(119c) Continuous Solid-Liquid Separation in Pharmaceutical Manufacturing

Authors: 
Gursch, J. S., Research Center Pharmaceutical Engineering GmbH
Hohl, R., Research Center Pharmaceutical Engineering GmbH
Dujmovic, D., Research Center Pharmaceutical Engineering GmbH
Brozio, J., Novartis Pharma AG
Krumme, M., Novartis Pharma AG
Rasenack, N., Novartis Pharma AG / Global Development
Khinast, J. G., Graz University of Technology

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.

 

References:

[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.