‘Use of enzymes in API manufacture produces a diverse range of cost savings’

How does biocatalysis work?

Rose Lance

Biocatalysis involves the implementation of natural catalysts, such as enzymes, in place of chemical catalysts in synthetic processes. This change can enable new, more sustainable routes for the production of intermediates and APIs. One of the biggest advantages of enzymes in organic synthesis is their remarkable selective properties, which gives a number of commercial benefits including better production of single stereoisomers, fewer side reactions, less reprocessing or purification steps, easier product separation and less pollution. The combination of all of these means lower costs. Biocatalysis has become an increasingly important tool for medicinal chemists, process chemists and polymer chemists, allowing the development of efficient and highly attractive organic synthetic processes on an industrial scale.

In what way does it reduce the cost of API manufacturing?

Changes in manufacturing procedures are a major contributor in improving operating margins. By pursuing a new manufacturing process, the original innovator of a pharmaceutical can compete with generic manufacturers using a different, more effective manufacturing process. Traditionally, production cost reductions have taken place in the later stages of clinical development, as innovators have been reluctant to make process changes after a product has been launched. However, pressures reduce costs have increased alongside regulatory demands and generic competition. As a result, innovators have increasingly been pursuing cost reductions earlier in product development.

Biocatalysis is one recognised technique that can be employed to reduce costs, providing a sustainable process and improving the quality of the API. By pursuing this type of manufacture earlier, the pharma innovator can protect themselves much better against future generic manufacturers and remain aligned to the latest regulatory demands.

The use of enzymes in the manufacture of APIs produces a diverse range of cost savings, particularly in terms of reductions in raw material inputs and overhead costs of equipment, labour, and energy usage by approximately 10-15 per cent. Costs of manufacture are reduced through various channels using this enzymatic method. Biocatalysis provides an opportunity for formulators and manufacturers to use enzymes to efficiently resolve an existing racemic mixture, creating new chiral centres or delivering a chirally pure compound through asymmetric reactions. This improves the production of single stereoisomers, creates fewer side reactions, allows easier separation of products, and reduces waste. Due to the efficiency of the technique, the total cost of implementing biocatalysis in drug manufacture is relatively low.

To use an example, the synthesis of the molecule, Duloxetine, through biocatalysis is vastly more cost-efficient due to the reduction in raw material input and raw material consumption. Raw materials no longer required include isopropyl alcohol, L-mandelic Acid, acetyl thiophene, formaldehyde, phenyl chloroformate/ ethylchloroformate, diisopropylethylamine and 2-Methoxy-2-methylpropane (MTBE). Therefore, the amount of components needed to be purchased and included into the formulation is reduced by as much as 10 – 15 per cent. There is also a notable reduction in overhead costs due to less process steps being involved – equipment costs, labour costs, and energy savings can be reduced by up to 15 per cent. The streamlined process, which has been dropped from nine steps to five or six, results in higher throughput and financial savings, with more batches being produced in the same timeframe. Combined, these factors have a positive effect on the cost of manufacture.

Besides application in the API industry, which are the other areas of pharma industry where biocatalysis is used?

Aside from its application in API production, biocatalysis has uses in several fields including specialty and fine chemicals. Other important uses of biocatalysis occur in the energy, polymer, agriculture and cosmetics industries.

Who are your clients in India? What has their response been?

Novozymes are currently working with many of the large innovator and generic manufacturers based in India; however the details surrounding these agreements are currently confidential.

Indian API industry hopes to become the top most producer of API in the world. Will biocatalysis be successful in fulfilling this dream?

As generics are set to be adopted in almost all major markets around the world in the next three to five years as countries try to reduce healthcare costs, India is an important market for biocatalysis in both the generic and intermediate markets. Factors, such as an increase in patent expiries of blockbuster drugs, an increased focus on generics adoption globally and the constant demand for reductions in manufacturing costs, are the driving forces for not only shaping the global API industry, but are behind the resurgences of Indian API companies in the global market. India has emerged as one of the most-favoured API producing nations, with one reason being its cost competitiveness in comparison with its foreign counterparts. With the prices of China-made APIs rising (metformin prices have doubled in the last 1-2 years), incorporating biocatalysis within the API manufacturing process can aid Indian manufacturers increase global market share by reducing costs further through raw material input and RMC and overhead cost reductions. API/Intermediate quality will also be improved by reducing intermediate use, and thus less carry over to final API, a reduction in chiral impurity carry over and less residual solvent carry over due to reduced solvent use.

What strategies have you planned for the Indian market in the next three years?

We have plans to roll out our enzyme offerings (lipases and proteases) to the market while working with the companies to help deliver the products and services they require to develop biocatalytic pathways. Novozymes is well known in various other industries and we want the Indian pharma market to learn about us and work with us.

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