulation, post-mixing and tableting as critical steps. To successfully identify and transfer critical process parameters (CPPs) in an accelerated and material-sparing manner, the roller compaction process on a Gerteis MINI-PACTOR^® (Gerteis Maschinen, Switzerland) and the high-speed tableting process on a Fette 1200i Tablet Press (Fette Compacting GmbH, Germany) were simulated using a Medelpharm STYL’One Evo Compaction Simulator (Medelpharm, France). This enabled process development and troubleshooting during transfer and scale-up. The hypothesis of over-lubrication and loss of tabletability after dry granulation was successfully investigated and confirmed. The knowledge obtained from these studies was directly applied to the clinical manufacturing.

Methods: Tablet blends of FEXUPRAZAN HCL were prepared based on a patented master formula published in international patent application PCT/KR2021/019265. To prepare intra-granular blend, 26.67% w/w of the drug along with 53.28% w/w microcrystalline cellulose, 14.00% w/w lactose monohydrate, and 1.00% w/w intra-granular magnesium stearate were mixed in a 250-mL amber glass bottle using a Turbula^® mixer (GlenMills, Clifton, NJ) at 23 RPM for 10 min. The intra-granular blend was evaluated for the bulk/tap density, true density (Accupyc gas displacement pycnometer), flow properties (FT4 shear-cell), elasticity/plasticity (Heckel analysis) and tablet studies (Compressibility, Compactability, Tabletability on the compaction simulator). The intra-granular blend was then roller compacted using a simulated Gerteis MINI-PACTOR^® profile on the compaction simulator with a constant roll speed=3 RPM and gap=1.5 mm to be consistent with the original parameters. Ribbons were generated at five different solid fractions (SF= 0.55, 0.60, 0.65, 0.70 and 0.8) and milled using a Gerteis small scale hand mill (1.0 mm square screen) which inherits the same in-line milling principle as the MINI-PACTOR^® machine. Sieve analyses were conducted using a Sonic Sifter to evaluate the particle size distribution of milled granules at each solid fraction. Subsequently, 5 g of milled granules at each solid fraction were mixed with 4.00% w/w croscarmellose sodium, 0.05% w/w iron oxide, and 1.00% w/w extra-granular magnesium stearate in a 30-mL amber glass bottle using a Turbula® mixer at 23 RPM for 10 min. The extra-granular blends were evaluated for true density and subsequently compressed to 150 mg tablets using a simulated profile of a Fette 1200i tablet press at 30 RPM on the compaction simulator equipped with 5.1 mm x 9.2 mm oval tooling.

Results: For intra-granular blend, Bulk Density=0.53 g/mL, Tapped Density=0.66 g/mL, and True Density=1.55 g/mL were determined along with the flow properties (Hausner Ratio=1.25 and Carr’s index=19.7). Additionally, FT4 shear-cell testing was performed in a 10 mL vessel using 3 KPa consolidation stress, and it revealed good flowability (FFc=13.1 and Dimensionless Cohesion, τ_c/σ₁=0.02). The Yield Pressure and %Strain Rate Sensitivity (%SRS) of the intra-granular blend based on the Heckel analysis was 78.5 MPa and 15.9% respectively (Fig. 1). Based on this analysis, the intra-granular blend was balanced between soft ductile and moderately hard/brittle with no risks of lamination or capping during high-speed compression cycle. The Gerteis MINI-PACTOR^® profile was simulated on the compaction simulator through a learning process by increasing the roll-force and calculating the ribbons solid fraction (Fig. 2). Simulations predicted that increasing the roll-force to 9 kN/cm could result in a ribbon solid fraction ~0.8, which could be a potential cause for loss of tabletability by dry granulation. The tabletability graphs generated from the compression profile for the extra-granular blends are depicted in Figure 3, and it revealed loss of tabletability by increasing the solid fraction of dry granules. Transferring the technology between two manufacturing facilities with major equipment differences required additional analysis to study the hypothesis of over-lubrication during the blending unit operation (by comparing the lubrication length for different scales of the blender) and the rotary tablet press feed-frame (by simulating the mean residence time). These analyses resulted in recommendations for the adjustment of lubrication level/time for the clinical manufacturing campaign.

Conclusion: An accelerated technology transfer for the development of 40 mgA Fexuprazan tablets in the U.S. has been successfully executed leveraging an expedited and material-sparing approach. Rapid process development and troubleshooting during transfer and scale-up were achieved by simulating the roller compaction and the high-speed tableting processes using Compaction Simulation. The hypothesis of loss of tabletability after dry granulation and over-lubrication during the blending unit operation and the rotary tablet press feed-frame was successfully investigated and confirmed. These studies helped di-risk and identify the optimal process parameters for the clinical manufacturing campaign using minimal API ( < 100 g), and shortened transfer and scale-up timelines ( < 1-month), which ultimately reduced development timelines and costs.

References: R.J. Roberts, R.C. Rowe, The compaction of pharmaceutical and other model materials - a pragmatic approach, Chemical Engineering Science, Volume 42, Issue 4, 1987, Pages 903-911.

Figure 1. Compaction classification of FEXUPRAZAN HCL TAB 40 MG DEV intra-granular blend using the percent strain rate sensitivity diagram (%SRS). Adapted from Roberts and Rowe (see the reference).



Figure 2. Predicted ribbons solid fraction as a function of actual roll-force on the Gerteis MINI-PACTOR® machine. The original value of roll-force = 9 kN/cm (red star) resulted in a ribbon solid fraction = 0.8. The green circle shows the desire range (2-4 kN/cm) for the roll-force on MINI-PACTOR®.



Figure 3. Tabletability profiles for the FEXUPRAZAN HCL TAB 40 MG DEV extra-granular blends based on the simulated Fette 1200i compression profile at 30 RPM.