421537 Continuous Solid-Liquid Separation in Pharmaceutical Manufacturing

Monday, November 9, 2015: 1:19 PM
Ballroom B (Salt Palace Convention Center)
Johannes S. Gursch1, Roland Hohl1, Diana Dujmovic1, Stephan Laske1, Joerg Brozio2, Markus Krumme2, Norbert Rasenack2 and Johannes G. Khinast3, (1)Research Center Pharmaceutical Engineering GmbH, Graz, Austria, (2)Novartis Pharma AG, Basel, Switzerland, (3)Institute of Process and Particle Engineering, Graz University of Technology, Graz, Austria

Continuous manufacturing processes offer many advantages for pharmaceutical production. Yet, continuous production is only slowly being adopted in the industry, main issue being a lack of ready-to-use continuous manufacturing equipment and missing process knowledge. In contrast to classical chemical production, small scale equipment would often be required for production of modern low-volume-high-value patient centred medication. In upstream production large efforts are already undertaken to close the existing technology gap [1]–[3]. Also, in secondary manufacturing many groups have formed, working on topics such as continuous wet granulation, -blending, -direct compaction or -thermal drying.[4], [5] However, at the interface between primary and secondary manufacturing, solid-liquid removal is a crucial step during pharmaceutical production.[6], [7] Nevertheless, little work has been reported regarding the development of continuous equipment for solid-liquid separation of pharmaceutical products, particularly to allow treatment of small process streams.

Commercially available continuous equipment for filtration and thermal drying was selected and thoroughly analyzed. Representative model APIs were chosen to evaluate the equipments aptitude to handle small process streams in a continuous pharmaceutical manufacturing environment.

The equipment's suitability for pharmaceutical production could be proven. Operation strategies for further enhancement of filtration performance were developed and successfully implemented. The achieved increase of permeate rates significantly sustains economic efficiency of the developed cross-flow filtration setup.  To allow solvent removal below regulatory limits a spin-flash dryer was used, enabling treatment of highly viscous slurries under extremely robust process conditions within a given design space.



[1]         H. Zhang, R. Lakerveld, P. L. Heider, M. Tao, M. Su, C. J. Testa, A. N. Dantonio, P. I. Barton, R. D. Braatz, B. L. Trout, A. S. Myerson, K. F. Jensen, and J. M. B. Evans, “Application of continuous crystallization in an integrated continuous pharmaceutical pilot plant,” Cryst. Growth Des., vol. 14, pp. 2148–2157, 2014.

[2]         M. O. Besenhard, A. Thurnberger, R. Hohl, E. Faulhammer, J. Rattenberger, and J. G. Khinast, “Continuous API-crystal coating via coacervation in a tubular reactor.,” Int. J. Pharm., vol. 475, no. 1–2, pp. 198–207, Nov. 2014.

[3]         M. Sen, A. Rogers, R. Singh, A. Chaudhury, J. John, M. G. Ierapetritou, and R. Ramachandran, “Flowsheet optimization of an integrated continuous purification-processing pharmaceutical manufacturing operation,” Chem. Eng. Sci., vol. 102, pp. 56–66, Oct. 2013.

[4]         J. Vercruysse, U. Delaet, I. Van Assche, P. Cappuyns, F. Arata, G. Caporicci, T. De Beer, J. P. Remon, and C. Vervaet, “Stability and repeatability of a continuous twin screw granulation and drying system.,” Eur. J. Pharm. Biopharm., vol. 85, no. 3 Pt B, pp. 1031–8, Nov. 2013.

[5]         R. Singh, M. Ierapetritou, and R. Ramachandran, “An engineering study on the enhanced control and operation of continuous manufacturing of pharmaceutical tablets via roller compaction.,” Int. J. Pharm., vol. 438, no. 1–2, pp. 307–26, Nov. 2012.

[6]         H. Zimmer and M. Drudel, “Optimized drying. Thermal processes. Mass spectrometric online gas analysis for improved process understanding, simplified maintenance, and shorter drying time,” CIT Plus, vol. 10, no. 10, pp. 92–93, 2007.

[7]         J. Burgbacher and J. Wiss, “Industrial Applications of Online Monitoring of Drying Processes of Drug Substances Using NIR,” Org. Process Res. Dev., vol. 12, no. 2, pp. 235–242, Feb. 2008.



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