3D Printed Reactors for Synthesis of Active Pharmaceutical Ingredients in Continuous Flow

09 Jun 2023 | Contributor(s): Maier, MC, Valotta, AHiebler, K, Soritz, S, Gavric, K, Grabner, B, Gruber-Woelfler, H

Advances in flow chemistry to produce active pharmaceutical ingredients (APIs) require performing reactions in tailor-made equipment as complexity of the planned setups increases. To react quickly and with low costs to these demanding reactions, additive manufacturing, also known as 3D printing,...

A Combined Feed-Forward/Feed-Back Control System for a QbD-Based Continuous Tablet Manufacturing Process

09 Jun 2023 | Contributor(s): Singh, Ravendra, Muzzio, Fernando J, Ierapetritou, Marianthi, Ramachandran, Rohit

Continuous pharmaceutical manufacturing together with PAT (Process Analytical Technology) provides a suitable platform for automatic control of the end product quality as desired by QbD (quality by design)-based efficient manufacturing. The precise control of the quality of the pharmaceutical...

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

09 Jun 2023 | Contributor(s): Gambacorta, G, Sharley, JS, Baxendale, IR

Due to their intrinsic physical properties, which includes being able to perform as volatile liquids at room and biological temperatures, fragrance ingredients/intermediates make ideal candidates for continuous-flow manufacturing. This review highlights the potential crossover between a...

A Continuous Process for Manufacturing Apremilast. Part I: Process Development and Intensification by Utilizing Flow Chemistry Principles

24 Apr 2024 | Contributor(s): Hsieh, Hsiao-Wu, Griffin, Daniel J., Ananthoji, Padmini, Avci, Nadide Hazal, Brown, Derek B., Ericson, Ari, Fostinis, James D., Irfan, Muhammad, Langille, Neil, Lovette, Michael A., Murray, James I., Spada, Simone, Thiel, Oliver R., Aiello, Frankie, Daou, Joseph, Goudas-Salomon, Nicole, Pan, Ende, Sarkar, Nandini, Wimalasinghe, Rasangi, Wu, Zufan Steven, Zeng, Alicia, Beaver, Matthew G., Cohen, Carolyn M.

Herein, we report the development of an integrated continuous manufacturing (CM) process for the penultimate step in the synthesis of apremilast, the drug substance (DS) of the commercial product Otezla. This development effort was motivated by the desire to create an alternative manufacturing...

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...

A model-based framework for design and analysis of PAT systems

09 Jun 2023 | Workshop | Contributor(s): Gani, Rafiqul, Singh, Ravendra, Gernaey, Krist

A multi-scale hybrid CFD-DEM-PBM description of a fluid-bed granulation process

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Sen, Maitraye, Barrasso, Dana Singh, Ravendra, Ramachandran, Rohit

In this study, a hybrid multi-scale model has been developed for a continuous fluid bed wet granulation process by dynamically coupling computational fluid dynamics (CFD) with a discrete element model (DEM) and population balance model (PBM). In this process, the granules are formed by spraying...

A Perspective on Continuous Flow Chemistry in the Pharmaceutical Industry

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Baumann, M, Moody, TSSmyth, M, Wharry, S

Continuous flow manufacture is an innovative technology platform, which is gaining momentum within the pharmaceutical industry. The key advantages of continuous flow include faster and safer reactions, which can be more environmentally friendly, smaller footprint, better quality product, and...

A Practical and Robust Multistep Continuous Process for Manufacturing 5-Bromo-N-(tert-butyl)pyridine-3-sulfonamide

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Yu, M, Strotman, NASavage, SA, Leung, S, Ramirez, A

A multistep continuous flow process involving (1) magnesium-halogen exchange, (2) sulfonylation with sulfuryl chloride, and (3) reaction with tert-butylamine was developed for the synthesis of an arylsulfonamide pharmaceutical intermediate in the synthesis of BMS-919373. The process was...

A retrofit strategy to achieve “Fast, Flexible, Future (F3)” pharmaceutical production processes

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Singh, Ravendra, Rozada-Sanchez, Raquel Wrate, Tim Muller, Frans Gernaey, Krist V Gani, Rafiqul, Woodley, John M

n the work reported here, a substrates adoption methodology for a series of similar substrates has been developed as part of a retrofit strategy. The objective is to achieve “fast, flexible and future” pharmaceutical production processes by adapting a generic modular process-plant template....

A systematic computer aided framework for design and analysis of PAT systems

09 Jun 2023 | Workshop | Contributor(s): Gernaey, Krist, Singh, Ravendra, Gani, Rafiqul

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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...

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...

A systematic framework to monitor mulling processes using Near Infrared spectroscopy

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Wu, Suyang, Panikar, Savitha S Singh, Ravendra Zhang, Jun Glasser, Benjamin, Ramachandran, Rohit

The optimal design of sensor location and setup is essential to ensure the accuracy and precision of in-line process monitoring of water/moisture content. This manuscript presents a systematic framework of using Near Infrared (NIR) spectroscopy to monitor moisture content in an alumina mulling...

A Validated Model for Design and Evaluation of Control Architectures for a Continuous Tablet Compaction Process

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Nunes de Barros, Fernando, Bhaskar, Aparajith, Singh, Ravendra

The systematic design of an advanced and efficient control strategy for controlling critical quality attributes of the tablet compaction operation is necessary to increase the robustness of a continuous pharmaceutical manufacturing process and for real time release. A process model plays a very...

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...

Advanced Control of Continuous Pharmaceutical Tablet Manufacturing Processes

09 Jun 2023 | Chapter Book | Contributor(s): Singh, Ravendra, Velazquez, Carlos Sahay, Abhishek Karry, Krizia M Muzzio, Fernando J Ierapetritou, Marianthi G, Ramachandran, Rohit

A novel manufacturing strategy based on continuous processing, integrated with online/inline monitoring tools, coupled with an advanced automatic feedback control system is highly desired for efficient Quality by Design (QbD)-based manufacturing of the next generation of pharmaceutical products...

Advanced Model Predictive Feedforward/Feedback Control of a Tablet Press

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Haas, Nicholas Townsend, Ierapetritou, Marianthi, Singh, Ravendra

In continuous pharmaceutical manufacturing, real-time precise control of critical quality attributes (CQAs) is necessary for quality by design (QbD)-based manufacturing and real-time release (RTR) with minimum consumption of time, space, and resources. Pharmaceutical tablets can be produced...

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...

An ontological knowledge-based system for the selection of process monitoring and analysis tools

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Singh, Ravendra, Gernaey, Krist V, Gani, Rafiqul

Efficient process monitoring and analysis tools provide the means for automated supervision and control of manufacturing plants and therefore play an important role in plant safety, process control and assurance of end product quality. The availability of a large number of different process...

Application of mechanistic models within a PAT framework

09 Jun 2023 | Website | Contributor(s): Gernaey, Krist, Sin, Gürkan Albo, E Woodley, John Singh, Ravendra, Gani, Rafiqul

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Characterization of NIR interfaces for the feeding and in-line monitoring of a continuous granulation process

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Román-Ospino, Andrés D, Tamrakar, Ashutosh Igne, Benoît Dimaso, Elyse Towns Airiau, Christian Clancy, Donald J Pereira, Glinka Muzzio, Fernando J Singh, Ravendra, Ramachandran, Rohit

This work describes the characterization of three NIR interfaces intended to monitor a continuous granulation process. Two interfaces (i.e. a barrel interface and a rotating paddle interface) were evaluated to monitor the API concentration at the entrance of the granulator, and a third interface...

Closed-loop feedback control of a continuous pharmaceutical tablet manufacturing process via wet granulation

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Singh, Ravendra, Barrasso, Dana Chaudhury, Anwesha Sen, Maitraye Ierapetritou, Marianthi Ramachandran, Rohit

The wet granulation route of tablet manufacturing in a pharmaceutical manufacturing process is very common due to its numerous processing advantages such as enhanced powder flow and decreased segregation. However, this route is still operated in batch mode with little (if any) usage of an...

Combined feedforward/feedback control of an integrated continuous granulation process

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Pereira, Glinka Cathy, Muddu, Shashank Venkat Román-Ospino, Andrés David Clancy, Don Igne, Benoit Airiau, Christian Muzzio, Fernando J Ierapetritou, Marianthi Ramachandran, Rohit, Singh, Ravendra

Continuous manufacturing offers shorter processing times and increased product quality assurance, among several other advantages. This makes it an ever-growing interest among pharmaceutical companies. A suitable efficient control system is however desired for continuous pharmaceutical...

Continuous end-to-end production of solid drug dosage forms: Coupling flow synthesis and formulation by electrospinning

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Balogh, Attila, Domokos, András, Farkas, Balázs, Farkas, Attila, Rapi, Zsolt, Kiss, Domokos, Nyiri, Zoltán, Eke, Zsuzsanna, Szarka, Györgyi, Örkényi, Róbert, Mátravölgyi, Béla, Faigl, Ferenc

Based on the concept of continuous manufacturing an end-to-end benchtop device was developed unprecedented for the production of solid drug dosage forms by connecting flow synthesis and formulation via electrospinning (ES). Together with the optimized two-step continuous-flow synthesis of...