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Using residence time distribution in pharmaceutical solid dose manufacturing–A critical review
09 Jun 2023 | 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,...
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Using Residence Time Distributions (RTDs) to Address the Traceability of Raw Materials in Continuous Pharmaceutical Manufacturing
09 Jun 2023 | 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,...
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Tracking raw material flow through a continuous direct compression line. Part II of II: Predicting dynamic changes in quality attributes of tablets due to disturbances in raw material properties using an independent residence time distribution model
09 Jun 2023 | Contributor(s):: Peterwitz, M, Buchgeister, SMeier, R, Schembecker, G
Continuous manufacturing of pharmaceuticals promises many advantages regarding economics and quality. However, tracing deviating material in such processes is much more challenging than in batch processes due to axial back-mixing. The literature has proven the traceability of disturbances in the...
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Solid-liquid axial dispersion performance of a mesoscale continuous oscillatory flow crystalliser with smooth periodic constrictions using a non-invasive dual backlit imaging technique
09 Jun 2023 | Contributor(s):: Onyemelukwe, II, Nagy, ZK, Rielly, CD
A dual backlit imaging technique has been developed for liquid and solid phase residence time distribution (RTD) measurements in a mesoscale (millilitre) continuous oscillatory flow crystalliser with smooth periodic constrictions (herein known as the SPC mesoscale crystalliser). The pixel-based...
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RTD-based material tracking in a fully-continuous dry granulation tableting line
09 Jun 2023 | Contributor(s):: Martinetz, M. C., Karttunen, A-P, Sacher, S., Wahl, P., Ketolainen, J., Khinast, J. G., Korhonen, O
Continuous manufacturing (CM) offers quality and cost-effectiveness benefits over currently dominating batch processing. One challenge that needs to be addressed when implementing CM is traceability of materials through the process, which is needed for the batch/lot definition and control...
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Residence time distribution of a continuously-operated capsule filling machine: Development of a measurement technique and comparison of three volume-reducing inserts
09 Jun 2023 | Contributor(s):: Kruisz, Julia, Faulhammer, Eva, Rehrl, Jakob, Scheibelhofer, Otto, Witschnigg, Andreas, Khinast, Johannes G.
This paper presents the measurement and analysis of the residence time distribution (RTD) of a tamping-pin capsule filling machine. The tamping speed and the amount of material inside the powder bowl proved to have a significant effect on the RTD. Various inserts into the powder bowl that reduce...
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Review: Continuous Manufacturing of Small Molecule Solid Oral Dosage Forms
09 Jun 2023 | Contributor(s):: Wahlich, John
Continuous manufacturing (CM) is defined as a process in which the input material(s) are continuously fed into and transformed, and the processed output materials are continuously removed from the system. CM can be considered as matching the FDA’s so-called ‘Desired State’ of pharmaceutical...
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Residence Time Distribution (RTD)-Based Control System for Continuous Pharmaceutical Manufacturing Process
09 Jun 2023 | Contributor(s):: Bhaskar, Aparajith, Singh, Ravendra
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Residence time distribution modelling and in line monitoring of drug concentration in a tablet press feed frame containing dead zones
09 Jun 2023 | Contributor(s):: Tanimura, Shinji, Singh, Ravendra Román-Ospino, Andrés D, Ierapetritou, Marianthi
The presence of a ‘significant dead zone’ in any continuous manufacturing equipment may affect the product quality and need to be investigated systematically. Dead zone will affect the residence time distribution (RTD) of continuous manufacturing and thus the mixing and product quality. Tablet...
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Reactor design and selection for effective continuous manufacturing of pharmaceuticals
09 Jun 2023 | Contributor(s):: Hu, Chuntian
Pharmaceutical production remains one of the last industries that predominantly uses batch processes, which are inefficient and can cause drug shortages due to the long lead times or quality defects. Consequently, pharmaceutical companies are transitioning away from outdated batch lines, in large...
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Quality Risk Assessment and Mitigation of Pharmaceutical Continuous Manufacturing Using Flowsheet Modeling Approach
09 Jun 2023 | Contributor(s):: Tian, Geng;, Koolivand, Abdollah, Arden, Nilou S., Lee, Sau, O'Connor, Thomas F.
Integrated flowsheet modeling is an engineering approach that can provide a framework for understanding the impact of process dynamics on drug quality and associated risks during production, thereby facilitating the development of robust continuous processes. In this investigation, flowsheet...
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Parametric Study of Residence Time Distributions and Granulation Kinetics as a Basis for Process Modeling of Twin-Screw Wet Granulation
09 Jun 2023 | Contributor(s):: Plath, Timo, Korte, Carolin, Sivanesapillai, Rakulan, Weinhart, Thomas
Twin-screw wet granulation is a crucial unit operation in shifting from pharmaceutical batch to continuous processes, but granulation kinetics as well as residence times are yet poorly understood. Experimental findings are highly dependent on screw configuration as well as formulation, and thus...
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Optimization of residence time distribution in RCDG and an assessment of its applicability in continuous manufacturing
09 Jun 2023 | Contributor(s):: Wilms, Annika, Kleinebudde, Peter
Knowledge of residence time is a critical aspect in developing control and material diversion strategies for continuous manufacturing processes in pharmaceutical manufacturing. Dry granulation is a promising continuous granulation technique as it is fast and economical. In this study, a...
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Modeling and simulation of continuous powder blending applied to a continuous direct compression process
09 Jun 2023 | Contributor(s):: Galbraith, Shaun C., Liu, Huolong, Cha, Bumjoon, Park, Seo-Young, Huang, Zhuangrong, Yoon, Seongkyu
Continuous manufacturing techniques are increasingly being adopted in the pharmaceutical industry and powder blending is a key operation for solid-dosage tablets. A modeling methodology involving axial and radial tanks-in-series flowsheet models is developed to describe the residence time...
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Mapping key process parameters to the performance of a continuous dry powder blender in a continuous direct compression system
09 Jun 2023 | Contributor(s):: Palmer, J, Reynolds, GK, Tahir, F, Yadav, IK, Meehan, E, Holman, J, Bajwa, G
This work aims to expand the typical raw material attributes that can successfully be processed on a continuous direct compression line with a particular focus on the continuous dry powder blender. Three grades of Acetaminophen were investigated as model active pharmaceutical ingredients and...
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Material tracking in a continuous direct capsule-filling process via residence time distribution measurements
09 Jun 2023 | Contributor(s):: Kruisz, Julia, Rehrl, Jakob, Faulhammer, Eva, Witschnigg, Andreas, Khinast, Johannes G.
Continuous production of pharmaceuticals requires traceability from the raw material to the final dosage form. With that regard, understanding the residence time distribution (RTD) of the whole process and its unit operations is crucial. This work describes a structured approach to characterizing...
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Measurement of residence time distributions and material tracking on three continuous manufacturing lines
09 Jun 2023 | Contributor(s):: Karttunen, Anssi-Pekka, Hörmannb,Theresa, De Leersnyder, Fien, Ketolainen, Jarkko, De Beer, Thomas, Hsiao, Wen-Kai, Korhonen, Ossi
Over the recent decade, benefits of continuous manufacturing (CM) of pharmaceutical products have been acknowledged widely. In contrast to batch processes, the product is not physically separated into batches in CM, which creates a few challenges. Product release is done for batches that should...
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Linking granulation performance with residence time and granulation liquid distributions in twin-screw granulation: An experimental investigation
09 Jun 2023 | Contributor(s):: Kumar, Ashish, Alakarjula, Maija, Vanhoorne, Valerie, Toiviainen, Maunu, De Leersnyder, Fien, Vercruysse, Jurgen, Juuti, Mikko, Ketolainen, Jarkko, Vervaet, Chris, Remon, Jean Paul, Gernaey, Krist V., De Beer, Thomas, Nopens, Ingmar
Twin-screw granulation is a promising wet granulation technique for the continuous manufacturing of pharmaceutical solid dosage forms. A twin screw granulator displays a short residence time. Thus, the solid-liquid mixing must be achieved quickly by appropriate arrangement of transport and...
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Inline Determination of Residence Time distributionin Hot-Melt-Extrusion
09 Jun 2023 | Contributor(s):: Wesholowski, Jens, Berghaus, Andreas, Thommes, Markus
In the framework of Quality-by-Design (QbD), the inline determination of process parameters or quality attributes of a product using sufficient process analytical technology (PAT) is a center piece for the establishment of continuous processes as a standard pharmaceutical technology. In this...
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Impact of material properties and process variables on the residence time distribution in twin screw feeding equipment
09 Jun 2023 | Contributor(s):: Van Snick, B, Kumar, A, Verstraeten, M, Pandelaere, K, Dhondt, J, Di Pretoro, G, De Beer, T, Vervaet, C, Vanhoorne, V
Screw feeders are integrated as dispensing units in most continuous manufacturing platforms. Hence, characterizing and modelling the residence time distribution (RTD) of materials in feeders is indispensable to understand the traceability of raw materials from the drum till tablet, enabling the...
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Grey-Box Approach for the Prediction of Variable Residence Time Distribution in Continuous Pharmaceutical Manufacturing
09 Jun 2023 | Contributor(s):: Elkhashap, A, Meier, R, Stenger, D, Abel, D
Axial dispersion models are used for the prediction of residence time distribution (RTD) of the flow occurring in various processes. Such models are essential for the understanding of the flow dynamics allowing monitoring, control and material tracing specially in the scope of continuous...
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From powder to tablets: Investigation of residence time distributions in a continuous manufacturing process train as basis for continuous process verification
09 Jun 2023 | Contributor(s):: Pauli, Victoria, Kleinebudde, Peter, Krumme, Markus
The essence of Continuous Manufacturing (CM) resides in the fact that continuous process units are directly connected to each other forming a continuous process train. The thorough understanding of material flow in this train based on suitable sensors, including on-line process analytical...
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Feed frame: The last processing step before the tablet compaction in pharmaceutical manufacturing
09 Jun 2023 | Contributor(s):: Sierra-Vega, Nobel, Romañach, Rodolfo J., Méndez, Rafael
The feed frame is a force-feeding device used in the die filling process. The die filling process is crucial within pharmaceutical manufacturing to guarantee the critical quality attributes of the tablets. In recent years, interest in this unit has increased because it can affect the properties...
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Development and Use of a Residence Time Distribution (RTD) Model Control Strategy for a Continuous Manufacturing Drug Product Pharmaceutical Process
09 Jun 2023 | Contributor(s):: Hurley, Samantha, Tantuccio, Anthony, Escotet-Espinoza, Manuel Sebastian, Flamm, Matthew, Metzger, Matthew
Residence-time-distribution (RTD)-based models are key to understanding the mixing dynamics of continuous manufacturing systems. Such models can allow for material traceability throughout the process and can provide the ability for removal of non-conforming material from the finished product....
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Development of a continuous direct compression platform for low-dose drug products
09 Jun 2023 | Contributor(s):: Van Snick, B, Holman, J, Vanhoorne, V, Kumar, A, De Beer, T, Remon, JP, Vervaet, C
In this work a continuous direct compression process was developed for a low-dosed drug product. Each unit operation of the GEA CDC-50 system was thoroughly investigated. This paper aimed to tackle the macroscopic and microscopic blend uniformity challenges inherently associated with continuous...