Fermentation and Enzymatic Chemistry
The production of high value APIs via fermentation is one of our core competencies. With roots back in the 1970s, when the processes for the production of Ergot alkoloids were introduced at a commercial scale at our Rozzano site, we are now one of the leading producers of many complex APIs using fermentation and subsequent chemical transformation of fermentation products. In addition to the Lysergic acid derivatives, we introduced immunosuppressants as a new class of fermentation products in the 1990s. Starting with Cyclosporine and Micophenolic acid, our portfolio has been constantly enlarged and now includes very complex and sensitive products like the mTOR inhibitor, Sirolimus, and the structurally related macrolide lactone, Tacrolimus. All our immunosuppresants are offered at commercial scale and further products are under development. This requires expertise in the fermentation process, and also very solid skills in the sophisticated isolation and purification techniques which are needed to provide our customers with high quality materials. The equipment available for biomass separation includes centrifuges and filter presses, purification is performed via liquid/liquid extraction and chromatography.
Biocatalysis: biology serving the commercialization process
Biotransformation, as a synthesis tool, is a key element in our technology portfolio, and assists in our ability to provide rapid, cost effective manufacture of high-purity pharmaceutical intermediates at a commercial scale. Enzyme-catalysed reactions use the selectivity provided by nature to provide efficient reactions under conditions that are ideally suited for the successful commercialization of APIs. We offer a comprehensive biocatalysis capability, including rapid biocatalytic screening and evaluation, process development and optimization, at both pilot and commercial scale manufacture.
Research and process development
We maintain a strong multidisciplinary approach to biotransformation, employing scientists well versed in both biocatalysis and organic synthesis. This position allows us to select chemical or enzymatic catalysis as is best suited to the needs of the project. Biotransformation finds its primary applications in routes where selective activity is required, including enantioselective, regioselective and chemoselective reactions. Close interaction with specialist enzyme companies provides us with libraries of enzymes known to be effective in a wide range of conversions and available at large scale. A targeted approach based on our expertise allows us to quickly determine the potential advantages of a particular biocatalytic process and to evaluate its competitiveness against alternative synthetic approaches. We have an active program to develop new enzymatic routes to solve specific synthesis challenges, and we manage the optimization of enzyme activity to ensure innovative solutions when required by a project.
Pilot and commercial scale manufacture
Using commercially available enzymes allows us to begin manufacturing products within exceptionally short lead times. We are renowned for rapid, high quality manufacture of complex materials. We have the technical experience and know-how to efficiently scale-up processes for commercial needs. Added to this capability, we have worldclass expertise in multi-step synthesis, which allows us to integrate biotransformation steps into both upstream and downstream reactions as part of a successful commercial scale-up.
The use of biotransformations to carry out chiral resolutions is now well established as an efficient and scaleable methodology for separation of a single enantiomer from racemic mixtures. We have substantial expertise in resolutions of racemic mixtures of esters, acids, alcohols, amino acids and amines using biocatalysis. Additionally, we have experience with lactone and dioxolactone resolutions and separation of isomeric mixtures of various compounds using biocatalysis. We typically use hydrolase enzymes in both hydrolytic and synthetic directions to provide the required enantiomer in a way that is optimal for the specific process. Our strength in this area relies our ability to rapidly integrate a biotransformation step into a chemical synthesis and to scale-up such processes quickly to produce multiple kilograms. We are then able to transfer such technologies seemlessly into our multi-tonne production facilities.
Products in our portfolio accessible via biocatalysis in enatiopure form
- Cis-4-Acetoxy-2-cyclopenten-1-ol via lipase technology
- Chiral alcohols via ADH technology
- Single enantiomer amines via transaminase technology
- Chiral epoxides via ADH technology
- Chiral acids and alcohols via lipase technology
- Mandelic acid derivatives and other chiral alpha-Hydroxycarboxylic acids via oxynitrilase technology