In his presentation at the “Mastering Process Chemistry” conference, sponsored by Cambridge Healthtech, John Warner, president and CTO of the recently formed Warner Babcock Institute for Green Chemistry, pointed to the oft-quoted E-factor or environmental factor.
This represents the mass efficiency of a process or mass waste/unit of a product, to demonstrate the huge potential for applying waste-prevention strategies to improve the cost-effectiveness of manufacturing. In pharmaceuticals production, it is not uncommon for the E-factor to be in excess of 100 g of waste for each 1 g of drug produced.
According to Warner, a key challenge in changing this dynamic relates back to the basic training of the organic chemists who are designing the reaction routes. Chemistry degree programs do not typically include courses in toxicology, notes Warner, so it tends not to be part of the thinking in the initial design stage of a process.
The emphasis in industry has been on designing the most efficient and rapid synthesis route. As the environmental impact and costs associated with disposing of toxic solvents and waste products have come to the forefront, greater emphasis is being given to reducing waste streams and minimizing energy input. In fact, Warner contends, more practical innovations in green chemistry are coming from industry than from academia.
Not only are green principles and practices becoming more mainstream in process chemistry, but they are also at the forefront of a movement to make environmental impact a priority upfront in the design of R&D and manufacturing processes.
Although, Process Analytical Technology (PAT) initiatives, Lean Six Sigma strategies, and Design of Experiments (DoE) are contributing to the adoption of engineering by design and improved operational efficiency, the potential to reap maximal rewards from the introduction of green chemistry requires that the constructs be an integral consideration and component in the initial design of complex synthetic processes.
While substitution of a safer solvent or use of a biocatalyst to drive a reaction to completion more efficiently is a useful strategy, a top-down design-based approach that incorporates green chemistry and engineering concepts and techniques throughout a process would have a greater impact on these complex, multi-step synthetic processes.
At the EPA Region 2 workshop in September 2007, “Seize the Moment: Opportunities for Green Chemistry and Green Engineering in the Pharmaceutical Industry,” David Constable, Ph.D. director, EHS product stewardship, corporate environment, health and safety, at GlaxoSmithKline, noted that the complexity inherent in pharmaceutical manufacturing related to the chemical syntheses, including the variety of structures produced and the regulatory issues, is a barrier to implementing change.
Constable highlighted two key tools used at GSK for assessing the greenness of chemistry, a solvent selection guide and a fast life-cycle assessment tool. Solvents represent one of the largest cost components in chemical synthetic processes when one combines the cost solvents with the disposal of mixed aqueous/solvent wastes. They account for 75–80% of the environmental impact and energy use in the life cycle of a pharmaceutical compound.
GSK’s solvent profile has improved over the past five years, according to Dr. Constable, with an overall reduction in chlorinated solvents, a 50% (kg/kg API) decrease in dichloromethane use in final processing (with methyl isobutyl ketone and ethyl acetate used as replacements), and a decline in dimethylformamide (DMF) of 95%. “We are working to influence our chemists, and they are doing a great job to try to green their syntheses,” he says.
Sharon Austin, of the EPA’s Chemical Engineering Branch, Office of Pollution Prevention and Toxics (OPPT), outlined some of the progress that has been made in reducing the industry’s environmental footprint through solvent substitution, by reducing the use of chemicals such as tetrahydrofuran, toluene, and dichloromethane, which significantly decrease the amount of toxins released into the air and water. She also reported on current Congressional activity to promote green chemistry, including a proposed bill that would provide funding for the National Academy of Sciences to investigate barriers to green chemistry R&D.
Economic incentives are the main driver of green chemistry implementation in the view of Neal Anderson, Ph.D., of Anderson’s Process Solutions. “Environmentally conscientious chemistry is profitable,” he notes.
Dr. Anderson describes three key factors to consider when designing the greenest synthesis route possible: early waste prevention (rather than managing waste at the end of the pipeline); judicious selection of starting materials; and the choice of a manufacturing process with high atom economy.
“We are seeing a switch from traditional yield calculations to an emphasis on atom economy,” concurs Tracy Williamson, chief of the industrial chemistry branch of the EPA’s OPPT. Atom economy is defined by the amount of material put into a process that ends up in the product. If, for example, a reagent contributes only a single atom to a product, the rest of the reagent would be waste, and the larger the reagent, the more waste produced.
Oxidation/reduction reactions are among the least green, atom-economical reactions. One way to improve the atom economy and reduce the environmental impact of an oxidation is to use a chromium catalyst to minimize the amount of toxic chromium needed. It would be even better to choose an oxidant that does not rely on chromium. The greenest solution, according to Anderson, “would be to select a starting material, perhaps one derived from fermentation, that is already at the correct oxidation state.”
“Green chemistry and green engineering need to work hand-in-hand at the design stage,” says Williamson. “The best green chemistry might not be feasible at commercial scale,” and that needs to be considered upfront.
It is especially important for pharmaceutical companies to explore alternative processes early on, because once a drug and its associated manufacturing process receives FDA approval, it may be cost prohibitive to make changes and risk having to repeat the regulatory review process.
Advances in Biocatalysis
Green chemistry incorporates concepts such as atom economy, convergency (higher process efficiency with fewer operations), reagent optimization (use of catalysis and more selective and recyclable reagents), and raw material efficiency.
In 2006, BioVerdant won the IChemE award in green chemistry and engineering for achieving substantial decreases in solvent and raw materials use and waste by replacing chemical transformation steps with biocatalytic alternatives.
Alex Tao, Ph.D., the company’s CSO, attributes advances in the discovery and characterization of novel biocatalytic enzymes in large part to the 100-fold decrease in the cost of genome sequencing—from about $1.00/base to $0.01/base in recent years—which has enabled the rapid and cost-effective generation and analysis of enzyme libraries.
“The emphasis in biochemical transformations is shifting from how it can be done most efficiently in the laboratory, to how does nature breakdown biomass and convert it into useful molecules using available chemical building blocks,” says Dr. Tao. Instead of trying to change individual chemical transformation steps that may be problematic, BioVerdant’s strategy involves modifying the entire synthetic route by generating new intermediates and reducing the number of reaction steps, while minimizing energy input and waste. In some processes, biocatalysts can be used to recycle an undesirable enantiomer and increase product yield. BioVerdant’s enzyme libraries include nitril hydratases, ketoreductases, oxynitrilases, aldolases, nitrilases, and epoxide hydrolases.
Codexis evolves enzymes for use as biocatalysts. “We design the enzyme so it is optimally functional in the conditions in a chemical reactor and ideally able to function in unnaturally harsh conditions,” says Christopher Davis, director of analytical biochemistry. Directed enzyme evolution done in the laboratory involves applying selective pressures to breed a new generation of enzymes with a targeted, optimized function.
An advantage of these biocatalysts and of green chemistry in general, is the ability to manufacture a product in more generic facilities, compared to the demands of traditional chemocatalysis, which typically requires high pressure and high or low temperature reactors.
Davis describes another green chemistry strategy called telescoping, which aims to minimize the carryover of impurities from one process step to the next. The ability to make a product or an intermediate without any side products eliminates purification steps, saving time, energy, cost, and waste.
Interest in biocatalysis is high in the generics industry, in particular, notes Dr. Tao, as generics manufacturers are actively seeking strategies to lower manufacturing costs and increase profit margins. He predicts that biocatalysis technology will improve incrementally, with advances in proteomics enabling molecular evolution to be more directed and structure-based and less dependent on random mutagenesis.
Another trend in green chemistry, Dr. Anderson notes, is the move away from extraction of pharmaceuticals and toward isolation of the product directly from the process stream, typically by crystallization followed by filtration. Compared to preparative chromatography, direct isolation might have a lower yield, but it offers the advantages of decreased cycle times and labor costs, less waste, and fewer steps so there are fewer opportunities for contamination or product loss.
“If you look at all the synthetic transformations, all the ways of making and purifying molecules, and you superimpose that on top of environmental regulations, potential hazards, and toxicities, and questions about biorenewability and persistence in the environment, I figure that more than 90% of what we do has a problem,” adds Warner.
These same issues affecting pharma also apply to the biotech industry. Furthermore, the production of biologicals from microbial, plant, or cellular feedstocks introduces the additional challenge of complex separations and purification processes. “The challenge is to be able to take a more diverse set of feedstocks and be able to manipulate and manage them efficiently, to separate biofeedstocks in a reactor and create product streams,” Warner says.
Germany-based greenovation Biotech is one example of a company developing technology to facilitate the production of therapeutic proteins from biofeedstocks. greenovation recently inked a joint process development agreement with Sartorius Stedim Biotech aimed at producing a GMP-compliant photo-bioreactor for process-scale applications of greenovation’s plant-based bryotechnology.
The biopharmaceutical industry can apply the knowledge it has gained on genetic engineering and bioprocessing to help hasten the switch from petroleum-based feedstocks to renewable feedstocks. Genetic technologies are, in general, not yet sufficiently optimized to make them an attractive alternative to chemical transformations, according to Dr. Constable.
“A culture change takes a long time,” he says. “We are making small, measurable gains.” Dr. Constable is confident that the industry will continue to realize incremental gains in the future. “Assessment of greenness must be a multivariate exercise,” and for improvement to continue it will be important to put the right green assessment tools into the hands of the chemists so they become routine.