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Enabling precision manufacturing of active pharmaceutical ingredients: workflow for seeded cooling continuous crystallisations

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posted on 2018-08-01, 11:06 authored by Cameron J. Brown, Thomas McGlone, Stephanie Yerdelen, Vijay Srirambhatla, Fraser Mabbott, Rajesh Gurung, Maria L. Briuglia, Bilal Ahmed, Hector Polyzois, John McGinty, Francesca Perciballi, Dimitris Fysikopoulos, Pol MacFhionnghaile, Humera Siddique, Vishal Raval, Tomas S. Harrington, Antony D. Vassileiou, Murray Robertson, Elke Prasad, Andrea Johnston, Blair Johnston, Alison Nordon, Jagjit S. Srai, Gavin Halbert, Joop H. Ter Horst, Chris J. Price, Chris RiellyChris Rielly, Jan Sefcik, Alastair J. Florence
Continuous manufacturing is widely used for the production of commodity products. Currently, it is attracting increasing interest from the pharmaceutical industry and regulatory agencies as a means to provide a consistent supply of medicines. Crystallisation is a key operation in the isolation of the majority of pharmaceuticals and has been demonstrated in a continuous manner on a number of compounds using a range of processing technologies and scales. Whilst basic design principles for crystallisations and continuous processes are known, applying these in the context of rapid pharmaceutical process development with the associated constraints of speed to market and limited material availability is challenging. A systematic approach for continuous crystallisation process design is required to avoid the risk that decisions made on one aspect of the process conspire to make a later development step or steps, either for crystallisation or another unit operation, more difficult. In response to this industry challenge, an innovative system-wide approach to decision making has been developed to support rapid, systematic, and efficient continuous seeded cooling crystallisation process design. For continuous crystallisation, the goal is to develop and operate a robust, consistent process with tight control of particle attributes. Here, an innovative system-based workflow is presented that addresses this challenge. The aim, methodology, key decisions and output at each at stage are defined and a case study is presented demonstrating the successful application of the workflow for the rapid design of processes to produce kilo quantities of product with distinct, specified attributes suited to the pharmaceutical development environment. This work concludes with a vision for future applications of workflows in continuous manufacturing development to achieve rapid performance based design of pharmaceuticals.


The authors would like to thank EPSRC, Centre for Innovative Manufacturing in Continuous Manufacturing and Crystallisation (Grant Ref EP/I033459/1) and Computationally Designed Templates for Exquisite Control of Polymorphic Form (Grant Ref EP/K039229/1) for funding this work. The authors would like to acknowledge that this work was carried out in the CMAC National Facility supported by UKRPIF (UK Research Partnership Fund) award from the Higher Education Funding Council for England (HEFCE) (Grant Ref HH13054).



  • Aeronautical, Automotive, Chemical and Materials Engineering


  • Chemical Engineering

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Molecular Systems Design and Engineering






518 - 549


BROWN, C.J. ... et al, 2018. Enabling precision manufacturing of active pharmaceutical ingredients: workflow for seeded cooling continuous crystallisations. Molecular Systems Design and Engineering, 3 (3), pp.518-549.


© The Royal Society of Chemistry


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This work is made available according to the conditions of the Creative Commons Attribution 3.0 Unported (CC BY 3.0) licence. Full details of this licence are available at: http://creativecommons.org/licenses/by/3.0/

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This is an Open Access Article. It is published by the Royal Society of Chemistry under the Creative Commons Attribution 3.0 Unported Licence (CC BY). Full details of this licence are available at: http://creativecommons.org/licenses/by/3.0/




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