Greener, cleaner and leaner

Concern regarding the environment has never been greater and pharma and biotech must help to ameliorate the situation. This means adopting a smart manufacturing approach that minimizes chemical hazards, waste and energy. It is encouraging to see Merck & Co. setting an example — earlier this year the company was awarded an environmental 'gold star' for its efforts to reduce greenhouse gases through effective energy management. ENERGY STAR is a US Environmental Protection Agency (EPA) programme that helps business and consumers adopt energy-efficient strategies. Merck has been awarded ENERGY STAR Partner of the Year status for the second year running, becoming the first pharmaceutical company to achieve this.

Energy efficiency is only one aspect of reducing the 'footprint' of the pharmaceutical industry. The holistic approach to environmentally friendly pharmaceutical manufacture is known as 'green chemistry'; a term coined by Paul Anastas in 1991, then head of Industrial Chemistry at EPA, who worked to develop the concept with John Warner of the University of Massachusetts. Anastas describes green chemistry as: "The design of new products and processes that reduce or eliminate the use and generation of hazardous substances." It aims to go way beyond traditional methods of reducing pollution and look at the whole life cycle of the manufacturing process to ensure its sustainability.

Green chemistry involves redesigning processes so that more of the raw material ends up in the product, rather than as waste, and searching for more benign solvents — or even no solvents at all if a reaction can be done in the solid state.

"We use innovative technologies to make our processes cleaner," says Mary Buzby, director of Environmental Technology at Merck. One example, which won the company an EPA Presidential Green Chemistry Challenge Award in 2006, involved redesigning the synthesis of sitagliptin, the active ingredient in the new type 2 diabetes treatment Januvia. Sitagliptin is a chiral β-amino acid derivative. The first generation synthesis was a viable manufacturing process, but involved eight steps, including a number of aqueous workups and several high molecular weight reagents, which ended up creating waste as they were not included in the final molecule. In the second generation synthesis, Merck researchers and their collaborators discovered a new reaction — the asymmetric catalytic hydrogenation of unprotected enamines (protecting groups are to be avoided in green chemistry). The new synthesis involved only three steps; allowed 95% recycling of the rhodium-containing catalyst; increased the yield of sitagliptin by nearly 50%; and cuts waste by approximately 200 kilograms for each kilogram of product. Over the lifetime of Januvia, at least 150 million kilograms of waste (including nearly 50 million kilograms of aqueous waste) will be eliminated. Furthermore, this new reaction is applicable to other pharmaceutical syntheses.

Catalysis was key to the redesign of this product synthesis. Using catalysts, rather than stoichiometric reagents, is preferred in green chemistry because the former are used in tiny amounts and may be recycled, while the latter merely create more waste. Enzyme catalysts are even better, as they can be used at low temperatures, saving energy and are purely biological (no heavy metals to worry about). This is where biotech companies such as Denmark's Novozymes are important. Recently voted one of the world's top 100 sustainable companies for its all-round performance, Novozymes also won a Presidential Green Chemistry Challenge Award for using its proprietary enzyme Lipozyme as an alternative to conventional hydrogenation in margarine production creating a healthier product (without trans-fats) in a cleaner process. California-based biotech Codexis uses directed evolution technology to develop highly specific enzymes. Three of these were used in a redesigned synthesis that vastly improved the manufacture of the key building block of the cholesterol-lowering drug Lipitor. This development, which also gained a Presidential Challenge Award, dramatically increases productivity and reduces waste, solvents and byproducts.

Enzyme companies could also help push forward another green chemistry principle of using renewable feedstocks, such as biomass or waste from other processes, rather than fossil fuels. Natural or engineered enzymes can break down the long polymer chains of starch or cellulose to simpler molecules such as ethanol.

Meanwhile, the pharmaceutical industry has begun to work together to implement green chemistry and sustainable solutions on a global basis. The Pharmaceutical Round Table of the American Chemical Society's Green Chemistry Institute brings many of the big pharmas together including Merck, AstraZeneca, Lilly, GSK and Pfizer. They have listed chemical reactions commonly used in manufacturing drugs, which are associated with either safety or waste hazard concerns, and aim to replace these with greener alternatives.

Solvents continue to be a major challenge; for example, there is a general wish to eliminate chlorinated solvents. "Merck has made tremendous strides in eliminating methylene chloride from our manufacturing processes," says John Leazer, research fellow in process research. "We are currently evaluating the potential of eliminating other nongreen solvents from our processes." Solvents are also used in the many chromatographic separations performed in drug manufacture. "We have actively pursued the use of supercritical fluid chromatography (SFC) where inexpensive and safe carbon dioxide replaces toxic, flammable and expensive hydrocarbons often used in conventional high performance liquid chromatography," adds Dr Leazer. "SFC technology can reduce solvent usage by as much as 95% and has the additional benefit of reducing organic waste and energy usage. Merck pioneered the use of kilogram-scale preparative SFC in the pharmaceutical industry and now routinely uses this approach in the development of new drug candidates."

It may seem that biotech manufacture is greener and cleaner from the solvent perspective, as most operations are performed in aqueous solution. But water is not exempt from the green chemistry agenda — it is an increasingly scarce global resource. Therefore, the Pharmaceutical Roundtable intends to next look at the environmental challenges of biotech, as well as small molecule manufacturing.