Critical review on the role of excipient properties in pharmaceutical powder-to-tablet continuous manufacturing

13 Aug 2024 | Peer-reviewed journal | Contributor(s): Sara Fathollahi, Pauline H. M. Janssen, Bastiaan H. J. Dickhoff, Henderik W. Frijlink

The pharmaceutical industry is gradually changing batch-wise manufacturing processes to continuous manufacturing processes, due to the advantages it has to offer. The final product quality and process efficiency of continuous manufacturing processes is among others impacted by the properties of...

Process intensification of pharmaceutical powder blending at commercial throughputs by utilizing semi-continuous mini-blending

13 Aug 2024 | Peer-reviewed journal | Contributor(s): Maarten Jaspers, Florian Tegel, Timo P. Roelofs, Fabian Starsich, Yunfei Li Song, Bernhard Meir, Richard Elkes, Bastiaan H.J. Dickhoff

Process intensification involves the miniaturization of equipment while retaining process throughput and performance. The pharmaceutical industry can benefit from this approach especially during drug product development, where the availability of active pharmaceutical ingredients (API) is often...

Matrix-assisted cocrystallization (MAC) simultaneous production and formulation of pharmaceutical cocrystals by hot-melt extrusion

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Boksa, Kevin, Otte, Andrew, Pinal, Rodolfo

A novel method for the simultaneous production and formulation of pharmaceutical cocrystals, matrix-assisted cocrystallization (MAC), is presented. Hot-melt extrusion (HME) is used to create cocrystals by coprocessing the drug and coformer in the presence of a matrix material. Carbamazepine...

Axial Chirality in the Sotorasib Drug Substance, Part 2: Leveraging a High-Temperature Thermal Racemization to Recycle the Classical Resolution Waste Stream

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Beaver, Matthew G., Brown, Derek B., Campbell, Kiersten, Fang, Yuan-Qing, Ford, David D., Mardirossian, Narbe, Nagy, Kevin D., Rötheli, Andreas R., Sheeran, Jillian W., Telmesani, Reem, Parsons, Andrew T.

The development and kilogram-scale demonstration of a high-temperature continuous-flow racemization process to recycle the off-enantiomer of an atropisomeric sotorasib intermediate is described. Part 1 of this two-part series details the design and execution of a classical resolution to generate...

Development and Scale-Up of a Continuous Manufacturing Process for a Hydrazine Condensation Reaction

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Zhu, Ruiheng, Reddy, Ramesh, Ding, Man, Xu, Ming, Deng, Chaoyi, Tadayon, Sam, Li, Hui, Depew, Kristopher, Lane, Benjamin

The development of a continuous manufacturing process for a hydrazine condensation reaction at high temperature is reported. This continuous process represents a safer approach to manufacture 3-phenyl-1H-pyrazol-5-amine at scale and exhibits better impurity control compared to a traditional batch...

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

25 Jun 2024 | Peer-reviewed journal | 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...

A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 3: Manganese-Catalyzed Asymmetric Epoxidation, Crystallization, and Filtration

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Maloney, Andrew J., Içten, Elçin, Capellades, Gerard, Beaver, Matthew G., Zhu, Xiaoxiang, Graham, Lauren R., Brown, Derek B., Griffin, Daniel J., Sangodkar, Rahul, Allian, Ayman, Huggins, Seth, Hart, Roger, Rolandi, Pablo, Walker, Shawn D., Braatz, Richard D.

This article describes the process characterization and development of models to inform a process control strategy to prepare (R,R)-epoxy ketone 2, an intermediate in the manufacture of carfilzomib. Model calibration for relevant unit operations and the development of a dynamic integrated...

Development and Scale-Up of a Continuous, High-Pressure, Asymmetric Hydrogenation Reaction, Workup, and Isolation

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Johnson, Martin D., May, Scott A., Calvin, Joel R., Remacle, Jacob, Stout, James R., Diseroad, William D., Zaborenko, Nikolay, Haeberle, Brian D., Sun, Wei-Ming, Miller, Michael T., Brennan, John

A fully continuous process including an asymmetric hydrogenation reaction operating at 70 bar hydrogen, aqueous extraction, and crystallization was designed, developed, and demonstrated at pilot scale. This paper highlights safety, quality, and throughput advantages of the continuous reaction and...

Polymorphs, Particle Size, and a Pandemic: Development of a Scalable Crystallization Process for Molnupiravir, an Antiviral for the Treatment of COVID-19

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Bade, Rachel, Bothe, Jameson R., Sirota, Eric, Brunskill, Andrew P. J., Newman, Justin A., Zhang, Yongqian, Tan, Melissa, Zheng, Michelle, Brito, Gilmar, Poirier, Marc, Fier, Patrick S., Xu, Yingju, Ward, Michael D., Stone, Kevin, Lee, Ivan H., Gmitter, Andrew J., Bernardoni, Frank, Zompa, Michael A., Luo, Hanlin, Patel, Sanjaykumar, Masiuk, Tina, Mora, Jeff, Ni, Tong, Okoh, Grace A., Tarabokija, James, Liu, Jiaying, Lowinger, Michael B., Mahmood, Tariq

Molnupiravir is a small-molecule active pharmaceutical ingredient (API) prodrug of a nucleoside analog that was demonstrated to be efficacious for the treatment of patients with COVID-19. Early in the pandemic, Merck & Co. Inc. partnered with Ridgeback Biotherapeutics to accelerate the...

Development of a Continuous Schotten–Baumann Route to an Acyl Sulfonamide

24 Apr 2024 | Peer-reviewed journal | Contributor(s): White, Timothy D., Berglund, K. Derek, Groh, Jennifer McClary, Johnson, Martin D., Yates, Matthew H.

The development and scale-up of a synthetic route to tasisulam sodium (5-bromo-thiophene-2-sulfonic acid 2,4-dichlorobenzoylamide sodium salt, hereafter referred to as tasisulam) utilizing continuous Schotten–Baumann reaction conditions is disclosed. A new synthetic route for the cytotoxic API...

Development of a Multi-Step Synthesis and Workup Sequence for an Integrated, Continuous Manufacturing Process of a Pharmaceutical

24 Apr 2024 | Peer-reviewed journal | Contributor(s): Heider, Patrick L., Born, Stephen C., Basak, Soubir, Benyahia, Brahim, Lakerveld, Richard, Zhang, Haitao, Hogan, Rachael, - Buchbinder, Louis, Wolfe, Aaron, Mascia, Salvatore, Evans, James M. B., Jamison, Timothy F., Jensen, Klavs F.

The development and operation of the synthesis and workup steps of a fully integrated, continuous manufacturing plant for synthesizing aliskiren, a small molecule pharmaceutical, are presented. The plant started with advanced intermediates, two synthetic steps away from the final active...

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 Distributions (RTDs) to Address the Traceability of Raw Materials in Continuous Pharmaceutical Manufacturing

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Engisch, William, Muzzio, Fernando

Continuous processing in pharmaceutical manufacturing is a relatively new approach that has generated significant attention. While it has been used for decades in other industries, showing significant advantages, the pharmaceutical industry has been slow in its adoption of continuous processing,...

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Baumann, M, Baxendale, IR

The implementation of continuous flow processing as a key enabling technology has transformed the way we conduct chemistry and has expanded our synthetic capabilities. As a result many new preparative routes have been designed towards commercially relevant drug compounds achieving more efficient...

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 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 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...