A Training on: Continuous Manufacturing (Direct Compaction) of Solid Dose Pharmaceutical Products

09 Jun 2023 | Contributor(s): Moghtadernejad, Sara, Escotet-Espinoza, M. Sebastian, Oka, Sarang, Singh, Ravendra, Liu, Zhanjie, Roman-Ospino, Andres D., Li, Tianyi, Razavi, Sonia, Panikar, Savitha, Scicolone, James, Callegari, Gerardo, Hausner, Douglas, Muzzio, Fernando

As the pharmaceutical industry increasingly adopts continuous manufacturing technology, significant attention must be paid to process analytical technology (PAT), process integration, and process control. Published information is no substitute for hands-on comprehensive training, which is...

A Two-Step Continuous-Flow Procedure towards Ribociclib

09 Jun 2023 | Contributor(s): Pellegatti, L, Hafner, A, Sedelmeier, J

This work describes the manufacturing of ribociclib following the concept of an end-to-end continuous-flow process. The active pharmaceutical ingredient (API) is produced in a two-step telescoped flow process with integrated in-line liquid-liquid extraction and semibatch crystallization.

A Validated Model for Design and Evaluation of Control Architectures for a Continuous Tablet Compaction Process

09 Jun 2023 | Contributor(s): Nunes de Barros, Fernando, Bhaskar, Aparajith, Singh, Ravendra

The systematic design of an advanced and efficient control strategy for controlling critical quality attributes of the tablet compaction operation is necessary to increase the robustness of a continuous pharmaceutical manufacturing process and for real time release. A process model plays a very...

A very boring 120 h: 15million tablets under a continuous state of control

09 Jun 2023 | Contributor(s): Holman, James, Tantuccio, Anthony, Palmera, Jhon, Doninck, Tom van, Meyer, Robert

The aimof this study is to showthe robustness of a commercial direct compression system running continuously under relevant process conditions for over 120 h. The study will apply a representative commercial control strategy including real time monitoring of process parameters, rejection of OOS...

A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 1: CDI-Promoted Amide Bond Formation

09 Jun 2023 | Contributor(s): Içten, Elçin, Maloney, Andrew J., Beaver, Matthew G., Shen, Dongying E., Zhu, Xiaoxiang, Graham, Lauren R., Robinson, Jo A., Huggins, Seth, Allian, Ayman, Hart, Roger, Walker,Shawn D., Rolandi, Pablo, Braatz, Richard D.

This article details process characterization efforts and the development of corresponding process models to inform a process control strategy to produce a carfilzomib drug substance intermediate, morpholine amide 3. Model calibration for relevant unit operations and development of a dynamic...

Accelerating biologics manufacturing by modeling or: Is Approval under the QbD and PAT approaches demanded by authorities acceptable without a digital-twin?

09 Jun 2023 | Contributor(s): Zobel-Roos, Steffen, Schmidt, Axel Mestmäcker, Fabian Mouellef, Mourad, Huter, Maximilian, Uhlenbrock, Lukas, Kornecki, Martin, Lohmann, Lara, Ditz, Reinhard, Strube, Jochen

Innovative biologics, including cell therapeutics, virus-like particles, exosomes, recombinant proteins, and peptides, seem likely to substitute monoclonal antibodies as the main therapeutic entities in manufacturing over the next decades. This molecular variety causes a growing need for a...

Acceleration of Anti-Markovnikov Hydroamination in the Synthesis of an Active Pharmaceutical Ingredient

09 Jun 2023 | Contributor(s): Mitic, A, Skovby, TDam-Johansen, K, Gernaey, KV

Slow chemical reactions are a big challenge in the modern pharmaceutical industry. Their accelerations together with the introduction of continuous manufacturing modes are major drivers for future development. One example reaction is hydroamination, a reaction between unsaturated hydrocarbons and...

Achieving Continuous Manufacturing for Final Dosage Formation: Challenges and How to Meet Them

09 Jun 2023 | Contributor(s): Byrn, Stephen, Futran, Maricio, Thomas, Hayden, Jayjock, Eric, Maron, Nicola, Meyer, Robert F., Myerson, Allan S., Thien, Michael P., Trout, Bernhardt L.

We describe the key issues and possibilities for continuous final dosage formation, otherwise known as downstream processing or drug product manufacturing. A distinction is made between heterogeneous processing and homogeneous processing, the latter of which is expected to add more value to...

A scaled down method for identifying the optimum range of L/S ratio in twin screw wet granulation using a regime map approach

09 Jun 2023 | Contributor(s): Pradhan, Shankali U., Bullard, Joseph W., Dale, Steven, Ojakovo, Peter, Bonnassieux, Alexandre

Twin screw wet granulation (TSWG) has gained momentum in the pharmaceutical industry for effective continuous granulation of solid dosage products. Liquid-to-solid (L/S) ratio is a key process parameter affecting granule properties. Identifying an optimum range of L/S ratio while reducing the...

A segmented flow platform for on-demand medicinal chemistry and compound synthesis in oscillating droplets

09 Jun 2023 | Contributor(s): Hwang, YJ, Coley, CWAbolhasani, M, Marzinzik, AL, Koch, G, Spanka, C, Lehmann, H, Jensen, KF

We report an automated flow chemistry platform that can efficiently perform a wide range of chemistries, including single/multi-phase and single/multi-step, with a reaction volume of just 14 mu L. The breadth of compatible chemistries is successfully demonstrated and the desired products are...

A Semi-Continuous Operations Model For Solid-Dose Manufacturing

09 Jun 2023 | Contributor(s): Pazhayattil, Ajay Babu, Sayeed-Desta, Naheed

This article will explore the evolving generic drug environment in the U.S. It will also describe an operations model for semi-continuous manufacturing of generic solid-dose products that will improve flexibility and enable just-in-time production.

A solution for low-dose feeding in continuous pharmaceutical processes

09 Jun 2023 | Contributor(s): Sacher, S, Heindl, NUrich, JAA, Kruisz, J, Khinast, JG

Continuous feeding of small quantities of powder is increasingly applied in pharmaceutical manufacturing. With that regard, what is crucial is not only the feasibility, but also the accuracy and stability. To enable stable processing, low amounts of various agents, e.g., lubricants, can be used....

A Stochastic Population Balance Equation Model for Nucleation and Growth of Crystals with Multiple Polymorphs

09 Jun 2023 | Contributor(s): Maggioni, Giovanni, Mazzotti, Marco

Understanding polymorph crystallization is important due to the different properties, such as bioavailability or crystal shape, exhibited by the different crystal forms. In this work, we present a model, based on population balance equations, describing the unseeded crystallization by cooling of...

A Structured Approach To Cope with Impurities during Industrial Crystallization Development

09 Jun 2023 | Contributor(s): Urwin, SJ, Levilain, GMarziano, I, Merritt, JM, Houson, I, Ter;Horst, JH

The perfect separation with optimal productivity, yield, and purity is very difficult to achieve. Despite its high selectivity, in crystallization unwanted impurities routinely contaminate a crystallization product. Awareness of the mechanism by which the impurity incorporates is key to...

A Study on In-Line Tablet Coating-the Influence of Compaction and Coating on Tablet Dimensional Changes

09 Jun 2023 | Contributor(s): Cahyadi, C., Tan, B. X., Chan, L. W., Heng, P. W. S.

Prior to coating, tablets are usually stored for a definite period to enable complete strain recovery and prevent subsequent volumetric expansion-related coating defects. In-line coating is defined as the coating of tablets immediately after compaction. In-line coating will be expected to improve...

A systematic computer aided framework for design and analysis of PAT systems

09 Jun 2023 | Contributor(s): Gernaey, Krist, Singh, Ravendra, Gani, Rafiqul

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A Systematic Framework for Data Management and Integration in a Continuous Pharmaceutical Manufacturing Processing Line

09 Jun 2023 | Contributor(s): Cao, Huiyi, Mushnoori, Srinivas, Higgins, Barry, Kollipara, Chandrasekhar, Fermier, Adam, Hausner, Douglas, Jha, Shantenu, Singh, Ravendra, Ierapetritou, Marianthi, Ramachandran, Rohit

As the pharmaceutical industry seeks more efficient methods for the production of higher value therapeutics, the associated data analysis, data visualization, and predictive modeling require dependable data origination, management, transfer, and integration. As a result, the management and...

A systematic framework for onsite design and implementation of a control system in a continuous tablet manufacturing process

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

A novel manufacturing strategy based on continuous processing integrated with online/inline monitoring tools coupled with an advanced control system is highly desired for efficient Quality by Design (QbD)-based pharmaceutical manufacturing. A control system ensures the predefined end product...

A Systematic Framework for Process Control Design and Risk Analysis in Continuous Pharmaceutical Solid-Dosage Manufacturing

09 Jun 2023 | Contributor(s): Su, Qinglin, Moreno, Mariana, Giridhar, Arun, Reklaitis, Gintaras, Nagy, Zoltan

The paradigm shift in the pharmaceutical industry to continuous manufacturing, which has recently progressed from conceptual demonstration to pilot production, has stimulated the development and application of process systems engineering (PSE) tools for implementing efficient and robust control...

A Systematic Framework for the Design and Implementation of Sensing and Control Architecture for a Continuous Pharmaceutical Manufacturing Plant

09 Jun 2023 | Contributor(s): Singh, Ravendra, Muzzio, Fernando J Ierapetritou, Marianthi, Ramachnadran, Rohit

The continuous pharmaceutical manufacture (CPM) plant and control architecture developed earlier is currently being widely implemented in industries [1,2]. CPM indeed provides an appropriate platform to implement suitable monitoring and control architecture, to improve product quality, and to...

A primary drying model-based comparison of conventional batch freeze-drying to continuous spin-freeze-drying for unit doses

09 Jun 2023 | Contributor(s): Leys, L., Vanbillemont, B., Van Bockstal, P. J., Lammens, J., Nuytten, G., Corver, J., Vervaet, C., De Beer, T.

An innovative continuous spin-freeze-drying technology for unit doses was recently developed. For this technology, a mechanistic primary drying model was developed allowing the calculation of the optimal dynamic drying trajectory for spin-frozen formulations. In this work, a model-based and...

A Process for the Formation of Nanocrystals of Active Pharmaceutical Ingredients with Poor Aqueous Solubility in a Nanoporous Substrate

09 Jun 2023 | Contributor(s): O'Mahony, M, Leung, AKFerguson, S, Trout, BL, Myerson, AS

A potential process for the formation of nanocrystals of the poorly soluble drug, ibuprofen, within a nanoporous material is demonstrated. Nanocrystalline ibuprofen (IBP) is prepared at <= 106 nm by adding a solution containing IBP to particles of controlled pore glass (CPG) within a column so...

A quality by design approach to investigate the effect of mannitol and dicalcium phosphate qualities on roll compaction

09 Jun 2023 | Contributor(s): Souihi, Nabil, Dumarey, Melanie, Wikstrom, Hakan, Tajarobi, Pirjo, Fransson, Magnus, Svensson, Olof, Josefson, Mats, Trygg, Johan

Roll compaction is a continuous process for solid dosage form manufacturing increasingly popular within pharmaceutical industry. Although roll compaction has become an established technique for dry granulation, the influence of material properties is still not fully understood. In this study, a...

A retrofit strategy to achieve “Fast, Flexible, Future (F3)” pharmaceutical production processes

09 Jun 2023 | Contributor(s): Singh, Ravendra, Rozada-Sanchez, Raquel Wrate, Tim Muller, Frans Gernaey, Krist V Gani, Rafiqul, Woodley, John M

n the work reported here, a substrates adoption methodology for a series of similar substrates has been developed as part of a retrofit strategy. The objective is to achieve “fast, flexible and future” pharmaceutical production processes by adapting a generic modular process-plant template....

A review of emerging technologies enabling improved solid oral dosage form manufacturing and processing

09 Jun 2023 | Contributor(s): Sohail Arshad, Muhammad, Zafar, Saman, Yousef, Bushra, Alyassin, Yasmine, Ali, Radeyah, AlAsiri, Ali, Chang, Ming-Wei, Ahmad, Zeeshan, Ali Elkordy, Amal, Faheem, Ahmed, Pitt, Kendal

Tablets are the most widely utilized solid oral dosage forms because of the advantages of self-administration, stability, ease of handling, transportation, and good patient compliance. Over time, extensive advances have been made in tableting technology. This review aims to provide an insight...