(W0930-11-65) Transfer of a Low Dose Formulation from Batch to Continuous Manufacturing: High-Shear Wet Granulation to Continuous Twin-Screw Wet Granulation

Purpose: Wet granulation is a key unit operation in pharmaceutical solid-oral dosage form (SODF) manufacturing to improve powder properties including flowability, compressibility, compactability, and uniformity of formulation [1]. Ensuring content uniformity is critical for therapeutic safety and efficacy of low-dose formulation [2]. Batch manufacturing (BM) via high-shear wet granulation (HSWG) is widely used to accomplish granulation for SODF processes. However, processing-time, labor-intensive nature, and low-production capacity make HSWG inefficient for many products [3,4]. Continuous manufacturing (CM) is a way to address these challenges. The implementation of Quality-by-Design (QbD) principles further motivates this shift, as many process conditions can be explored in a single experiment. The continuous twin-screw wet granulation (TSWG) technique offers advantages over the traditional HSWG process, such as greater reproducibility, granulation in a material, time and energy-saving way of adopting process analytical technology (PAT) tools for real-time process monitoring and control [1]. This research aims to transfer a model low-dose pharmaceutical formulation, previously developed using HSWG, to a continuous TSWG process. The study compared two critical quality attributes (CQA), content uniformity (CU) and granule size distribution (GSD), produced by these two techniques. A definitive screening design (DSD) was utilized in the TSWG process to discern critical process parameters (CPP) that influence CU and GSD, with the goal of defining an optimal design space that yields the targeted CQA.

Methods: The High-Shear Mixer Gral-25 (Collette, Germany) representing BM and the Dome-Ex Granulator and DG-Dryer system (Dalton, Osaka, Japan) representing CM were used for wet granulation of a low-dose model theophylline formulation. The HSWG system produced a batch of granules which provided a comparator for the TSWG process. Thirteen design points calculated according to the DSD were applied in the TSWG system. Three CPPs were varied at the following levels:  L/S ratio (0.2, 0.3, & 0.4), feed rate (1.50, 1.75, & 2.00 kg/hr.), and screw speed (100, 140, & 180 rpm). The drying temperature of 75°C was maintained for both systems. The granules from HSWG were dried overnight in a tray dryer, while the TSWG process dried granules with the integrated DG-Dryer system. Three samples were collected for each experimental condition and granule size was measured with dynamic image analysis via the Canty Solid Sizer (J.M. Canty, NY, USA). The assay was analyzed with Hewlett Packard UV-vis Spectrophotometer (Agilent HP, Germany). The resulting granule sizes were used to construct GSDs, and assay percentage was used to define CU. Statistical analysis, including contour potting and CPP significance (α= < 0.05), was performed in JMP® (Version 17.2.0. SAS Institute Inc., Cary, NC, USA). The optimal design space was constructed after calculating the significant CPP from the DSD using MATLAB (MathWorks Inc., MA, US).

Results: The results from the HSWG and TSWG granulation experiments are shown in (figure 1). The GSDs produced by HSWG (figure 1A) and TSWG (figure 1C) processes are highlighted in green to show the dv50 values. The dv50 of the granules from the HSWG experiment was found to be 272 µm, which served as the target granule size for the TSWG process in this study. The range of dv50 values was 201 µm to 454 µm across the TSWG DSD. A total of 8 experimental conditions for TSWG showed an increased dv50 compared to HSWG, which demonstrated a successful transfer from BM to CM. The average assay percentage for HSWG was 99% and for TSWG was 101% (figure 1B and 1D). The comparability between the HSWG and TSWG CQA results suggests a successful transfer of a low-dose formulation from BM to CM. The statistical analysis of three CPP (L/S ratio, feed rate, and screw speed) was visualized using leverage plots in figure 2. L/S ratio was found to be the most significant CPP for each CQA. The second significant CPP was feed rate, but it was only significantly affecting LOD. Screw speed was not significant for any of the CPPs. This statistical analysis gave us the confidence to work with the L/S ratio and feed rate as CPPs for further analysis. The contour plots were created for L/S ratio and feed rate, while keeping the screw speed (140 rpm) and drying condition (75 °C) constant (figure 3A). These contour plots provided ranges for each CPP that can be applied in the experimental conditions in the TSWG for achieving target CQAs. An optimal design space has been created using these ranges of CPPs for a future response surface study (figure 3B). The two CPPs of this response surface study L/S and feed rate will range from 0.26 to 0.3 and from 1.8 to 2.0 respectively.

Conclusion: This study explored the transition from batch HSWG to continuous TSWG process, identifying the L/S ratio as a key parameter to control GSD.  An optimal design space was defined based on the CPP results from the DSD. Therefore, the study successfully demonstrated a transfer from batch to continuous manufacturing.

References: 1. Beer P, Wilson D, Huang Z, De Matas M. Transfer from High‐Shear Batch to Continuous Twin Screw Wet Granulation: A Case Study in Understanding the Relationship Between Process Parameters and Product Quality Attributes. Journal of pharmaceutical sciences. 2014 Oct 1;103(10):3075-82.
2. Kukkar V, Anand V, Kataria M, Gera M, Choudhury PK. Mixing and formulation of low dose drugs: underlying problems and solutions. Thai J Pharm Sci. 2008 Dec 31;32(3-4):43-58.
3. Mahours GM, Shaaban DE, Shazly GA, Auda SH. The effect of binder concentration and dry mixing time on granules, tablet characteristics and content uniformity of low dose drug in high shear wet granulation. Journal of Drug Delivery Science and Technology. 2017 Jun 1;39:192-9.
4. Liu B, Wang J, Zeng J, Zhao L, Wang Y, Feng Y, Du R. A review of high shear wet granulation for better process understanding, control and product development. Powder technology. 2021 Mar 1;381:204-23.
5. Waněk A, Menarini L, Giatti F, Kubelka T, Consoli F, Funaro C, Stasiak P, Štěpánek F. Manufacturing process transfer to a 30 kg/h continuous direct compression line with real-time composition monitoring. International Journal of Pharmaceutics. 2024 Apr 10:124100.


Figure 1: (A) Overlay log distribution plot of cumulative GSD of HSWG, (B) Assay percentage of HSWG, (C) Overlay log distribution plot of cumulative GSD of TSWG, (D) Assay percentage of Continuous TSWG and (E) LOD of Continuous TSWG.


Figure 2: (A) Leverage plots of LOD leverage residuals against Screw speed, L/S Ratio & Feed rate and parameters estimates of LOD (B) Leverage plots of DV50 leverage residuals against Screw speed, L/S Ratio & Feed rate and parameters estimates of Dv50, (C) Leverage plots of Assay leverage residuals against Screw speed, L/S Ratio & Feed rate and parameters estimates of Assay


Figure 2: (A) Contour plot of LOD, DV50 and Assay% and (B) Optimal Design Space