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A Compact Device for the Integrated Filtration, Drying, and Mechanical Processing of Active Pharmaceutical Ingredients
09 Jun 2023 | Contributor(s): Capellades, G, Neurohr, CAzad, M, Brancazio, D, Rapp, K, Hammersmith, G, Myerson, AS
Recent changes in the pharmaceutical sector call for the development of novel manufacturing approaches to reduce costs and improve control over product quality. In this area, the development of compact, plug-and-play devices that fit in a continuous manufacturing system has gained interest in...
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A Continuous Flow Sulfuryl Chloride-Based Reaction—Synthesis of a Key Intermediate in a New Route toward Emtricitabine and Lamivudine
25 Jun 2024 | Contributor(s): Souza, Juliana M. de, Berton, Mateo, Snead, David R., McQuade, D. Tyler
We demonstrate a continuous two-step sequence in which sulfenyl chloride is formed, trapped by vinyl acetate, and chlorinated further via a Pummerer rearrangement. These reactions produce a key intermediate in our new approach to the oxathiolane core used to prepare the antiretroviral medicines...
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A Continuous Flow Sulfuryl Chloride-Based Reaction—Synthesis of a Key Intermediate in a New Route toward Emtricitabine and Lamivudine
23 Jul 2024 | Contributor(s): Souza, Juliana M. de, Berton, Mateo, Snead, David R., McQuade, D. Tyler
We demonstrate a continuous two-step sequence in which sulfenyl chloride is formed, trapped by vinyl acetate, and chlorinated further via a Pummerer rearrangement. These reactions produce a key intermediate in our new approach to the oxathiolane core used to prepare the antiretroviral medicines...
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A Hybrid MPC-PID Control System Design for the Continuous Purification and Processing of Active Pharmaceutical Ingredients
09 Jun 2023 | Contributor(s): Sen, M, Singh, R, Ramachandran, R
In this work, a hybrid MPC (model predictive control)-PID (proportional-integral-derivative) control system has been designed for the continuous purification and processing framework of active pharmaceutical ingredients (APIs). The specific unit operations associated with the purification and...
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A large-scale experimental comparison of batch and continuous technologies in pharmaceutical tablet manufacturing using ethenzamide
09 Jun 2023 | Contributor(s): Matsunami, Kensaku, Nagato, Takuya, Hasegawa, Koji, Sugiyama, Hirokazu
This paper compares batch and continuous technologies in terms of product quality and process performance in pharmaceutical tablet manufacturing using ethenzamide as the active pharmaceutical ingredient. Batch and continuous processes using wet granulation were investigated by performing...
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A modeling and control framework for extraction processes
05 Sep 2024 | Peer-reviewed journal | Contributor(s): Peter Neugebauer, Jakob Rehrl, Peter Poechlauer, Dirk Kirschneck, Martin Horn, Martin Steinberger, Stephan Sacher, Joscha Boehm, Daniel Moser
Many continuously operated pharmaceutical process routes have been presented recently. Most of these cover the synthesis of the active pharmaceutical ingredient (API) or solid dosage processing. However, the API purification is also gaining attraction. One widespread and waste-intensive unit...
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A perspective on Quality-by-Control (QbC) in pharmaceutical continuous manufacturing
09 Jun 2023 | Peer-reviewed journal | Contributor(s): Su, Qinglin, Ganesh, Sudarshan Moreno, Mariana Bommireddy, Yasasvi, Gonzalez, Marcial, Reklaitis, Gintaras V., Nagy, Zoltan K.
The Quality-by-Design (QbD) guidance issued by the US Food and Drug Administration (FDA) has catalyzed the modernization of pharmaceutical manufacturing practices including the adoption of continuous manufacturing. Active process control was highlighted recently as a means to improve the QbD...
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A perspective on Quality-by-Control (QbC) in pharmaceutical continuous manufacturing
09 Jun 2023 | Peer-reviewed journal | Contributor(s): Su, Qinglin, Ganesh, Sudarshan Moreno, Mariana Bommireddy, Yasasvi, Gonzalez, Marcial, Reklaitis, Gintaras V., Nagy, Zoltan K.
The Quality-by-Design (QbD) guidance issued by the US Food and Drug Administration (FDA) has catalyzed the modernization of pharmaceutical manufacturing practices including the adoption of continuous manufacturing. Active process control was highlighted recently as a means to improve the QbD...
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A Scalable Two-Step Continuous Flow Synthesis of Nabumetone and Related 4-Aryl-2-butanones
24 Apr 2024 | Peer-reviewed journal | Contributor(s): Viviano, Monica, Glasnov, Toma N., Reichart, Benedik, Tekautz, Guenter, Kappe, C. Oliver
Three different continuous flow strategies for the generation of important 4-aryl-2-butanone derivatives including the anti-inflammatory drug nabumetone [4-(6-methoxy-2-naphthalenyl)-2-butanone] and the aroma compounds raspberry ketone [4-(4-hydroxyphenyl)-2-butanone] and its methyl ether...
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A Shared Vision for Pharmaceutical Development and Manufacturing in the 21st Century: Contributions of the PAT Initiative
28 Mar 2024 | Document | Contributor(s): Ajaz S. Hussain
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A systematic framework for onsite design and implementation of a control system in a continuous tablet manufacturing process
09 Jun 2023 | Peer-reviewed journal | Contributor(s): Singh, Ravendra, Sahay, Abhishek Muzzio, Fernando Ierapetritou, Marianthi, Ramachandran, Rohit
A novel manufacturing strategy based on continuous processing integrated with online/inline monitoring tools coupled with an advanced control system is highly desired for efficient Quality by Design (QbD)-based pharmaceutical manufacturing. A control system ensures the predefined end product...
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A Systematic Framework for Process Control Design and Risk Analysis in Continuous Pharmaceutical Solid-Dosage Manufacturing
09 Jun 2023 | Peer-reviewed journal | Contributor(s): Su, Qinglin, Moreno, Mariana, Giridhar, Arun, Reklaitis, Gintaras, Nagy, Zoltan
The paradigm shift in the pharmaceutical industry to continuous manufacturing, which has recently progressed from conceptual demonstration to pilot production, has stimulated the development and application of process systems engineering (PSE) tools for implementing efficient and robust control...
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A Three-Minute Synthesis and Purification of Ibuprofen: Pushing the Limits of Continuous-Flow Processing
10 May 2024 | Peer-reviewed journal | Contributor(s): Snead, David R., Jamison, Timothy F.
In a total residence time of three minutes, ibuprofen was assembled from its elementary building blocks with an average yield of above 90 % for each step. A scale-up of this five-stage process (3 bond-forming steps, one work-up, and one in-line liquid–liquid separation) provided ibuprofen at a...
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A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 1: CDI-Promoted Amide Bond Formation
09 Jun 2023 | Peer-reviewed journal | Contributor(s): Içten, Elçin, Maloney, Andrew J., Beaver, Matthew G., Shen, Dongying E., Zhu, Xiaoxiang, Graham, Lauren R., Robinson, Jo A., Huggins, Seth, Allian, Ayman, Hart, Roger, Walker,Shawn D., Rolandi, Pablo, Braatz, Richard D.
This article details process characterization efforts and the development of corresponding process models to inform a process control strategy to produce a carfilzomib drug substance intermediate, morpholine amide 3. Model calibration for relevant unit operations and development of a dynamic...
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Achieving Continuous Manufacturing for Final Dosage Formation: Challenges and How to Meet Them
09 Jun 2023 | Peer-reviewed journal | Contributor(s): Byrn, Stephen, Futran, Maricio, Thomas, Hayden, Jayjock, Eric, Maron, Nicola, Meyer, Robert F., Myerson, Allan S., Thien, Michael P., Trout, Bernhardt L.
We describe the key issues and possibilities for continuous final dosage formation, otherwise known as downstream processing or drug product manufacturing. A distinction is made between heterogeneous processing and homogeneous processing, the latter of which is expected to add more value to...
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Adequacy and Verifiability of Pharmaceutical Mixtures and Dose Units by Variographic Analysis (Theory of Sampling) - A Call for a Regulatory Paradigm Shift
09 Jun 2023 | Peer-reviewed journal | Contributor(s): Esbensen, Kim H, Román-Ospino, Andrés D., Sanchez, Adriluz, Romañach, Rodolfo J.
In spite of intense efforts in the last 20 years, the current state of affairs regarding evaluation of adequacy of pharmaceutical mixing is at an impressive standstill, characterized by two draft guidances, one withdrawn, and the other never approved. We here analyze the regulatory, scientific...
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Advanced methodologies for cocrystal synthesis
09 Jun 2023 | Peer-reviewed journal | Contributor(s): Douroumis, D, Ross, SA, Nokhodchi, A
Pharmaceutical cocrystals are multicomponent systems composed of two or more molecules and held together by H-bonding. Currently, cocrystals provide exciting opportunities in the pharmaceutical industry for the development and manufacturing of new medicines by improving poor physical properties...
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Advanced Real-Time Process Analytics for Multistep Synthesis in Continuous Flow
09 Jun 2023 | Peer-reviewed journal | 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...
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Advances in Twin-Screw Granulation Processing
09 Jun 2023 | Peer-reviewed journal | Contributor(s): Nandi, Uttom, Trivedi, Vivek, Ross, Steven A., Douroumis, Dennis
Twin-screw granulation (TSG) is a pharmaceutical process that has gained increased interest from the pharmaceutical industry for its potential for the development of oral dosage forms. The technology has evolved rapidly due to the flexibility of the equipment design, the selection of the process...
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Advancing Flow Chemistry Portability: A Simplified Approach to Scaling Up Flow Chemistry
25 Jun 2024 | Peer-reviewed journal | Contributor(s): Lévesque, François, Rogus, Nicholas J., Spencer, Glenn, Grigorov, Plamen, McMullen, Jonathan P., Thaisrivongs, David A., Davies, Ian W., Naber, John R.
We report mixing characterization of five lab-scale and eight production-scale static mixers using a modified fourth Bourne reaction. An efficient inline method relying on UV–vis spectroscopy was developed to streamline analysis of the product distribution. As a result of these studies, we have...
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Advancing Flow Chemistry Portability: A Simplified Approach to Scaling Up Flow Chemistry
23 Jul 2024 | Peer-reviewed journal | Contributor(s): Lévesque, François, Rogus, Nicholas J., Spencer, Glenn, Grigorov, Plamen, McMullen, Jonathan P., Thaisrivongs, David A., Davies, Ian W., Naber, John R.
We report mixing characterization of five lab-scale and eight production-scale static mixers using a modified fourth Bourne reaction. An efficient inline method relying on UV–vis spectroscopy was developed to streamline analysis of the product distribution. As a result of these studies, we have...
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Analytical Procedure Development
09 Jun 2023 | Document
Guideline provides a foundation for consistent development of analytical methods to maintain precision and accuracy, contirubting to the maintenance of quality products.
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Analytical Validation
09 Jun 2023 | Document
Guideline establishes the requirements for validationg analytical methods, ensuring consistency in the routeine measurements of pharmaceutical products and their intermediates.
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Anti-fouling control of plug-flow crystallization via heating and cooling cycle
09 Jun 2023 | Peer-reviewed journal | Contributor(s): Koswara, Andy, Nagy, Zoltan K.
Plug-flow crystallization (PFC) is a promising continuous pharmaceutical crystallization process but is prone to fouling due to uncontrolled crystallization on the reactor surface (encrustation). This results in operational issues such as (1) flow blockage, (2) increased thermal resistance, and...
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API Continuous Cooling and Antisolvent Crystallization for Kinetic Impurity Rejection in cGMP Manufacturing
09 Jun 2023 | Peer-reviewed journal | Contributor(s): Johnson, MD, Burcham, CLMay, SA, Calvin, JR, Groh, JM, Myers, SS, Webster, LP, Roberts, JC, Reddy, VR, Luciani, CV, Corrigan, AP, Spencer, RD, Moylan, R, Boyse, R, Murphy, JD, Stout, JR
Crystallization of 204 kg of final active pharmaceutical ingredient was accomplished continuously using a cascade of mixed suspension mixed product removal crystallizers in cGMP manufacturing. This article describes the journey taken to transform a set of technical to final batch crystallizations...