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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 comparative review of multi-rate moving horizon estimation schemes for bioprocess applications
09 Jun 2023 | Contributor(s): Elsheikh, Mohamed, Hille, Rubin Tatulea-Codrean, Alexandru, Kramer, Stefan
Advanced control and monitoring of bioprocesses are dependent on accurate state and parameter information. At the same time, bioprocesses are well known for their time-varying behavior and difficulty of obtaining online measurements of the important process states. The selection and the tuning of...
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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 Continuous Operation Concept for a Rotary Tablet Press Using Mass Flow Operating Points
09 Jun 2023 | Contributor(s): Martinetz, Michael Christian, Rehrl, Jakob Aigner, Isabella Sacher, Stephan, Khinast, Johannes
Abstract In a continuous pharmaceutical manufacturing line the rotary tablet press was viewed as the master of control concept and defined the mass flow through the entire process. According to a conventional control concept, missing mass flow from an upstream unit operation leads to a shutdown...
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A fast moving horizon estimation algorithm based on nonlinear programming sensitivity
09 Jun 2023 | Contributor(s): Zavala, Victor M, Laird, Carl D, Biegler, Lorenz T
Moving horizon estimation (MHE) is an efficient optimization-based strategy for state estimation. Despite the attractiveness of this method, its application in industrial settings has been rather limited. This has been mainly due to the difficulty to solve, in real-time, the associated dynamic...
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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 hybrid neural network-first principles approach to process modeling
09 Jun 2023 | Contributor(s): Psichogios, Dimitris C., Ungar, Lyle H.
A hybrid neural networkâ€first principles modeling scheme is developed and used to model a fedbatch bioreactor. The hybrid model combines a partial first principles model, which incorporates the available prior knowledge about the process being modeled, with a neural network which...
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A hybrid NIR-soft sensor method for real time in-process control during continuous direct compression manufacturing operations
09 Jun 2023 | Contributor(s): Cogoni, Giuseppe, Husain, Anas, Alam, Md Anik, Liu, Yang Angela, Kamyar, Reza
Near Infrared (NIR) spectroscopy is commonly utilized for continuous manufacturing as Process Analytical Technology (PAT) tool. This paper focus on a continuous direct compression manufacturing process, in which an NIR PAT probe is integrated into the tablet press feed frame and into the tablet...
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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 Moving Horizon Estimator for processes with multi-rate measurements: A Nonlinear Programming sensitivity approach
09 Jun 2023 | Contributor(s): Lopez-Negrete, Rodrigo, Biegler, Lorenz T.
Moving Horizon Estimation (MHE) provides a framework that allows one to incorporate both frequent and infrequent observations easily because it uses a window of past measurements, where the slower ones can be introduced as they become available. Also, MHE allows for the use of constraints on the...
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A Moving Horizon-Based Approach for Least-Squares Estimation
09 Jun 2023 | Contributor(s): Robertson, Douglas G., Lee, Jay H., Rawlings, James B.
A general formulation of the moving horizon estimator is presented. An algorithm with a fixed-size estimation window and constraints on states, disturbances, and measurement noise is developed, and a probabilistic interpretation is given. The moving horizon formulation requires only one more...
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A novel robust digital design of a network of industrial continuous cooling crystallizers of dextrose monohydrate: From laboratory experiments to industrial application
09 Jun 2023 | Contributor(s): Nagy, Zoltan K., Szilagyi, Botond Pal, Kanjakha, Tabar, Iman Beheshti ;
This paper presents the first-ever industrial application of the digital design of a complex, large-scale industrial continuous crystallization network. The aim of the work is to optimize a large-scale continuous crystallization network used for the purification of dextrose monohydrate, by...
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A PAT-based qualification of pharmaceutical excipients produced by batch or continuous processing
09 Jun 2023 | Contributor(s): Hertrampf A., Müller H., Menezes J.C., Herdling T.
Pharmaceutical excipients have an influence on the main requirements for medicinal products (viz., quality, safety and efficacy) but also on their manufacturability. During product lifecycle it may become necessary to introduce minor changes (e.g., to continuously improve it) or major changes in...
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A Perspective on Quality by Design: A Preclinical Opportunity
28 Mar 2024 | Document | Contributor(s): Ajaz S. Hussain
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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 review of emerging technologies enabling improved solid oral dosage form manufacturing and processing
09 Jun 2023 | Peer-reviewed journal | Contributor(s): Sohail Arshad, Muhammad, Zafar, Saman, Yousef, Bushra, Alyassin, Yasmine, Ali, Radeyah, AlAsiri, Ali, Chang, Ming-Wei, Ahmad, Zeeshan, Ali Elkordy, Amal, Faheem, Ahmed, Pitt, Kendal
Tablets are the most widely utilized solid oral dosage forms because of the advantages of self-administration, stability, ease of handling, transportation, and good patient compliance. Over time, extensive advances have been made in tableting technology. This review aims to provide an insight...
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A review of PAT strategies in secondary solid oral dosage manufacturing of small molecules
09 Jun 2023 | Peer-reviewed journal | Contributor(s): Laske, Stephan, Paudel, Amrit, Scheibelhofer, Otto, Sacher, Stephan, Hoermann, Theresa, Khinast, Johannes, Kelly, Adrian, Rantannen, Jukka, Korhonen, Ossi, Stauffer, Fanny, De Leersnyder, Fien, De Beer, Thomas, Mantanus, Jerome, Chavez, Pierre-Francois, Thoorens, Benjamin, Ghiotti, Patrizia, Schubert, Martin, Tajarobi, Pirjo, Haeffler, Gunnar, Lakio, Satu, Fransson, Magnus, Sparen, Anders, Abrahmsen-Alami, Susanna, Folestad, Staffan, Funke, Adrian, Backx, Ivo, Kavsek, Barbara, Kjell, Francois, Michaelis, Marc, Page, Trevor, Palmer, John, Schaepman, Alexander, Sekulic, Sonja, Hammond, Steve, Braun, Birgit, Colegrove, Brenda
Pharmaceutical solid oral dosage product manufacturing is a well-established, yet revolutionizing area. To this end, process analytical technology (PAT) involves interdisciplinary and multivariate (chemical, physical, microbiological and mathematical) methods for material (e.g. materials,...
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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 Systematic Framework for the Design and Implementation of Sensing and Control Architecture for a Continuous Pharmaceutical Manufacturing Plant
09 Jun 2023 | Peer-reviewed journal | Contributor(s): Singh, Ravendra, Muzzio, Fernando J Ierapetritou, Marianthi, Ramachnadran, Rohit
The continuous pharmaceutical manufacture (CPM) plant and control architecture developed earlier is currently being widely implemented in industries [1,2]. CPM indeed provides an appropriate platform to implement suitable monitoring and control architecture, to improve product quality, and to...
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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...