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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 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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Continuous manufacturing: Changing the paradigm in the pharmaceutical manufacturing sector
23 Sep 2024 | Magazine | Contributor(s): Indu Bhushan
The author explains how continuous manufacturing is reshaping pharmaceutical production
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Pharmaceutical Continuous Manufacturing: Content Uniformity With PAT And RTR
16 Sep 2024 | Website | Contributor(s): Richard Steiner
In pharmaceutical continuous manufacturing (PCM), technical solutions ensuring critical quality attributes for content uniformity and unit dose exist for online, in-line, and at-line measurements. Process analytical technology (PAT) allows in-line measurement and control of critical process...
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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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Orodispersible films: Product transfer from lab-scale to continuous manufacturing
23 Jul 2024 | Peer-reviewed journal | Contributor(s): Thabet, Yasmin, Breitkreutz, Joerg
Orodispersible films have been described as new beneficial dosage forms for special patient populations. Due to various production settings, different requirements on film formulations are required for non- continuous and continuous manufacturing. In this study, a continuous coating machine was...
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Orodispersible films: Product transfer from lab-scale to continuous manufacturing
23 Jul 2024 | Peer-reviewed journal | Contributor(s): Thabet, Yasmin, Breitkreutz, Joerg
Orodispersible films have been described as new beneficial dosage forms for special patient populations. Due to various production settings, different requirements on film formulations are required for non- continuous and continuous manufacturing. In this study, a continuous coating machine was...
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The effect of binder types on the breakage and drying behavior of granules in a semi-continuous fluid bed dryer after twin screw wet granulation
23 Jul 2024 | Peer-reviewed journal | Contributor(s): Vandevivere, L., Denduyver, P., Portier, C., Häusler, O., De Beer, T., Vervaet, C., Vanhoorne, V.
Current study investigated the effect of different binder types on the granule drying process and the granule breakage behavior in a semi-continuous fluid bed dryer integrated in the C25 ConsiGma-system. The studied binders (i.e. hydroxypropyl pea starch, hydroxypropyl methylcellulose E15,...
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Delta-mannitol to enable continuous twin-screw granulation of a highly dosed, poorly compactable formulation
23 Jul 2024 | Peer-reviewed journal | Contributor(s): Vanhoorne, V., Almey, R., De Beer, T., Vervaet, C.
In current study, it was investigated if the moisture-mediated polymorphic transition from δ- to β-mannitol during twin screw granulation (TSG) also took place in high drug loaded formulations and if the specific granule morphology associated with the polymorphic transition could enable tableting...
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Twin Screw Melt Granulation: Alternative Approach for Improving Solubility and Permeability of a Non-steroidal Anti-inflammatory Drug Ibuprofen
23 Jul 2024 | Peer-reviewed journal | Contributor(s): Nyavanandi, Dinesh, Narala, Sagar, Mandati, Preethi, Alzahrani, Abdullah, Kolimi, Praveen, Almotairy, Ahmed, Repka, Michael A.
The current research is focused on investigating the suitability of the twin screw melt granulation (TSMG) approach for improving the solubility of a non-steroidal anti-inflammatory (NSAIDs) drug (ibuprofen), by developing granules using lipid surfactants. The solubility of the drug within the...
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Application of Transition-Metal Catalysis, Biocatalysis, and Flow Chemistry as State-of-the-Art Technologies in the Synthesis of LCZ696
23 Jul 2024 | Peer-reviewed journal | Contributor(s): Gu, Xingxian, Zhao, Jibin, Chen, Like, Li, Yunzhong, Yu, Bo, Tian, Xiangguang, Min, Zhongcheng, Xu, Su, Gu, Huijuan, Sun, Junjie, Lu, Xiaoquan, Chang, Meng, Wang, Xufan, Zhao, Liqun, Ye, Shengqing, Yang, Hongwei, Tian, Yingtao, Gao, Feng, Gai, Yu, Jia, Guanghua, Wu, Jingjing, Wang, Yan, Zhang, Jianghua, Zhang, Xuesong, Liu, Weichun, Gu, Xin, Luo, Xi, Dong, Hai, Wang, Huaimin, Schenkel, Berthold, Venturoni, Francesco, Filipponi, Paolo, Guelat, Bertrand, Allmendinger, Thomas, Wietfeld, Bernhard, Hoehn, Pascale, Kovacic, Nikola, Hermann, Luca, Schlama, Thierry, Ruch, Thomas, Derrien, Nadine, Piechon, Philippe, Kleinbeck, Florian
LCZ696 is a novel treatment for patients suffering from heart failure that combines the two active pharmaceutical ingredients sacubitril and valsartan in a single chemical compound. While valsartan is an established drug substance, a new manufacturing process suitable for large-scale commercial...
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One-Step Synthesis of 2-Fluoroadenine Using Hydrogen Fluoride Pyridine in a Continuous Flow Operation
23 Jul 2024 | Peer-reviewed journal | Contributor(s): Salehi Marzijarani, Nastaran, Snead, David R., McMullen, Jonathan P., Lévesque, François, Weisel, Mark, Varsolona, Richard J., Lam, Yu-hong, Liu, Zhijian, Naber, John R.
We report the development of a one-pot synthesis of 2-fluoroadenine from an inexpensive 2,6-diaminopurine starting material using diazonium chemistry in a continuous fashion. Given the sensitivity of this transformation to temperature, we conducted critical experiments to study the exothermicity...
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Process Intensification via End-to-End Continuous Manufacturing of Atorvastatin Calcium Using an Integrated, Modular Reaction-Crystallization-Spherical Agglomeration-Filtration-Drying Process
23 Jul 2024 | Peer-reviewed journal | Contributor(s): Parvaresh, Rojan, Nagy, Zoltan K.
Continuous manufacturing can show potential benefits over batch processing in lower turnaround times and smaller footprint in addition to higher productivity, adaptability, and consistent product quality. Although these possible benefits exist, there are also challenges in integrating the various...
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Process analytics for the new era of continuous RNA manufacturing
23 Jul 2024 | Website | Contributor(s): Botonjic-Sehic, Edita
In this article, Edita Botonjic-Sehic, Head of Process Analytics and Data Science at ReciBioPharm, examines the need for a digitally controlled continuous manufacturing process to correct the shortcomings of the current standard of batch processing. She highlights the critical role in-line...
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Blend uniformity monitoring in a continuous manufacturing mixing process for a low-dosage formulation using a stream sampler and near infrared spectroscopy
19 Jul 2024 | Peer-reviewed journal | Contributor(s): Rodolfo Romanach, Raúl S. Rangel-Gil, Juan M. Nasrala-Álvarez, Rafael Méndez
Continuous manufacturing has the potential to offer several benefits for the production of oral solid dosage forms, including reduced costs, low-scale equipment, and the application of process analytical technology (PAT) for real-time process control. This study focuses on the implementation of...
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Implementation of a fully integrated continuous manufacturing line for direct compression and coating at a commercial pharmaceutical facility – Part 1: Operational considerations and control strategy
25 Jun 2024 | Peer-reviewed journal | Contributor(s): Conway, Stephen L., Rosas, Juan G., Overton, Paul, Tugby, Neil, Cryan, Phillip, Witulski, Frank, Hurley, Samantha, Wareham, Laura, Tantuccio, Anthony, Ramasamy, Manoharan, Lalloo, Anita, Gibbs, Mason, Meyer, Robert F.
We implement a fully integrated continuous manufacturing (CM) line for direct compression and coating of a pharmaceutical oral solid dosage form in a commercial production facility. In this first paper of a two-part series, we describe process design and operational choices made to introduce CM...
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Implementation of a fully integrated CM direct compression and coating process at a commercial pharmaceutical facility - Part 2: PAT and RTD results for normal operational conditions batches.
25 Jun 2024 | Peer-reviewed journal | Contributor(s): Rosas, JG, Brush, P, Thompson, B, Miller, C, Overton, P, Tugby, N, Stoliarskaia, D, Hurley, S, Ramasamy, M, Conway, SL
This is the second of two articles detailing the continuous manufacturing (CM) development and implementation activities for an marketed product which have been realized in novel, qualified equipment, using validated control strategy elements to enable manufacture of batches under current good...
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Telescoped Hybrid Batch–Flow Synthesis of 2-Butylbenzofuran
25 Jun 2024 | Peer-reviewed journal | Contributor(s): Dedè, Fabiana, Ciancimino, Cristina, Danelli, Piero, Piccolo, Oreste, Vigo, Daniele
The present work describes the development of an improved synthesis of the pharmaceutically relevant building block 2-butylbenzofuran (BBF). The telescoped hybrid batch–flow process is composed of three steps and affords the final product in high yield and purity. The key cyclization step is...
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Modular Synthesis of Benzoylpyridines Exploiting a Reductive Arylation Strategy
25 Jun 2024 | Peer-reviewed journal | Contributor(s): Alfano, Antonella Ilenia, Smyth, Megan, Wharry, Scott, Moody, Thomas S., Baumann, Marcus
Herein we disclose a telescoped flow strategy to access electronically differentiated bisaryl ketones as potentially new and tunable photosensitizers containing both electron-rich benzene systems and electron-deficient pyridyl moieties. Our approach merges a light-driven (365 nm) and...
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Development of a Horizontal Dynamically Mixed Flow Reactor for Laboratory Scale-Up of Photochemical Wohl–Ziegler Bromination
25 Jun 2024 | Peer-reviewed journal | Contributor(s): Pratley, Cassie, Shaalan, Youssef, Boulton, Lee, Jamieson, Craig, Murphy, John A., Edwards, Lee J.
Flow reactors with enhanced mixing are of interest to the pharmaceutical industry for a range of photochemical applications. Taylor–Couette (vortex, dynamically mixed) reactors have been reported to have intensified mixing and have been used with heterogeneous systems. Our photochemical workflow...
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A Tandem Ring Closure and Nitrobenzene Reduction with Sulfide Provides an Improved Route to an Important Intermediate for the Anti-Tuberculosis Drug Candidate Sutezolid
25 Jun 2024 | Peer-reviewed journal | Contributor(s): Kalmode, Hanuman P., Ravikumar, Ongolu, Paymode, Dinesh J., Bachert, John, Burns, Justina M., Stringham, Rodger W., Aleshire, Sarah L., Nelson, Ryan C.
Sutezolid is an in-development thiomorpholine derivative of the FDA-approved tuberculosis (TB) treatment linezolid. Current synthetic routes for preparing sutezolid start with thiomorpholine as a key structural building block; unfortunately, this material was identified as a major cost driver for...
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Continuous-Flow Synthesis of the Nucleobase Unit of Remdesivir
25 Jun 2024 | Peer-reviewed journal | Contributor(s): Guo, Yongxing, Liu, Minjie, Jiang, Meifen, Tao, Yuan, Cheng, Dang, Chen, Fen-Er
In this work, the nucleobase unit of the antiviral drug remdesivir, 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine, was synthesized through five-step continuous flow. By adapting batch synthetic chemistry, 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine was successfully produced through sequential flow...
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Continuous Platinum-Mediated Hydrogenation of Refametinib Iodo-nitroaniline Key Intermediate DIM-NA: The Combined Challenges of Selectivity and Catalyst Deactivation
25 Jun 2024 | Peer-reviewed journal | Contributor(s): Baramov, Todor, Hassfeld, Jorma, Gottfried, Michael, Bauer, Hermann, Herrmann, Tanja, Ben Said, Mourad, Roggan, Stefan
The chemoselective, continuous, multistep reduction of iodo-nitroaromatics in a fixed-bed hydrogenation reactor has been investigated. This transformation poses challenges upon both the catalyst and process conditions if high yields are to be achieved. First, the stability and selectivity of four...