Development of a Continuous Flow Grignard Reaction to Manufacture a Key Intermediate of Ipatasertib

25 Jun 2024 | 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...

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...

Innovation and Continuous Improvement in Pharmaceutical Manufacturing

28 Mar 2024 | Document | Contributor(s): Ajaz Hussain (Chairperson) Raafat Fahmy (CVM), William Bargo (CVM), Robert Coleman, Robert (ORA), Elise Murphy (ORA), Frank Holcombe Jr (CDER), Chris Watts (CDER), See Lam (CDER), Jon Clark (CDER), Christopher Joneckis (CBER), John Dietrick (CDER), Diana Kolaitis (ORA), Vilayat Sayeed (CDER), Mai Huynh (CVM), Norman Schmuff (CDER), Andrew Chang (CBER)

The PAT Team and Manufacturing Science Working Group Report: A Summary of Learning, Contributions and Proposed Next Steps for Moving towards the "Desired State" of Pharmaceutical Manufacturing in the 21st Century

A Perspective on Quality by Design: A Preclinical Opportunity

28 Mar 2024 | Document | Contributor(s): Ajaz S. Hussain

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

The Subcommittee on Process Analytical Technologies (PAT): Closing Remarks

28 Mar 2024 | Document | Contributor(s): Ajaz S. Hussain

The Process Analytical Technology Initiative: PAT and the Pharmacopeias

28 Mar 2024 | Document | Contributor(s): Ajaz S. Hussain

The PAT Initiative A part of the Pharmaceutical Quality for the 21st Century Initiative  PAT and the USP Opportunities for the USP to support the PAT Framework

Utilizing PAT to Monitor and Control Bulk Biotech Processes

27 Mar 2024 | Document | Contributor(s): Rick E. Cooley

1.What is and isn’t PAT? 2.Implementing PAT in Manufacturing: What does it take? 3.Characteristics of bulk, biotech API processes 4.Why PAT? 5.Review of PAT technologies utilized 6.PAT application examples

Continuous Manufacturing for Pharmaceutical Solid Dosage Forms (On-Demand)

31 Jan 2024 | Seminars | Contributor(s): Atul Dubey, Fernando Muzzio, Gerardo Callegari, Lucy L. Botros, Ravendra Singh, James Scicolone, Andres Roman, Sonia Modarres Razavi

Course Description: This self-paced curriculum contains fourteen self-paced modules and three recordings of live virtual education on Pharmaceutical Continuous Manufacturing (PCM). Learners will have access to the following: A recording of the introductory session covering topics such as...

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

09 Jun 2023 | Peer-reviewed journal | 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 | Peer-reviewed journal | 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 optimization of process analytical technology for the inline quantification of multiple drugs in fixed dose combinations during continuous processing

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Dadou, SM, Tian, YWLi, S, Jones, DS, Andrews, GP

Complications associated with uncontrolled hypertension are considered the major cause of premature death worldwide. Fixed-dose combinations (FDCs) offer an alternative approach to polypharmacy with the aim to improve patient compliance. Process Analytical Technology (PAT) is gaining momentum as...

The Use of PAT and Off-line Methods for Monitoring of Roller Compacted Ribbon and Granule Properties with a View to Continuous Processing

09 Jun 2023 | Peer-reviewed journal | Contributor(s): McAuliffe M.A.P., Omahony G.E., Blackshields C.A., Collins J.A., Egan D.P., Kiernan L., Oneill E., Lenihan S., Walker G.M., Crean A.M.

Real-time process monitoring using process analytical technology (PAT) tools can augment process understanding, enable improved process control, and hence facilitate the production of high-quality pharmaceutical products. While beneficial for batch processes, the availability of PAT tools to...

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

09 Jun 2023 | Peer-reviewed journal | 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...

The development of an inline Raman spectroscopic analysis method as a quality control tool for hot melt extruded ramipril fixed-dose combination products

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Andres, G.P., Jones D.S., Senta-Loys Z., Almajaan A., Li S., Chevallier O., Elliot C., Healy A.M., Kelleher J.F., Madi A.M., Gilvary G.C., Tian Y.a

Currently in the pharmaceutical industry, continuous manufacturing is an area of significant interest. In particular, hot-melt extrusion (HME) offers many advantages and has been shown to significantly reduce the number of processing steps relative to a conventional product manufacturing line. To...

The Current Scientific and Regulatory Landscape in Advancing Integrated Continuous Biopharmaceutical Manufacturing

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Adam C Fisher, Mark-Henry Kamga, Cyrus Agarabi, Kurt Brorson, Sau L Lee, Seongkyu Yoon

There is a trend across the pharmaceutical sector toward process intensification and continuous manufacturing to produce small-molecule drugs or biotechnology products. For biotechnology products, advancing the manufacturing technology behind upstream and downstream processes has the potential to...

The development and validation of a quality by design based process analytical tool for the inline quantification of Ramipril during hot-melt extrusion

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Dadou, Suha, Senta-Loys, Zoe, Almajaan, Ammar, Li, Shu, Jones, David, Healy, Anne, Tian, Yiwei, Andrews, Gavin

Continuous processing is superseding conventional batch processing as a means of manufacturing within the pharmaceutical Research Article/industry. This paradigm shift has led to the implementation of Process Analytical Technology (PAT) as a semi-automatic, predictive tool offering real-time...

Surrogate-based Optimization for Pharmaceutical Manufacturing Processes

09 Jun 2023 | Peer-reviewed journal | 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...

Supervisory Control System for Monitoring a Pharmaceutical Hot Melt Extrusion Process

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Markl, Daniel, Wahl, Patrick R, Menezes, José C, Koller, Daniel M, Kavsek, Barbara, Francois, Kjell, Roblegg, Evaa, Khinast, Johannes G.

Continuous pharmaceutical manufacturing processes are of increased industrial interest and require uni- and multivariate Process Analytical Technology (PAT) data from different unit operations to be aligned and explored within the Quality by Design (QbD) context. Real-time pharmaceutical process...

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

09 Jun 2023 | Peer-reviewed journal | 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 | Peer-reviewed journal | 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...