Some companies have already made a large step in reducing their carbon footprints and environmental impact by drastically altering production processes. The product portfolio of our business group in DSM consists mainly of semisynthetic penicillins (SSPs) and semisynthetic cephalosporins (SSCs). The production processes of these wellestablished APIs of the betalactam type traditionally starts with an already green process step: fermentation of a microorganism yielding an aqueous slurry containing both the producing biomass, byproducts and the required precursor for the product. The precursor must then be obtained in a purified form from this broth. This is generally where the non-green processing begins. Isolating a pure product requires the use of many chemicals, such as several types of organic solvents. Furthermore, for converting the precursor antibiotic into the various APIs, a range of other chemicals is required.

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The move towards greener processes for the production of the beta-lactam precursor products, as well as for the conversion of these into the final SSPs and SSCs, is based on using enzymes as biocatalysts. Being compounds of biological origin, enzymes require an aqueous environment to perform their catalytic action. Therefore, solvents are no longer used in this part of the process, which considerably reduces the ecological footprint of the production process.

In 2000, enzymatically produced SSCs were introduced onto the market, followed in 2002 by SSPs produced via similar enzymatic routes. The change to industrial scale enzymatic manufacturing processes was accomplished after several years of intensive R&D. This resulted in significantly higher purity and stability, the absence of residual solvents and improved physical characteristics of the products.¹ The absence of solvents and many chemicals from the chemical production processes also results in products with a noticeably better smell and taste.

Since the enzymatic product is more pure, the crystal size increases somewhat (while crystal form and habit remained the same) and a significant improvement in flow ability is observed; for example, the compressibility index as a measure for flow ability improved from approximately 45% to 33%.¹ Improved flow characteristics were also found in the compacted grades produced for capsulating and tabletting. Additionally, less dust formation reduced the risks of sensitization for workers handling the products. The benefits are, thus, not only for the environment, but for API and final dosage form (FD) manufacturers and, ultimately, for patients. Testing of these green APIs by FD manufacturers led mostly to enthusiastic reactions. At first, it seemed that all hurdles towards a better production method, as well as a better product, had been overcome, but the biggest obstacle still remained.