Reducing energy consumption and carbon footprint are major focus areas for the pharmaceutical industry. Many articles are
being published describing the need for and advantages of sustainable processing. However, achieving this is not as simple
as reducing the amount of business travel, using energy-saving light bulbs or even bringing renewable energy sources into
the business. More drastic measures must be taken to make a business sustainable.
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 use of many different chemicals has a negative effect on the environment; for example, the use of volatile organic substances
often leads to emissions, and energy consuming solvent production and recovery processes. Moreover, the use of a lot of chemicals
in the production process also has implications for the impurity profiles of the antibiotic products themselves.
Since SSPs and SSCs have been well established in the market for many years, the current safe impurity profiles of these products
are increasingly covered by the monographs in the different pharmacopeias. It is well known in the business that chlorinated
solvents are not healthy. In general, it is now recognized that omitting the use of such substances would be better for human
health. 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.
