Continuous Flow Intensification for the Synthesis of High-Purity Warfarin

10 May 2024 | Contributor(s): Silva-Brenes, Diana V., Reyes-Vargas, Stephanie K., Duconge, Jorge, Vlaar, Cornelis, Stelzer, Torsten, Monbaliu, Jean-Christophe M.

While racemic warfarin was initially commercialized as a rodenticide, it has become the most prescribed anticoagulant drug for prevention of blood clots and is part of the World Health Organization’s list of essential medicines. The synthesis of warfarin appears straightforward, consisting of a...

Rapid production of the anaesthetic mepivacaine through continuous, portable technology

24 Apr 2024 | Contributor(s): Díaz-Kruik, Pablo, Paradisi, Francesca

Local anaesthetics such as mepivacaine are key molecules in the medical sector, so ensuring their supply chain is crucial for every health care system. Rapid production of mepivacaine from readily available commercial reagents and (non-dry) solvents under safe conditions using portable,...

Multi-step Flow Synthesis of the Anthelmintic Drug Praziquantel

24 Apr 2024 | Contributor(s): Phull, Manjinder Singh, Bohara, Chander Singh, Gundla, Rambabu, Mainkar, Prathama S., Jadav, Surender Singh

Praziquantel (PZQ; Brand name: Biltricide) is categorized as an anthelminthic drug, and it is used for the treatment of Schistosomiasis and other parasitic infections. The World Health Organization (WHO) has classified it as one of the essential and emergency medicines needed across the globe....

Continuous Flow-Facilitated CB2 Agonist Synthesis, Part 2: Cyclization, Chlorination, and Amination

24 Apr 2024 | Contributor(s): Prieschl, Michael, Sagmeister, Peter, Moessner, Christian, Sedelmeier, Joerg, Williams, Jason D., Kappe, C. Oliver

A new route to the cannabinoid receptor type 2 agonist, RG7774, has been developed circumventing an alkylation with poor regioselectivity as the final step. In the new synthetic route, this side chain is incorporated from the beginning. In this article, the development of the final four...

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...

Videometric mass flow control: A new method for real-time measurement and feedback control of powder micro-feeding based on image analysis

09 Jun 2023 | Contributor(s): Madarasz, L, Kote, AGyurkes, M, Farkas, A, Hambalko, B, Pataki, H, Fulop, G, Marosi, G, Lengyel, L, Casian, T, Csorba, K, Nagy, ZK

The present paper reports the first monitoring and control of ultra-low dose powder feeding using a camera image-based mass flow measurement system. Caffeine was fed via a single-screw microfeeder as a model active pharmaceutical ingredient (API). The mass, mass flow and sizes of the particles...

Using a material property library to find surrogate materials for pharmaceutical process development

09 Jun 2023 | Contributor(s): Escotet-Espinoza, MS, Moghtadernejad, SScicolone, J, Wang, YF, Pereira, G, Schafer, E, Vigh, T, Klingeleers, D, Ierapetritou, M, Muzzio, FJ

Material properties are known to have a significant impact on pharmaceutical manufacturing performance, particularly for solid product processes. Evaluating the performance of a specific material, for example an active pharmaceutical ingredient or excipient, is critical during development stages...

Using residence time distribution in pharmaceutical solid dose manufacturing–A critical review

09 Jun 2023 | Contributor(s): Bhalode, Pooja, Tian, Huayu Gupta, Shashwat Razavi, Sonia M Roman-Ospino, Andres Talebian, Shahrzad Singh, Ravendra Scicolone, James V Muzzio, Fernando J, Ierapetritou, Marianthi

While continuous manufacturing (CM) of pharmaceutical solid-based drug products has been shown to be advantageous for improving the product quality and process efficiency in alignment with FDA’s support of the quality-by-design paradigm (Lee, 2015; Ierapetritou et al., 2016; Plumb, 2005; Schaber,...

Using residence time distribution in pharmaceutical solid dose manufacturing–A critical review

09 Jun 2023 | Contributor(s): Bhalode, Pooja, Tian, Huayu Gupta, Shashwat Razavi, Sonia M Roman-Ospino, Andres Talebian, Shahrzad Singh, Ravendra Scicolone, James V Muzzio, Fernando J, Ierapetritou, Marianthi

While continuous manufacturing (CM) of pharmaceutical solid-based drug products has been shown to be advantageous for improving the product quality and process efficiency in alignment with FDA’s support of the quality-by-design paradigm (Lee, 2015; Ierapetritou et al., 2016; Plumb, 2005; Schaber,...

The scope of PAT in real-time advanced control of tablet quality

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

Continuous pharmaceutical manufacturing together with process analytical technology (PAT) provides a suitable platform for automatic feed-forward/feed-back (FF/FB) control of the end product quality as desired by quality by design (QbD)-based efficient manufacturing. The precise control of the...

The Evolving State of Continuous Processing in Pharmaceutical API Manufacturing: A Survey of Pharmaceutical Companies and Contract Manufacturing Organizations

09 Jun 2023 | Contributor(s): McWilliams, JC, Allian, ADOpalka, SM, May, SA, Journet, M, Braden, TM

This manuscript provides the results of an in-depth survey assessment of the capabilities, experience, and perspectives on continuous processing in the pharmaceutical sector, with respondents from both pharmaceutical companies and Contract Manufacturing Organizations (CMOs). The survey includes...

Surrogate-based Optimization for Pharmaceutical Manufacturing Processes

09 Jun 2023 | Contributor(s): Wang, Zilong, Escotet-Espinoza, M Sebastian Singh, Ravendra, Ierapetritou, Marianthi

The development of pharmaceutical manufacturing processes has been facilitated by recent advances in the process simulation area. However, since the simulations are usually complex and the analytical expressions of the model can be unknown, it is difficult to directly apply traditional...

Small-Volume Continuous Manufacturing of Merestinib. Part 1. Process Development and Demonstration

09 Jun 2023 | Contributor(s): Cole, KP, Reizman, BJHess, M, Groh, JM, Laurila, ME, Cope, RF, Campbell, BM, Forst, MB, Burt, JL, Maloney, TD, Johnson, MD, Mitchell, D, Polster, CS, Mitra, AW, Boukerche, M, Conder, EW, Braden, TM, Miller, RD, Heller, MR, Phillips, JL, Howell, JR

Development of a small volume continuous process that used a combination of batch and flow unit operations to manufacture the small molecule oncolytic candidate merestinib is described. Continuous processing was enabled following the identification and development of suitable chemical...

Small-Volume Continuous Manufacturing of Merestinib. Part 2.Technology Transfer and cGMP Manufacturing

09 Jun 2023 | Contributor(s): Reizman, Brandon J., Hess, Molly, Burt, Justin L., Maloney, Todd D., Johnson, Martin D., Laurila, Michael E., Cope, Richard F., Luciani, Carla V., Buser, Jonas Y., Campbell, Bradley M., Forst, Mindy B., Mitchell, David, Braden, Timothy M., Lippelt, Christopher K., Boukerche, Moussa, Starkey, Derek R., Miller, Richard D., Chen, Jing, Sun, Baoquan, Kwok, Martin, Zhang, Xin, Tadayon, Sam, Huang, Ping

Technology transfer of a small volume continuous (SVC) process and Current Good Manufacturing Practices (cGMP) manufacturing of merestinib are described. A hybrid batch-SVC campaign was completed at a contract manufacturing organization under cGMP. The decision process by which unit operations...

Simplified end-to-end continuous manufacturing by feeding API suspensions in twin-screw wet granulation

09 Jun 2023 | Contributor(s): Schmidt, A, de, Waard, HMoll, KP, Kleinebudde, P, Krumme, M

This study focussed on investigating the coupling of continuous manufacturing of drug substance and continuous manufacture of drug product. An important step in such an integrated end-to-end continuous manufacturing was envisioned by dosing the API as suspension into a twin-screw wet granulation...

Separation and Purification in the Continuous Synthesis of Fine Chemicals and Pharmaceuticals

09 Jun 2023 | Contributor(s): O'Mahony, M, Ferguson, SStelzer, T, Myerson, A

The use to both chemists and chemical engineers working in flow synthesis, this chapter provides a summary of separation and purification operations that can be applied to flow synthesis reaction streams. Both single and biphasic separations for the liquid phase are detailed. Separation and...

Simulation-Based Design of an Efficient Control System for the Continuous Purification and Processing of Active Pharmaceutical Ingredients

09 Jun 2023 | Contributor(s): Sen, M, Singh, R, Ramachandran, R

In this study, an efficient system-wide controlsystem has been designed for the integrated continuous purification and processing of the active pharmaceutical ingredient (API). The control strategy is based on the regulatory PID controller which is most widely used in the manufacturing industry...

Sampling and Analysis in Flow: The Keys to Smarter, More Controllable, and sustainable Fine-Chemical Manufacturing

09 Jun 2023 | Contributor(s): Morin, Mathieu, Zhang, Wenyao, Mallik, Debasis, Organ, Michael G

Process analytical technology (PAT) is a system designed to help chemists better understand and control manufacturing processes. PAT systems operate through the combination of analytical devices, reactor control elements, and mathematical models to ensure the quality of the final product through...

Scaling continuous API synthesis from milligram to kilogram: extending the enabling benefits of micro to the plant

09 Jun 2023 | Contributor(s): Berton, M, de, Souza, JMAbdiaj, I, McQuade, DT, Snead, DR

The signature benefits of continuous flow are largely a result of a reactor's micro-sized features. However, as the technology gains industrial traction in the synthesis of active pharmaceutical ingredients (API), the reactors must be scaled to larger size to meet production demands. Often, the...

Residence Time Distribution (RTD)-Based Control System for Continuous Pharmaceutical Manufacturing Process

09 Jun 2023 | Contributor(s): Bhaskar, Aparajith, Singh, Ravendra

Recent advances in integrated process analytical techniques, modeling, and control strategies to enable continuous biomanufacturing of monoclonal antibodies

09 Jun 2023 | Contributor(s): Chopda, Viki, Gyorgypal, Aron Yang, Ou Singh, Ravendra Ramachandran, Rohit Zhang, Haoran Tsilomelekis, George Chundawat, Shishir PS, Ierapetritou, Marianthi G

Continuous bioprocessing is significantly changing the biological drugs (or biologics) manufacturing landscape by potentially improving product quality, process stability, and overall profitability, as was similarly seen during the adoption of advanced manufacturing processes for small molecule...

Residence Time Distribution as a Traceability Method for Lot Changes in A Pharmaceutical Continuous Manufacturing System

09 Jun 2023 | Contributor(s): Sánchez-Paternina, Adriluz, Martínez-Cartagena, Pedro Li, Jingzhe Scicolone, James Singh, Ravendra Lugo, Yleana C Romañach, Rodolfo J Muzzio, Fernando J, Román-Ospino, Andrés D

Residence time distribution (RTD) models were developed to track raw material lots and investigate batch transitions in a continuous manufacturing system. Two raw materials with similar physical properties (granular metformin and lactose) were identified via Principal Component Analysis (PCA)...

Residence time distribution modelling and in line monitoring of drug concentration in a tablet press feed frame containing dead zones

09 Jun 2023 | Contributor(s): Tanimura, Shinji, Singh, Ravendra Román-Ospino, Andrés D, Ierapetritou, Marianthi

The presence of a ‘significant dead zone’ in any continuous manufacturing equipment may affect the product quality and need to be investigated systematically. Dead zone will affect the residence time distribution (RTD) of continuous manufacturing and thus the mixing and product quality. Tablet...

Reactor design and selection for effective continuous manufacturing of pharmaceuticals

09 Jun 2023 | Contributor(s): Hu, Chuntian

Pharmaceutical production remains one of the last industries that predominantly uses batch processes, which are inefficient and can cause drug shortages due to the long lead times or quality defects. Consequently, pharmaceutical companies are transitioning away from outdated batch lines, in large...

Quality Risk Assessment and Mitigation of Pharmaceutical Continuous Manufacturing Using Flowsheet Modeling Approach

09 Jun 2023 | Contributor(s): Tian, Geng;, Koolivand, Abdollah, Arden, Nilou S., Lee, Sau, O'Connor, Thomas F.

Integrated flowsheet modeling is an engineering approach that can provide a framework for understanding the impact of process dynamics on drug quality and associated risks during production, thereby facilitating the development of robust continuous processes. In this investigation, flowsheet...