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

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, Pól Macfhionnghaile, Humera Siddique, Vishal Raval, Tomás S. Harrington, Antony D. Vassileiou, Murray Robertson, Elke Prasad, Andrea JohnstonBlair Johnston, Alison Nordon, Jagjit S. Srai, Gavin Halbert, Joop H. ter Horst, Chris J. Price, Chris D. Rielly, Jan Sefcik, Alastair J. Florence

Research output: Contribution to journalArticlepeer-review

68 Citations (Scopus)
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Continuous manufacturing is widely used for the production of commodity products. Currently, it is attracting increasing interest from 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 systems-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.
Original languageEnglish
Pages (from-to)518-549
Number of pages32
JournalMolecular Systems Design & Engineering
Issue number3
Early online date20 Feb 2018
Publication statusPublished - 1 Jun 2018


  • crystallisation
  • crystallization
  • future manufacturing
  • continuous manufacturing


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