This article is part of PharmTech's supplement "API Synthesis and Formulation 2009."
Applications of BiocatalysisBy Hans Kierkels, senior scientist, and Oliver May, corporate scientist of biocatalysis, DSM Pharmaceutical Products
A special challenge in manufacturing pharmaceuticals is the increasing complexity that requires many steps in the synthesis of a given molecule. On average, eight steps are required for the synthesis of an API, according to a recent analysis (1). The dynamics of drug development are challenging as well. The high attrition rate of drug candidates usually does not justify extensive route scouting and process development in early-development phases. In these phases, the focus is on speed of delivery rather than on manufacturing cost-efficiencies. This limited focus often leads to suboptimal routes and poorly developed processes for manufacturing clinical trial material.
A changing toolbox
The mindset of scientists involved in route scouting and process research and development is changing slowly, and only a few pharmaceutical companies have captured those developments. Flexible and open partnering approaches with enzyme-service providers and contract manufacturers that provide access to a broad enzyme toolbox and offer interdisciplinary route-scouting expertise are just emerging. The main impact of biocatalysis is still in developing second-generation processes for late clinical phase or launched APIs. Two recently introduced processes highlight the benefit of biocatalysis.
A biocatalytic route to aliskiren
An excellent example of a successful process substitution was recently reported for producing an intermediate used in the synthesis of aliskiren, a renin inhibitor used to treat hypertension. A key step in the synthesis of aliskiren is an enzymatic resolution catalyzed by pig-liver esterase (PLE). PLE is a versatile biocatalyst for organic chemists because it has a broad substrate spectrum and excellent enantio- and regio-selectivity.
The commercially available PLE is animal derived. Its quality can vary significantly from batch to batch, and it is therefore not safe or suitable for pharmaceutical applications. To address this problem, DSM and its collaboration partner, the Graz University of Technology in Austria, identified different isoforms of PLE. Using capabilities in enzyme development and production, a highly efficient and patented microbial expression system and fermentation process was developed for different isoforms of PLE that runs at a 25,000-L scale at DSM (5). This system delivers nonanimal-derived PLE isoforms (PharmaPLEs, DSM) at a large scale for pharmaceutical applications.
The PharmaPLE-based production process replaced an established chemical process. The overall productivity of the process increased more than 50%. Waste production was significantly reduced by avoiding the double-resolution steps in the first-generation chemical process, which generated a large amount of organic and inorganic waste. A life-cycle analysis showed a 50% reduction of greenhouse gas emission for the enzymatic process.