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A Continuous Process for Manufacturing Apremilast. Part II: Process Characterization to Establish a Parametric Control Strategy
| Contributor(s):: Griffin, Daniel J., Avci, Nadide Hazal, Sarkar, Nandini, Fostinis, James D., Klitzing, Nicholas, Murray, James I., Wimalasinghe, Rasangi, Spada, Simone, Zeng, Alicia, Beaver, Matthew G., Hsieh, Hsiao-Wu
This is Part II of a series on the development and characterization of an integrated continuous manufacturing (CM) process developed for the penultimate step in the synthesis of the drug substance Apremilast (Otezla). Part I gives the development history and highlights the achieved process...
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Twin screw granulation as a simple and efficient tool for continuous wet granulation
| Contributor(s):: Keleb, EI, Vermeire, A, Vervaet, C, Remon, JP
The modification of a twin screw extruder for continuous wet granulation was investigated. Modification of the extruder setup as well as the screw design allowed the continuous wet granulation of alpha-lactose monohydrate without the need of a wet sieving step. The robustness of twin screw...
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RTD-based material tracking in a fully-continuous dry granulation tableting line
| 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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Method for characterization of loss-in-weight feeder equipment
| Contributor(s):: William E. Engisch, Fernando J. Muzzio
This paper presents a method for evaluating the steady state performance of loss-in-weight powder feeding equipment and then demonstrates the use of the method in evaluating the performance of a K-Tron KT35 loss-in-weight feeder for three pharmaceutical grade powders. The method describes in...
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Impact of Vertical Blender Unit Parameters on Subsequent Process Parameters and Tablet Properties in a Continuous Direct Compression Line
| Contributor(s):: Kreiser, MJ, Wabel, C, Wagner, KG
The continuous manufacturing of solid oral-dosage forms represents an emerging technology among the pharmaceutical industry, where several process steps are combined in one production line. As all mixture components, including the lubricant (magnesium stearate), are passing simultaneously through...
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Grey-Box Approach for the Prediction of Variable Residence Time Distribution in Continuous Pharmaceutical Manufacturing
| 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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Foam granulation: new developments in pharmaceutical solid oral dosage forms using twin screw extrusion machinery
| Contributor(s):: Thompson, M. R., Weatherley, S., Pukadyil, R. N., Sheskey, P. J.
This paper investigates foam granulation in a twin screw extruder as a new continuous wet granulation technique for pharmaceutical powder drug formulations. Foamed aqueous binder has a reportedly lower soak-to-spread ratio than drop or spray liquid addition in batch granulation. This work...
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Fluidization characterization in the ConSigma 25 dryer via process data - A method of advanced quality assurance in continuous manufacturing
| Contributor(s):: Rehrl, Jakob, Hoermann-Kincses, Theresa, Sibanc, Rok, Hsiao, Wen-Kai, Franke, Meik, Khinast, Johannes
Wet granulation lines in pharmaceutical manufacturing facilities typically comprise a dryer that removes the excess moisture content after wet granulation. In this study, a semi-continuous dryer installed in the ConsiGma 25 wet granulation line was investigated. The goal was to highlight specific...
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Feedrate deviations caused by hopper refill of loss-in-weight feeders
| Contributor(s):: William E. Engisch, Fernando J. Muzzio
Continuous powder processing requires accurate and consistent feed streams of the raw materials which makes loss-in-weight feeders invaluable. Periodic hopper refill of the feeders, which is needed for continuous operation, can lead to inconsistent and poor feeding performance. This paper...
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Evaluating the potential for optimization of axial back-mixing in continuous pharmaceutical manufacturing
| Contributor(s):: Peterwitz, M, Schembecker, G
In continuous pharmaceutical manufacturing, the degree of back-mixing has two contrary effects on the propagation of disturbances through a process. Firstly, back-mixing results in the contamination of adjacent material by strong disturbances and additional losses. However, the available...
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Effects of Process and Design Parameters on Granule Size Distribution in a Continuous High Shear Granulation Process
| Contributor(s):: Meng, Wei, Oka, Sarang, Liu, Xue, Omer, Thamer, Ramachandran, Rohit, Muzzio, Fernando J.
Wet granulation is widely used in the pharmaceutical industry. This advantageous technology is capable of enhancing compression and powder handling, decreasing ingredient segregation, and promoting blend and content uniformity. Currently, a high level of interest exists in the continuous version...
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Effects of processing parameters and blade patterns on continuous pharmaceutical powder mixing
| Contributor(s):: Osorio, JG, Muzzio, FJ
The present study summarizes the experimental characterization of a new continuous powder mixer (GCG-70 by Glatt (R)) using common pharmaceutical ingredients. The powder hold-up and residence time distribution were used to characterize the bulk behavior of the mixer as a function of impeller...
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Diminished segregation in continuous powder mixing
| Contributor(s):: Oka, S, Sahay, A, Meng, W, Muzzio, F
Binary powder mixtures with variable segregation tendencies were mixed in a tumbling batch blender and in a continuous convective tubular blender. The degree of homogeneity of the final blend obtained from the continuous blender was found to be much higher than that from the batch V-blender, for...
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Development of a continuous direct compression platform for low-dose drug products
| 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...
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Continuous manufacturing process monitoring of pharmaceutical solid dosage form: A case study
| Contributor(s):: Roggo, Yves, Pauli, Victoria, Jelsch, Morgane, Pellegatti, Laurent, Elbaz, Frantz, Ensslin, Simon, Kleinebudde, Peter, Krumme, Markus
The most prevalent pharmaceutical dosage forms at present are granular solids in the form of oral tablets and capsules. While effective in releasing drug rapidly upon contact with gastrointestinal fluid, their manufacture, which relies on particulate processing, is fraught with difficulties...
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Continuous manufacture of polymeric cellular dosage forms
| Contributor(s):: Blaesi, Aron H, Saka, Nannaji
The most prevalent pharmaceutical dosage forms at present are granular solids in the form of oral tablets and capsules. While effective in releasing drug rapidly upon contact with gastrointestinal fluid, their manufacture, which relies on particulate processing, is fraught with difficulties...
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Comparison of a continuous ring layer wet granulation process with batch high shear and fluidized bed granulation processes
| Contributor(s):: Jarvinen, MA, Paavola, M, Poutiainen, S, Itkonen, P, Pasanen, V, Uljas, K, Leiviska, K, Juuti, M, Ketolainen, J, Jarvinen, K
The traditional batch wet granulation processes encounter several challenges, such as problems in the scale-up step, batch-to-batch variability together with the multivariate and difficult to control nature of the process. A continuous wet granulation technique could be a possible solution for...
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Characteristics of residence time distribution in a continuous high shear mixer granulation using scraper rotation
| Contributor(s):: Tomita, Yosuke, Takeuchi, Yoshiko, Natsuyama, Susumu, Takeuchi, Hirofumi
Characteristics of residence time distribution (RTD) in a continuous high shear mixer granulation were investigated to promote the development of a continuous manufacturing process in the pharmaceutical industry. A continuous granulator with an impeller and a scraper was utilized. The tracer...
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A multivariate approach to predict the volumetric and gravimetric feeding behavior of a low feed rate feeder based on raw material properties
| Contributor(s):: Bostijn, N, Dhondt, J, Ryckaert, A, Szabo, E, Dhondt, W, Van Snick, B, Vanhoorne, V, Vervaet, C, De Beer, T
In this study, the volumetric and gravimetric feeding behavior of 15 pharmaceutical powders on a low feed rate feeder was correlated with their material properties through a multivariate approach. The powders under investigation differ substantially in terms of material properties, making the...