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6. Biocatalysis in Flow

Markus Schober

 

Senior Scientist Synthetic Biochemistry, Advanced Manufacturing Technologies, GSK

Lead for Continuous Synthesis of Chiral Amines- Transaminases in Flow Workstream (App F)

 

In App F we were investigating the application of transaminases in flow. These enzymes offer a more environmental friendly and selective way to access chiral amines which are common products in the life science industry. Our goal in AppF was to investigate if continuous processing was feasible for these enzymes, both to investigate if common issues with these enzymes, like product inhibition and unfavourable equilibrium, could be solved, as well as to reduce the manufacturing footprint by minimizing downtimes and inter-batch cleaning. Related to that we were aiming to identify suitable immobilization supports for our enzymes to increase their long-term stability and compatibility with organic solvent. Another key element of our workstream was to identify simpler and more efficient separation methods for biocatalytic processes to improve manufacturability and reduce the waste streams generated.

 

The work conducted in App F has led to several key advances in the three targeted areas. At GSK a platform for continuous enzymatic processes has been established based on a collaborative approach by several groups (synthetic biochemistry, flow chemistry, process analytical technologies, engineering). The knowledge obtained has been shared with people outside of the project and will reduce development time for upcoming biocatalytic processes in flow.  Immobilization of a transaminase currently evaluated for its use with one of AstraZeneca’s portfolio compounds has significantly improved the stability of the enzyme. The next challenge will be to improve its compatibility with organic solvents, thereby leading to increased solubility which will benefit continuous manufacturing. Johnson Matthey were able to identify suitable immobilization methods for a range of their transaminases which supports plans to launch a proprietary range of “off-the-shelf” immobilised enzymes.

 

Based on the knowledge obtained in App F, we should be aiming expand the application of continuous processes in flow to other important enzyme classes. A huge opportunity lies in the application of continuous enzymatic reactions in system biocatalysis. Since enzymatic reactions are often able to work in similar process conditions they could be coupled in a modular approach in so called enzymatic cascades, which would significantly reduce the number of synthetic steps and lead to an immense reduction of manufacturing times and costs. Building on the connections established in our current workstream we should directly couple biocatalytic up and downstream in line and aim for a more automated monitoring using advanced processes analytical technologies