(656c) In silico Process Design and Scale-up for an Amorphous Solid Dispersion Manufactured By Hot Melt Extrusion
AIChE Annual Meeting
2023
2023 AIChE Annual Meeting
Pharmaceutical Discovery, Development and Manufacturing Forum
Predictive Scale-Up/Scale-Down for Pharmaceuticals and Biopharmaceuticals #2
Tuesday, November 7, 2023 - 1:12pm to 1:33pm
Email for correspondence: josip.matic@rcpe.at, EwaldJonathan.Meyer@pfizer.com
Hot melt extrusion (HME) is a continuous manufacturing process increasingly used as an environmentally sustainable technique to produce amorphous solid dispersions (ASDs) of poorly water soluble active pharmaceutical ingredients (APIs). The extruders used for the processing are module co-rotating intermeshing twin screw extruders. A careful selection of the screw configuration and process parameters is required for achieving a stable ASD. Considering potential process setup permutations and it being a continuous manufacturing technology, HME requires high amounts of API than typically available in the early development stages. Additionally, significant experimental iterations are required to generate substantial process understanding for establishing controls that would apply from development to commercial scales. To address these challenges, our groups have worked on the development of in silico and experimental tools for simpler process development and scale-up.
To this date, most of the HME process development and scale-up activities are performed experimentally and empirically. To enhance sustainability and the speed of rational, science-based process development, the objective of this work was to create supportive in silico tools [1]–[9]. The fundamental idea behind HME process modeling is the breakdown and the detailed analysis of the key process aspects, among which the most prominent can be the analysis of flow patterns developed as a result of the rotation and geometry of the individual screw element pairs. In this work the process design space identified at a small scale was further studied and scaled up to the pilot and production scales using in silico tools. This was achieved by 3D Smoothed Particle Hydrodynamics (SPH) simulations of individual screw elements that comprise the screw configuration and reduced-order 1D HME process simulations. The 1D HME simulations guided the process setup and scale-up by providing process maps for different experimental permutations. Process understanding generated through this approach allowed rapid process scale-up, in a sustainable manner by minimizing the number of actual experiments and the API use.
Literature
[1] J. Matić, A. Witschnigg, M. Zagler, S. Eder, and J. Khinast, “A novel in silico scale-up approach for hot melt extrusion processes,†Chem. Eng. Sci., vol. 204, pp. 257–269, Aug. 2019, doi: 10.1016/j.ces.2019.04.016.[2] J. Matić, A. Paudel, H. Bauer, R. A. L. Garcia, K. Biedrzycka, and J. G. Khinast, “Developing HME-Based Drug Products Using Emerging Science: a Fast-Track Roadmap from Concept to Clinical Batch,†AAPS PharmSciTech, vol. 21, no. 5, p. 176, Jul. 2020, doi: 10.1208/s12249-020-01713-0.
[3] J. Matić et al., “Towards predicting the product quality in hot-melt extrusion: Small scale extrusion,†Int. J. Pharm. X, vol. 2, p. 100062, Dec. 2020, doi: 10.1016/j.ijpx.2020.100062.
[4] A. Eitzlmayr and J. Khinast, “Co-rotating twin-screw extruders: Detailed analysis of conveying elements based on smoothed particle hydrodynamics. Part 1: Hydrodynamics,†Chem. Eng. Sci., vol. 134, pp. 861–879, Sep. 2015, doi: 10.1016/j.ces.2015.04.055.
[5] A. Eitzlmayr, J. Matić, and J. G. Khinast, “Analysis of flow and mixing in screw elements of corotating twin-screw extruders via SPH,†AIChE J., vol. 63, no. 6, pp. 2451–2463, Jun. 2017, doi: 10.1002/aic.15607.
[6] A. Eitzlmayr et al., “Experimental characterization and modeling of twin-screw extruder elements for pharmaceutical hot melt extrusion,†AIChE J., vol. 59, no. 11, pp. 4440–4450, Nov. 2013, doi: 10.1002/aic.14184.
[7] A. Eitzlmayr et al., “Mechanistic modeling of modular co-rotating twin-screw extruders,†Int. J. Pharm., vol. 474, no. 1–2, pp. 157–176, Oct. 2014, doi: 10.1016/j.ijpharm.2014.08.005.
[8] R. Baumgartner, J. Matić, S. Schrank, S. Laske, J. J. G. J. Khinast, and E. Roblegg, “NANEX: Process design and optimization,†Int. J. Pharm., vol. 506, no. 1–2, pp. 35–45, Jun. 2016, doi: 10.1016/j.ijpharm.2016.04.029.
[9] J. Matić, C. Alva, S. Eder, K. Reusch, A. Paudel, and J. Khinast, “Towards predicting the product quality in hot-melt extrusion: Pilot plant scale extrusion,†Int. J. Pharm. X, vol. 3, p. 100084, Dec. 2021, doi: 10.1016/j.ijpx.2021.100084.
Hot melt extrusion (HME) is a continuous manufacturing process increasingly used as an environmentally sustainable technique to produce amorphous solid dispersions (ASDs) of poorly water soluble active pharmaceutical ingredients (APIs). The extruders used for the processing are module co-rotating intermeshing twin screw extruders. A careful selection of the screw configuration and process parameters is required for achieving a stable ASD. Considering potential process setup permutations and it being a continuous manufacturing technology, HME requires high amounts of API than typically available in the early development stages. Additionally, significant experimental iterations are required to generate substantial process understanding for establishing controls that would apply from development to commercial scales. To address these challenges, our groups have worked on the development of in silico and experimental tools for simpler process development and scale-up.
To this date, most of the HME process development and scale-up activities are performed experimentally and empirically. To enhance sustainability and the speed of rational, science-based process development, the objective of this work was to create supportive in silico tools [1]–[9]. The fundamental idea behind HME process modeling is the breakdown and the detailed analysis of the key process aspects, among which the most prominent can be the analysis of flow patterns developed as a result of the rotation and geometry of the individual screw element pairs. In this work the process design space identified at a small scale was further studied and scaled up to the pilot and production scales using in silico tools. This was achieved by 3D Smoothed Particle Hydrodynamics (SPH) simulations of individual screw elements that comprise the screw configuration and reduced-order 1D HME process simulations. The 1D HME simulations guided the process setup and scale-up by providing process maps for different experimental permutations. Process understanding generated through this approach allowed rapid process scale-up, in a sustainable manner by minimizing the number of actual experiments and the API use.
Literature
[1] J. Matić, A. Witschnigg, M. Zagler, S. Eder, and J. Khinast, “A novel in silico scale-up approach for hot melt extrusion processes,†Chem. Eng. Sci., vol. 204, pp. 257–269, Aug. 2019, doi: 10.1016/j.ces.2019.04.016.[2] J. Matić, A. Paudel, H. Bauer, R. A. L. Garcia, K. Biedrzycka, and J. G. Khinast, “Developing HME-Based Drug Products Using Emerging Science: a Fast-Track Roadmap from Concept to Clinical Batch,†AAPS PharmSciTech, vol. 21, no. 5, p. 176, Jul. 2020, doi: 10.1208/s12249-020-01713-0.
[3] J. Matić et al., “Towards predicting the product quality in hot-melt extrusion: Small scale extrusion,†Int. J. Pharm. X, vol. 2, p. 100062, Dec. 2020, doi: 10.1016/j.ijpx.2020.100062.
[4] A. Eitzlmayr and J. Khinast, “Co-rotating twin-screw extruders: Detailed analysis of conveying elements based on smoothed particle hydrodynamics. Part 1: Hydrodynamics,†Chem. Eng. Sci., vol. 134, pp. 861–879, Sep. 2015, doi: 10.1016/j.ces.2015.04.055.
[5] A. Eitzlmayr, J. Matić, and J. G. Khinast, “Analysis of flow and mixing in screw elements of corotating twin-screw extruders via SPH,†AIChE J., vol. 63, no. 6, pp. 2451–2463, Jun. 2017, doi: 10.1002/aic.15607.
[6] A. Eitzlmayr et al., “Experimental characterization and modeling of twin-screw extruder elements for pharmaceutical hot melt extrusion,†AIChE J., vol. 59, no. 11, pp. 4440–4450, Nov. 2013, doi: 10.1002/aic.14184.
[7] A. Eitzlmayr et al., “Mechanistic modeling of modular co-rotating twin-screw extruders,†Int. J. Pharm., vol. 474, no. 1–2, pp. 157–176, Oct. 2014, doi: 10.1016/j.ijpharm.2014.08.005.
[8] R. Baumgartner, J. Matić, S. Schrank, S. Laske, J. J. G. J. Khinast, and E. Roblegg, “NANEX: Process design and optimization,†Int. J. Pharm., vol. 506, no. 1–2, pp. 35–45, Jun. 2016, doi: 10.1016/j.ijpharm.2016.04.029.
[9] J. Matić, C. Alva, S. Eder, K. Reusch, A. Paudel, and J. Khinast, “Towards predicting the product quality in hot-melt extrusion: Pilot plant scale extrusion,†Int. J. Pharm. X, vol. 3, p. 100084, Dec. 2021, doi: 10.1016/j.ijpx.2021.100084.