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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.
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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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
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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Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 4─Applications of Process Analytical Technology in Heterogeneous Biocatalytic Hydroxylation
Contributor(s):: Qin, Yangzhong, Mattern, Keith A., Zhang, Victoria, Abe, Kotoe, Kim, Jungchul, Zheng, Michelle, Gangam, Rekha, Kalinin, Alexei, Kolev, Joshua N., Axnanda, Stephanus, Dance, Zachary E. X., Ayesa, Umme, Ji, Yining, Grosser, Shane T., Appiah-Amponsah, Emmanuel, McMullen, Jonathan P.
Belzutifan has been approved recently by the U.S. Food and Drug Administration (FDA) for treating patients with certain types of Von Hippel-Lindau (VHL) disease-associated tumors. Although a commercial synthetic process has been established to make belzutifan, a further optimized process with...
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Development of a Commercial Flow Barbier Process for a Pharmaceutical Intermediate
Contributor(s):: Braden, Timothy M., Johnson, Martin D., Kopach, Michael E., Groh, Jennifer McClary, Spencer, Richard D., Lewis, Jeffrey, Heller, Michael R., Schafer, John P., Adler, Jonathan J.
A flow Barbier process was developed to produce a key intermediate in the edivoxetine·HCl registered sequence. The control strategy was developed based on a critical understanding of integrated parameters and design space requirements for a continuous stirred tank reactor (CSTR) process. In this...
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Synthesis of a Highly Functionalized Quinazoline Organozinc toward KRAS G12C Inhibitor Divarasib (GDC-6036), Enabled through Continuous Flow Chemistry
Contributor(s):: Kelly, Sean M., Lebl, René, Malig, Thomas C., Bass, Thomas M., Kummli, Dominique, Kaldre, Dainis, Orcel, Ugo, Tröndlin, Lars, Linder, David, Sedelmeier, Joerg, Bachmann, Stephan, Han, Chong, Zhang, Haiming, Gosselin, Francis
The development of a scalable continuous flow process to synthesize a densely functionalized quinazoline organozinc intermediate toward KRAS G12C inhibitor divarasib (GDC-6036) is reported herein. A traditional cryogenic batch metalation process was initially employed, but instability of the...
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Development of a Continuous Flow Grignard Reaction to Manufacture a Key Intermediate of Ipatasertib
Contributor(s):: Kaldre, Dainis, Stocker, Severin, Linder, David, Reymond, Helena, Schuster, Andreas, Lamerz, Jens, Hildbrand, Stefan, Püntener, Kurt, Berry, Malcolm, Sedelmeier, Jörg
This article outlines the development of a continuous flow process for the manufacture of a key intermediate of the active pharmaceutical ingredient ipatasertib for the treatment of metastatic castration-resistant prostate cancer and triple-negative metastatic breast cancer. The reaction sequence...
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Match-Making Reactors to Chemistry: A Continuous Manufacturing-Enabled Sequence to a Key Benzoxazole Pharmaceutical Intermediate
Contributor(s):: Yayla, Hatice G., Peng, Feng, Mangion, Ian K., McLaughlin, Mark, Campeau, Louis-Charles, Davies, Ian W.DiRocco, Daniel A., Knowles, Robert R.
The focus of this study was to develop a chemical reaction sequence toward a key benzoxazole building block, required for clinical manufacturing of a lead candidate in the respiratory disease area. The chemistry consisted of initial low-temperature reactions with an organometallic reagent to...
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Automated and continuous synthesis of drug substances
| Contributor(s):: Sacher, Stephan, Castillo, Ismael, Rehrl, Jakob, Sagmeister, Peter, Lebl, René, Kruisz, Julia, Celikovic, Selma, Sipek, Martin, Williams, Jason D., Kirschneck, Dirk, Kappe, C. Oliver, Horn, Martin
A continuous synthesis line was developed integrating different common reaction steps namely nitration, substitution and hydrogenation. Mesalazine as model drug substance was produced from 2-chlorobenzoic acid in continuous flow mode. A multi-instrument PAT strategy was implemented to equip the...
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PAT-based design of agrochemical co-crystallization processes: A case-study for the selective crystallization of 1:1 and 3:2 co-crystals of p-toluenesulfonamideitriphenylphosphine oxide
| Contributor(s):: Powell, KA, Croker, DMRielly, CD, Nagy, ZK
In this study, the selective crystallization and characterization of the stoichiometric forms of the p-to-luenesulfonamide/triphenylphosphine oxide (p-TSA-TPPO) co-crystal system in acetonitrile (MeCN) is demonstrated using batch and semi-batch crystallizers. In the batch study, both 1:1 and 3:2...
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Monitoring of the combined cooling and antisolvent crystallisation of mixtures of aminobenzoic acid isomers using ATR-UV/vis spectroscopy and FBRM
| Contributor(s):: Saleemi, AN, Rielly, CD, Nagy, ZK
During the manufacturing of active pharmaceutical ingredients crystalline products in the purest forms are required. Quite often multiple components are present during crystallisation, which requires their continuous monitoring and finally separation. The current work demonstrates the application...
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Control of three different continuous pharmaceutical manufacturing processes: Use of soft sensors
| Contributor(s):: Rehrl, J, Karttunen, APNicolai, N, Hormann, T, Horn, M, Korhonen, O, Nopens, I, De, Beer, T, Khinast, JG
One major advantage of continuous pharmaceutical manufacturing over traditional batch manufacturing is the possibility of enhanced in-process control, reducing out-of-specification and waste material by appropriate discharge strategies. The decision on material discharge can be based on the...
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Continuous downstream processing of milled electrospun fibers to tablets monitored by near-infrared and Raman spectroscopy
| Contributor(s):: Szabo, E, Zahonyi, PGyurkes, M, Nagy, B, Galata, DL, Madarasz, L, Hirsch, E, Farkas, A, Andersen, SK, Vigh, T, Verreck, G, Csontos, I, Marosi, G, Nagy, ZK
Electrospinning is a technology for manufacture of nano- and micro-sized fibers, which can enhance the dissolution properties of poorly water-soluble drugs. Tableting of electrospun fibers have been demonstrated in several studies, however, continuous manufacturing of tablets have not been...
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Advanced Real-Time Process Analytics for Multistep Synthesis in Continuous Flow
| Contributor(s):: Sagmeister, Peter, Lebl, René, Castillo, Ismael, Rehrl, Jakob, Kruisz, Julia, Sipek, Martin, Horn, Martin, Sacher, Stephan, Cantillo, David, Williams, Jason D, Kappe, Oliver
In multistep continuous flow chemistry, studying complex reaction mixtures in real time is a significant challenge, but provides an opportunity to enhance reaction understanding and control. We report the integration of four complementary process analytical technology tools (NMR, UV/Vis, IR and...