Interested in linking to "Green Processing"?
You may use the Headline, Deck, Byline and URL of this article on your Web site. To link to this article, select and copy the HTML code below and paste it on your own Web site.
By Angelo De Palma, Ph.D., Contributing Editor
After a long struggle, chemical manufacturers have recognized the economic value of green chemistry. Now, pharmaceutical manufacturers are following their lead, guided by the U.S. Environmental Protection Agency’s principles of green chemistry (see Principles of Green Chemistry below). In the process, they’re achieving significant efficiencies.
For example, consider process analytical technologies (PAT). While those who use PAT understand the efficiency benefits it offers, they may not realize that it also offers environmental benefits. “Process analytical technologies impact most, if not all, green chemistry principles,” says Julie B. Manley, senior industrial coordinator at the American Chemical Society’s Green Chemistry Institute (Washington, D.C.).
“PAT is about timely measurements with the goal of understanding and controlling pharmaceutical processes,” she says. “The better you understand your process, the better you can address green processing issues.” For example, using PAT for drying operations can reduce energy consumption by 80% while eliminating the lion’s share of off-spec product (itself considered chemical waste) and its attendant solvent and reagent waste.
At this point, most green pharma implementations are done after a drug has been approved. This parallels the way that traditional process analytics tests product after it has been produced, instead of during production. PAT not only offers manufacturers a way to “quality by design,” but a route for “green by design,” Manley says.
Pfizer’s green chemistry program began with improvements to the process used to make its blockbuster antidepressant Zoloft (see Taking the Green Chemistry Challenge below), but the changes were substantial enough to require resubmission of the Zoloft CMC. “Pharmaceutical companies hate refiling,” says Buzz Cue, Ph.D., a consultant who helped Pfizer go green. The company recognized the economic advantages, however, and soon began investigating green processing for all its manufacturing. An effort that began at Groton, Conn., soon spread to Pfizer’s Michigan and San Diego facilities.
Solvent reduction is the sweet spot for greening any pharmaceutical process, says Cue. About 80% of pharmaceutical waste results from solvent use, with the remainder related to reagents and raw materials. Solvent recycling is a step in the right direction, but recovery is costly and inefficient. When redistillation is the only option, PAT can help optimize that operation.
Adopting nontoxic solvents is not always possible, but works far more often than one might think. Relatively benign solvents derived from renewable sources, such as ethyl acetate and 2-methyl THF, are now making inroads into pharmaceutical processing, “and they’re every bit as good as methylene chloride,” Cue says.
Cue also likes what he calls “embryonic” processing such as flow or continuous reactors to cut down on reaction time and energy and solvent usage. “Pharmaceuticals are very much still a batch industry, with everything done in the equivalent of giant round-bottom flasks,” he notes. “Continuous processing eases scaleup, leading to lower solvent usage and robust, rugged processes, which FDA likes very much.”
Enzymes are the ultimate green processing agents: catalytic, specific and environmentally benign. The food, cleaning products and personal care industries use hundreds of tons of dirt-cheap enzymes, both as ingredients and as process reagents. High-fructose corn syrup, the world’s largest-volume sweetener, is produced using an amylase (sugar-processing) enzyme that costs pennies per gram.
For a host of reasons, pharmaceutical processors have been reluctant to adopt enzyme-based processes. Organic chemists, for example, avoid water-based reactions like vampires shun mirrors. More importantly, aqueous operations steps are starkly discontinuous within an otherwise traditional chemical-pharmaceutical process. To make an enzyme step work, chemists must isolate the intermediate at some reasonable level of purity from the organic reaction pot, transfer it to aqueous media, reisolate it and send it back upstairs to the organic reactor.
|Nelo Rivera, Karl Hansen and Yi Hsiao (left to right) were part of a team of scientists from Merck's facility in Rahway, N.J., who were recognized by the Institution of Chemical Engineers for their waste reduction efforts in 2005. Photo courtesy of Craig Hammell.
Lipases are the most popular enzymes in pharmaceutical manufacturing, used mostly for resolving racemic acids by condensation with alcohol to form esters, or through the reverse reaction. Processors are not thrilled about enzymatic resolutions where half the product is discarded. Still, with most drugs investigated, if not developed, in enantiomerically pure form, lipase resolutions are here to stay. An even greener approach — especially for companies already considering a lipase step — is to introduce chirality through enzymes at a different point in the synthesis.
Enzymes are top performers for introducing chirality through reductions of prochiral ketones, aldehydes, imines and other unsaturated functional groups. Interested manufacturers can tap into expertise at enzyme specialty companies such as Novozymes (Franklinton, N.C.) and Dyadic (Jupiter, Fla.). Neither company has much pharmaceutical industry experience, but both are nevertheless interested in demonstrating how enzymes can “green” chemical-pharmaceutical manufacturing.
PharmaManufacturing.com is the site for knowledge, news and analysis for manufacturing and other professionals working in the pharmaceutical, biopharmaceutical and biotech industries.