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Development of a high-fidelity digital twin using the discrete element method for a continuous direct compression process. Part 1. Calibration workflow
24 Oct 2024 | Peer-reviewed journal | Contributor(s): Peter Toson, Marko Matić, Theresa Hörmann-Kincses, Michela Beretta, Jakob Rehrl, Johannes Poms, Thomas O’Connor, Abdollah Koolivand, Geng Tian, Scott M. Krull, Johannes G. Khinast, Dalibor Jajcevic, Johan Remmelgas
In this work, a high-fidelity digital twin was developed to support the design and testing of control strategies for drug product manufacturing via direct compression. The high-fidelity digital twin platform was based on typical pharmaceutical equipment, materials, and direct compression...
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Continuous Processing. Continuous Evolution
08 Oct 2024 | Magazine | Contributor(s): Douglas Hausner
Continuous processing for small molecule products has been a hot topic for years, but where does the industry stand with it today? We speak with Doug Hausner, Senior Manager, Continuous Manufacturing, Oral Solid Dose, Pharma Services at Thermo Fisher Scientific, to find out.
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Continuous micro feeding and mixing of solid dosage forms under vibrational excitation
08 Oct 2024 | Peer-reviewed journal | Contributor(s): Haifeng Lu, Liang Zhang, Hui Du, Xiaolei Guo, Haifeng Liu
Continuous manufacturing has intrigued many researchers in the pharmaceutical industry in the post-COVID-19 world. We experimentally studied the discharge characteristics of pharmaceutical excipients under vibrational excitation. The successful accurate dosing and filling of powders at fill...
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Systematic investigation of the impact of screw elements in continuous wet granulation
10 Sep 2024 | Peer-reviewed journal | Contributor(s): Katharina Kiricenko, Peter Kleinebudde, Robin Meier
Twin-screw wet granulation (TSG) is a continuous manufacturing technique either for granules as final dosage form or as an intermediate before tableting or capsule filling. A comprehensive process understanding is required to implement TSG, considering various parameters influencing granule and...
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Matrix-assisted cocrystallization (MAC) simultaneous production and formulation of pharmaceutical cocrystals by hot-melt extrusion
23 Jul 2024 | Peer-reviewed journal | Contributor(s): Boksa, Kevin, Otte, Andrew, Pinal, Rodolfo
A novel method for the simultaneous production and formulation of pharmaceutical cocrystals, matrix-assisted cocrystallization (MAC), is presented. Hot-melt extrusion (HME) is used to create cocrystals by coprocessing the drug and coformer in the presence of a matrix material. Carbamazepine...
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Axial Chirality in the Sotorasib Drug Substance, Part 2: Leveraging a High-Temperature Thermal Racemization to Recycle the Classical Resolution Waste Stream
25 Jun 2024 | Peer-reviewed journal | Contributor(s): Beaver, Matthew G., Brown, Derek B., Campbell, Kiersten, Fang, Yuan-Qing, Ford, David D., Mardirossian, Narbe, Nagy, Kevin D., Rötheli, Andreas R., Sheeran, Jillian W., Telmesani, Reem, Parsons, Andrew T.
The development and kilogram-scale demonstration of a high-temperature continuous-flow racemization process to recycle the off-enantiomer of an atropisomeric sotorasib intermediate is described. Part 1 of this two-part series details the design and execution of a classical resolution to generate...
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Development and Scale-Up of a Continuous Manufacturing Process for a Hydrazine Condensation Reaction
25 Jun 2024 | Peer-reviewed journal | Contributor(s): Zhu, Ruiheng, Reddy, Ramesh, Ding, Man, Xu, Ming, Deng, Chaoyi, Tadayon, Sam, Li, Hui, Depew, Kristopher, Lane, Benjamin
The development of a continuous manufacturing process for a hydrazine condensation reaction at high temperature is reported. This continuous process represents a safer approach to manufacture 3-phenyl-1H-pyrazol-5-amine at scale and exhibits better impurity control compared to a traditional batch...
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A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 3: Manganese-Catalyzed Asymmetric Epoxidation, Crystallization, and Filtration
25 Jun 2024 | Peer-reviewed journal | Contributor(s): Maloney, Andrew J., Içten, Elçin, Capellades, Gerard, Beaver, Matthew G., Zhu, Xiaoxiang, Graham, Lauren R., Brown, Derek B., Griffin, Daniel J., Sangodkar, Rahul, Allian, Ayman, Huggins, Seth, Hart, Roger, Rolandi, Pablo, Walker, Shawn D., Braatz, Richard D.
This article describes the process characterization and development of models to inform a process control strategy to prepare (R,R)-epoxy ketone 2, an intermediate in the manufacture of carfilzomib. Model calibration for relevant unit operations and the development of a dynamic integrated...
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Development and Scale-Up of a Continuous, High-Pressure, Asymmetric Hydrogenation Reaction, Workup, and Isolation
25 Jun 2024 | Peer-reviewed journal | Contributor(s): Johnson, Martin D., May, Scott A., Calvin, Joel R., Remacle, Jacob, Stout, James R., Diseroad, William D., Zaborenko, Nikolay, Haeberle, Brian D., Sun, Wei-Ming, Miller, Michael T., Brennan, John
A fully continuous process including an asymmetric hydrogenation reaction operating at 70 bar hydrogen, aqueous extraction, and crystallization was designed, developed, and demonstrated at pilot scale. This paper highlights safety, quality, and throughput advantages of the continuous reaction and...
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Polymorphs, Particle Size, and a Pandemic: Development of a Scalable Crystallization Process for Molnupiravir, an Antiviral for the Treatment of COVID-19
25 Jun 2024 | Peer-reviewed journal | Contributor(s): Bade, Rachel, Bothe, Jameson R., Sirota, Eric, Brunskill, Andrew P. J., Newman, Justin A., Zhang, Yongqian, Tan, Melissa, Zheng, Michelle, Brito, Gilmar, Poirier, Marc, Fier, Patrick S., Xu, Yingju, Ward, Michael D., Stone, Kevin, Lee, Ivan H., Gmitter, Andrew J., Bernardoni, Frank, Zompa, Michael A., Luo, Hanlin, Patel, Sanjaykumar, Masiuk, Tina, Mora, Jeff, Ni, Tong, Okoh, Grace A., Tarabokija, James, Liu, Jiaying, Lowinger, Michael B., Mahmood, Tariq
Molnupiravir is a small-molecule active pharmaceutical ingredient (API) prodrug of a nucleoside analog that was demonstrated to be efficacious for the treatment of patients with COVID-19. Early in the pandemic, Merck & Co. Inc. partnered with Ridgeback Biotherapeutics to accelerate the...
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Improvement of a pharmaceutical powder mixing process in a tote blender via DEM simulations
04 Jun 2024 | Peer-reviewed journal | Contributor(s): Benedict Benque, Luca Orefice, Thomas Forgber, Matthias Habeler, Beate Schmid, Johan Remmelgas, Johannes Khinast
An industrial-scale pharmaceutical powder blending process was studied via discrete element method (DEM) simulations. A DEM model of two active pharmaceutical ingredient (API) components and a combined excipient component was calibrated by matching the simulated response in a dynamic angle of...
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A modified Kushner-Moore approach to characterising small-scale blender performance impact on tablet compaction
03 Jun 2024 | Peer-reviewed journal | Contributor(s): Hikaru G. Jolliffe, Martin Prostredny, Carlota Mendez Torrecillas, Ecaterina Bordos, Collette Tierney, Ebenezer Ojo, Richard Elkes, Gavin Reynolds, Yunfei Li Song, Bernhard Meir, Sara Fathollahi, John Robertson
Continuous Direct Compaction (CDC) has emerged as a promising route towards producing solid dosage forms while reducing material, development time and energy consumption. Understanding the response of powder processing unit operations, especially blenders, is crucial. There is a substantial body...
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Development of a Continuous Schotten–Baumann Route to an Acyl Sulfonamide
24 Apr 2024 | Peer-reviewed journal | Contributor(s): White, Timothy D., Berglund, K. Derek, Groh, Jennifer McClary, Johnson, Martin D., Yates, Matthew H.
The development and scale-up of a synthetic route to tasisulam sodium (5-bromo-thiophene-2-sulfonic acid 2,4-dichlorobenzoylamide sodium salt, hereafter referred to as tasisulam) utilizing continuous Schotten–Baumann reaction conditions is disclosed. A new synthetic route for the cytotoxic API...
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Development of a Multi-Step Synthesis and Workup Sequence for an Integrated, Continuous Manufacturing Process of a Pharmaceutical
24 Apr 2024 | Peer-reviewed journal | Contributor(s): Heider, Patrick L., Born, Stephen C., Basak, Soubir, Benyahia, Brahim, Lakerveld, Richard, Zhang, Haitao, Hogan, Rachael, - Buchbinder, Louis, Wolfe, Aaron, Mascia, Salvatore, Evans, James M. B., Jamison, Timothy F., Jensen, Klavs F.
The development and operation of the synthesis and workup steps of a fully integrated, continuous manufacturing plant for synthesizing aliskiren, a small molecule pharmaceutical, are presented. The plant started with advanced intermediates, two synthetic steps away from the final active...
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Influence of refilling on dosing accuracy of loss-in-weight powder feeders in continuous manufacturing
19 Feb 2024 | Peer-reviewed journal | Contributor(s): Jochen Thies, Peter Kleinebudde, Fabiola N. Santamaría Alvarez
Continuous manufacturing is a novel concept to produce high quality drug products. The manufacture of solid dosage forms starts with the feeding of materials, which is consider a critical step because it could have a high influence on the quality of the final product. Therefore, this unit...
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MOOC I Blending - Flow and Mixing Regime
29 Nov 2023 | Teaching Materials | Contributor(s): RCPE
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MOOC I Feeding - Refill Strategy
29 Nov 2023 | Teaching Materials | Contributor(s): RCPE
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MOOC I Blending Basics
29 Nov 2023 | Teaching Materials | Contributor(s): RCPE
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MOOC I Continuous Blender Types
29 Nov 2023 | Teaching Materials | Contributor(s): RCPE
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MOOC I Feeding - Twin Screw Feeder
29 Nov 2023 | Teaching Materials | Contributor(s): RCPE
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MOOC I Feeding - Disturbances
29 Nov 2023 | Teaching Materials | Contributor(s): RCPE
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MOOC I Continuous Blend Analysis
29 Nov 2023 | Teaching Materials | Contributor(s): RCPE
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Pharmaceutical Continuous Manufacturing: A Guide to Control Strategies for Solid Oral Dose Drugs
23 Aug 2023 | Technical Guides | Contributor(s): Atul Dubey
Advanced manufacturing technologies like pharmaceutical continuous manufacturing (PCM) can provide potential efficiencies for many medicines and their ingredients, thereby facilitating geographic diversity in manufacturing and supply chain resilience. One of the ways the U.S. Pharmacopeia (USP)...
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Videometric mass flow control: A new method for real-time measurement and feedback control of powder micro-feeding based on image analysis
09 Jun 2023 | Peer-reviewed journal | Contributor(s): Madarasz, L, Kote, AGyurkes, M, Farkas, A, Hambalko, B, Pataki, H, Fulop, G, Marosi, G, Lengyel, L, Casian, T, Csorba, K, Nagy, ZK
The present paper reports the first monitoring and control of ultra-low dose powder feeding using a camera image-based mass flow measurement system. Caffeine was fed via a single-screw microfeeder as a model active pharmaceutical ingredient (API). The mass, mass flow and sizes of the particles...
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Wet Granulation in a Twin-Screw Extruder: Implications of Screw Design
09 Jun 2023 | Peer-reviewed journal | Contributor(s): Thompson, M. R., Sun, J.
Wet granulation in twin-screw extrusion machinery is an attractive technology for the continuous processing of pharmaceuticals. The performance of this machinery is integrally tied to its screw design yet little fundamental knowledge exists in this emerging field for granulation to intelligently...