An audit of pharmaceutical continuous manufacturing regulatory submissions and outcomes in the US

20 Nov 2024 | Peer-reviewed journal | Contributor(s): Adam C. Fisher, William Liu, Andreas Schick, Mahesh Ramanadham, Sharmista Chatterjee, Raphael Brykman, Sau L. Lee, Steven Kozlowski, Ashley B. Boam, Stelios C. Tsinontides, Michael Kopcha

Continuous manufacturing (CM) sends materials directly and continuously to the next step of a process, eliminating hold times and reducing processing times. The potential benefits of CM include improved product quality, reduced waste, lower costs, and increased manufacturing flexibility and...

The role of digital twins in driving sustainability

29 Oct 2024 | Peer-reviewed journal | Contributor(s): Deborah McElhone, Barrie Cassey, Kamal Abu-Hassan

As the pharmaceutical sector endeavours to become more sustainable, we hear how digital twins – virtual replicas of systems or products that can help predict performance – are supporting the industry in its efforts.

Continuous Processing. Continuous Evolution

08 Oct 2024 | Magazine | Contributor(s): Douglas Hausner

Continuous processing for small molecule products has been a hot topic for years, but where does the industry stand with it today? We speak with Doug Hausner, Senior Manager, Continuous Manufacturing, Oral Solid Dose, Pharma Services at Thermo Fisher Scientific, to find out.

Continuous manufacturing: Changing the paradigm in the pharmaceutical manufacturing sector

23 Sep 2024 | Magazine | Contributor(s): Indu Bhushan

The author explains how continuous manufacturing is reshaping pharmaceutical production

Pharmaceutical Continuous Manufacturing: Content Uniformity With PAT And RTR

16 Sep 2024 | Website | Contributor(s): Richard Steiner

In pharmaceutical continuous manufacturing (PCM), technical solutions ensuring critical quality attributes for content uniformity and unit dose exist for online, in-line, and at-line measurements. Process analytical technology (PAT) allows in-line measurement and control of critical process...

The Rise of Continuous Manufacturing in Pharma

13 Aug 2024 | Website | Contributor(s): Editorial Team

"Mr Indu Bhushan, CEO and Director of STEERLife shares his insights on the transformative journey of continuous manufacturing, and the advanced technologies that have propelled this paradigm shift. He also throws light on how continuous manufacturing has accelerated drug development...

Orodispersible films: Product transfer from lab-scale to continuous manufacturing

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Thabet, Yasmin, Breitkreutz, Joerg

Orodispersible films have been described as new beneficial dosage forms for special patient populations. Due to various production settings, different requirements on film formulations are required for non- continuous and continuous manufacturing. In this study, a continuous coating machine was...

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...

Continuous Manufacturing in the Pharmaceutical Industry: Enhancing Drug Production

23 Jul 2024 | Website | Contributor(s): Timmerman, Siebe

A significant shift towards continuous manufacturing (CM) is currently underway in the pharmaceutical industry. Unlike the more commonly used batch processing, CM operates continuously. This method potentially offers increased efficiency, agility, and flexibility in the manufacturing of drug...

The effect of binder types on the breakage and drying behavior of granules in a semi-continuous fluid bed dryer after twin screw wet granulation

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Vandevivere, L., Denduyver, P., Portier, C., Häusler, O., De Beer, T., Vervaet, C., Vanhoorne, V.

Current study investigated the effect of different binder types on the granule drying process and the granule breakage behavior in a semi-continuous fluid bed dryer integrated in the C25 ConsiGma-system. The studied binders (i.e. hydroxypropyl pea starch, hydroxypropyl methylcellulose E15,...

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...

Twin Screw Melt Granulation: Alternative Approach for Improving Solubility and Permeability of a Non-steroidal Anti-inflammatory Drug Ibuprofen

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Nyavanandi, Dinesh, Narala, Sagar, Mandati, Preethi, Alzahrani, Abdullah, Kolimi, Praveen, Almotairy, Ahmed, Repka, Michael A.

The current research is focused on investigating the suitability of the twin screw melt granulation (TSMG) approach for improving the solubility of a non-steroidal anti-inflammatory (NSAIDs) drug (ibuprofen), by developing granules using lipid surfactants. The solubility of the drug within the...

Application of Transition-Metal Catalysis, Biocatalysis, and Flow Chemistry as State-of-the-Art Technologies in the Synthesis of LCZ696

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Gu, Xingxian, Zhao, Jibin, Chen, Like, Li, Yunzhong, Yu, Bo, Tian, Xiangguang, Min, Zhongcheng, Xu, Su, Gu, Huijuan, Sun, Junjie, Lu, Xiaoquan, Chang, Meng, Wang, Xufan, Zhao, Liqun, Ye, Shengqing, Yang, Hongwei, Tian, Yingtao, Gao, Feng, Gai, Yu, Jia, Guanghua, Wu, Jingjing, Wang, Yan, Zhang, Jianghua, Zhang, Xuesong, Liu, Weichun, Gu, Xin, Luo, Xi, Dong, Hai, Wang, Huaimin, Schenkel, Berthold, Venturoni, Francesco, Filipponi, Paolo, Guelat, Bertrand, Allmendinger, Thomas, Wietfeld, Bernhard, Hoehn, Pascale, Kovacic, Nikola, Hermann, Luca, Schlama, Thierry, Ruch, Thomas, Derrien, Nadine, Piechon, Philippe, Kleinbeck, Florian

LCZ696 is a novel treatment for patients suffering from heart failure that combines the two active pharmaceutical ingredients sacubitril and valsartan in a single chemical compound. While valsartan is an established drug substance, a new manufacturing process suitable for large-scale commercial...

One-Step Synthesis of 2-Fluoroadenine Using Hydrogen Fluoride Pyridine in a Continuous Flow Operation

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Salehi Marzijarani, Nastaran, Snead, David R., McMullen, Jonathan P., Lévesque, François, Weisel, Mark, Varsolona, Richard J., Lam, Yu-hong, Liu, Zhijian, Naber, John R.

We report the development of a one-pot synthesis of 2-fluoroadenine from an inexpensive 2,6-diaminopurine starting material using diazonium chemistry in a continuous fashion. Given the sensitivity of this transformation to temperature, we conducted critical experiments to study the exothermicity...

Process Intensification via End-to-End Continuous Manufacturing of Atorvastatin Calcium Using an Integrated, Modular Reaction-Crystallization-Spherical Agglomeration-Filtration-Drying Process

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Parvaresh, Rojan, Nagy, Zoltan K.

Continuous manufacturing can show potential benefits over batch processing in lower turnaround times and smaller footprint in addition to higher productivity, adaptability, and consistent product quality. Although these possible benefits exist, there are also challenges in integrating the various...

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...

Process analytics for the new era of continuous RNA manufacturing

23 Jul 2024 | Website | Contributor(s): Botonjic-Sehic, Edita

In this article, Edita Botonjic-Sehic, Head of Process Analytics and Data Science at ReciBioPharm, examines the need for a digitally controlled continuous manufacturing process to correct the shortcomings of the current standard of batch processing. She highlights the critical role in-line...

Blend uniformity monitoring in a continuous manufacturing mixing process for a low-dosage formulation using a stream sampler and near infrared spectroscopy

19 Jul 2024 | Peer-reviewed journal | Contributor(s): Rodolfo Romanach, Raúl S. Rangel-Gil, Juan M. Nasrala-Álvarez, Rafael Méndez

Continuous manufacturing has the potential to offer several benefits for the production of oral solid dosage forms, including reduced costs, low-scale equipment, and the application of process analytical technology (PAT) for real-time process control. This study focuses on the implementation of...

Implementation of a fully integrated continuous manufacturing line for direct compression and coating at a commercial pharmaceutical facility – Part 1: Operational considerations and control strategy

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Conway, Stephen L., Rosas, Juan G., Overton, Paul, Tugby, Neil, Cryan, Phillip, Witulski, Frank, Hurley, Samantha, Wareham, Laura, Tantuccio, Anthony, Ramasamy, Manoharan, Lalloo, Anita, Gibbs, Mason, Meyer, Robert F.

We implement a fully integrated continuous manufacturing (CM) line for direct compression and coating of a pharmaceutical oral solid dosage form in a commercial production facility. In this first paper of a two-part series, we describe process design and operational choices made to introduce CM...

Implementation of a fully integrated CM direct compression and coating process at a commercial pharmaceutical facility - Part 2: PAT and RTD results for normal operational conditions batches.

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Rosas, JG, Brush, P, Thompson, B, Miller, C, Overton, P, Tugby, N, Stoliarskaia, D, Hurley, S, Ramasamy, M, Conway, SL

This is the second of two articles detailing the continuous manufacturing (CM) development and implementation activities for an marketed product which have been realized in novel, qualified equipment, using validated control strategy elements to enable manufacture of batches under current good...

Telescoped Hybrid Batch–Flow Synthesis of 2-Butylbenzofuran

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Dedè, Fabiana, Ciancimino, Cristina, Danelli, Piero, Piccolo, Oreste, Vigo, Daniele

The present work describes the development of an improved synthesis of the pharmaceutically relevant building block 2-butylbenzofuran (BBF). The telescoped hybrid batch–flow process is composed of three steps and affords the final product in high yield and purity. The key cyclization step is...

Modular Synthesis of Benzoylpyridines Exploiting a Reductive Arylation Strategy

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Alfano, Antonella Ilenia, Smyth, Megan, Wharry, Scott, Moody, Thomas S., Baumann, Marcus

Herein we disclose a telescoped flow strategy to access electronically differentiated bisaryl ketones as potentially new and tunable photosensitizers containing both electron-rich benzene systems and electron-deficient pyridyl moieties. Our approach merges a light-driven (365 nm) and...

Development of a Horizontal Dynamically Mixed Flow Reactor for Laboratory Scale-Up of Photochemical Wohl–Ziegler Bromination

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Pratley, Cassie, Shaalan, Youssef, Boulton, Lee, Jamieson, Craig, Murphy, John A., Edwards, Lee J.

Flow reactors with enhanced mixing are of interest to the pharmaceutical industry for a range of photochemical applications. Taylor–Couette (vortex, dynamically mixed) reactors have been reported to have intensified mixing and have been used with heterogeneous systems. Our photochemical workflow...

A Tandem Ring Closure and Nitrobenzene Reduction with Sulfide Provides an Improved Route to an Important Intermediate for the Anti-Tuberculosis Drug Candidate Sutezolid

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Kalmode, Hanuman P., Ravikumar, Ongolu, Paymode, Dinesh J., Bachert, John, Burns, Justina M., Stringham, Rodger W., Aleshire, Sarah L., Nelson, Ryan C.

Sutezolid is an in-development thiomorpholine derivative of the FDA-approved tuberculosis (TB) treatment linezolid. Current synthetic routes for preparing sutezolid start with thiomorpholine as a key structural building block; unfortunately, this material was identified as a major cost driver for...

Continuous-Flow Synthesis of the Nucleobase Unit of Remdesivir

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Guo, Yongxing, Liu, Minjie, Jiang, Meifen, Tao, Yuan, Cheng, Dang, Chen, Fen-Er

In this work, the nucleobase unit of the antiviral drug remdesivir, 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine, was synthesized through five-step continuous flow. By adapting batch synthetic chemistry, 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine was successfully produced through sequential flow...