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...

The Use of a Closed Feed Frame for the Development of Near-Infrared Spectroscopic Calibration Model to Determine Drug Concentration

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Movilla-Meza, Nathaly A., Sierra-Vega, Nobel O., Alvarado-Hernández, Bárbara B., Méndez, Rafael, Romañach, Rodolfo J.

Purpose: This study evaluates the use of the closed feed frame as a material sparing approach to develop near-infrared (NIR) spectroscopic calibration models for monitoring blend uniformity. The effect of shear induced by recirculation on NIR spectra was also studied. Methods: Calibration models...

Delta-mannitol to enable continuous twin-screw granulation of a highly dosed, poorly compactable formulation

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Vanhoorne, V., Almey, R., De Beer, T., Vervaet, C.

In current study, it was investigated if the moisture-mediated polymorphic transition from δ- to β-mannitol during twin screw granulation (TSG) also took place in high drug loaded formulations and if the specific granule morphology associated with the polymorphic transition could enable tableting...

Cleaning of direct compression continuous manufacturing equipment through displacement of API residues by excipients

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Patel, Dhavalkumar S, Méndez, Rafael, Romañach, Rodolfo J

This feasibility study evaluates a cleaning process designed to avoid the use of detergents and reduce operator exposure to the active pharmaceutical ingredient (API). The continuous manufacturing equipment was cleaned using excipients to displace ibuprofen residues from the system. The cleaning...

Control oriented modeling of twin-screw granulation in the ConsiGmaTM-25 production plant

09 Jul 2024 | Peer-reviewed journal | Contributor(s): Johannes Khinast, Martin Horn, Jakob Rehrl, Selma Celikovic, Johannes Poms

ConsiGmaTM-25 is a continuous production plant integrating a twin-screw granulation, fluid bed drying, granule conditioning, and a tableting unit. The particle size distribution (PSD), active pharmaceutical ingredient (API) content, and liquid content of wet granules after twin-screw...

Continuous Flow Intensification for the Synthesis of High-Purity Warfarin

10 May 2024 | Peer-reviewed journal | 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 | Peer-reviewed journal | 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 | Peer-reviewed journal | 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 | Peer-reviewed journal | 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 | Peer-reviewed journal | 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...

Visualization and understanding of the granulation liquid mixing and distribution during continuous twin screw granulation using NIR chemical imaging

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Vercruysse, Jurgen, Toiviainen, Maunu, Fonteyne, Margot, Helkimo, Niko, Ketolainen, Jarkko, Juuti, Mikko, Delaet, Urbain, Van Assche, Ivo, Remon, Jean Paul, Vervaet, Chris, De Beer, Thomas

Over the last decade, there has been increased interest in the application of twin screw granulation as a continuous wet granulation technique for pharmaceutical drug formulations. However, the mixing of granulation liquid and powder material during the short residence time inside the screw...

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,...

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,...

Use of the channel fill level in defining a design space for twin screw wet granulation

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Gorringe, L. J., Kee, G. S., Saleh, M. F., Fa, N. H., Elkes, R. G.

Twin screw wet granulation is a key process in the continuous manufacture of oral solid dosage forms. Previous Research Article has qualitatively suggested that the channel fill level influences the granules produced. In this paper a quantitative measure of the total volumetric fraction of the...

TPLS as predictive platform for twin-screw wet granulation process and formulation development

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Ryckaert, A., Van Hauwermeiren, D., Dhondt, J., De Man, A., Funke, A., Djuric, D., Vervaet, C., Nopens, I., De Beer, T.

In recent years, the interest in continuous manufacturing techniques, such as twin-screw wet granulation, has increased. However, the understanding of the influence of the combination of raw material properties and process settings upon the granule quality attributes is still limited. In this...

Transfer from High-Shear Batch to Continuous Twin Screw Wet Granulation: A Case Study in Understanding the Relationship Between Process Parameters and Product Quality Attributes

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Beer, Paul, Wilson, David, Huang, Zhenyu, De Matas, Marcel

A twin screw to high-shear batch granulation technology switch was evaluated for a pharmaceutical development project. Differences in granule (particle size distribution and porosity) and tablet (dissolution) quality attributes were analysed for both continuous and batch technologies. Liquid to...

Twin screw granulation - review of current progress

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Thompson, M. R.

Twin screw granulation (TSG) is a new process of interest to the pharmaceutical community that can continuously wet granulate powders, doing so at lower liquid concentrations and with better product consistency than found by a high shear batch mixer. A considerable body of Research Article has...

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 Use of Near-Infrared and Microwave Resonance Sensing to Monitor a Continuous Roller Compaction Process

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Austin, John, Gupta, Anshu, Mcdonnell, Ryan, Reklaitis, Gintaras V., Harris, Michael T

Roller compaction is commonly used in the pharmaceutical and nutraceutical industries to increase and narrow the size distribution of a particulate material, making it easier to process. Both the moisture content of the material and the density of the roller compacted ribbon affect the uniformity...

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 Influence of Equipment Design and Process Parameters on Granule Breakage in a Semi-Continuous Fluid Bed Dryer after Continuous Twin-Screw Wet Granulation

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Ryckaert, Alexander, Ghijs, Michael, Portier, Christoph, Djuric, Dejan, Funke, Adrian, Vervaet, Chris, De Beer, Thomas

The drying unit of a continuous from-powder-to-tablet manufacturing line based on twin-screw granulation (TSG) is a crucial intermediate process step to achieve the desired tablet quality. Understanding the size reduction of pharmaceutical granules before, during, and after the fluid bed drying...

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 effect of screw configuration and formulation variables on liquid requirements and granule quality in a continuous twin screw wet granulation process

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Vandevivere, L., Van Wijmeersch, E., Hausler, O., De Beer, T., Vervaet, C., Vanhoorne, V.

The effect of two screw configurations with varying stagger angle was evaluated on the liquid amount required to produce good quality granules for a highly (mannitol-based) and a poorly (DCP-based) soluble formulation containing different binders. It is generally known that the use of a higher...