Industry Takes Steps Toward Greener API Manufacturing

Making active pharmaceutical ingredients (APIs) requires long chains of chemical reactions and large quantities of solvents. Ask API manufacturers how they'd like to improve this process, and the responses are likely to be "make the reactions faster," "make the reactions cheaper," or "make the reactions more efficient." Then after all these economically driven answers, you might here, "make the reactions more environmentally friendly."

Large pharmaceutical companies can each produce anywhere from 3000 to 5000 metric tons of hazardous waste per year, most of it (by volume) solvent. Several companies have developed methods for solvent recycling and recovery. AstraZeneca reduced its hazardous waste by 6% from 2001 to 2004 and Merck produced about 17% less waste in 2001 than it did in 1999. But, many green manufacturing programs center on waste management rather than on making the entire process green from the start. Are environmental factors a key concern for the industry or is it just an afterthought (i.e., secondary to economics and other factors)?

"In this day and age, where there's sometimes a very fast-paced development timeline, not all the latest environmental features can be incorporated," says Gary Erickson, director of the Technology Center at Roche Colorado (Denver, CO, www.rochecolorado.com). "Incorporating innovative green manufacturing elements is something we need to think about throughout the life of the product."

The green–oil connection.

Industry observers agree that production processes would be a greener venture if drug makers developed their API manufacturing techniques with the environment in mind from the start, rather than focusing on solvent recovery later in the game. To address this issue, university-based scientists are developing ways to reduce solvent use, make one-pot reactions, and cut waste from beginning to end of the process.

Planting the seed

Virtue may be its own reward, but making a process greener is seldom enough to entice a manufacturer into altering an established production process. The time, expense, and regulatory filings needed to change an established manufacturing process are enough to make any drug manufacturer shake in its boots. Bringing greener chemistries to the API manufacturing process depends on planning ahead.

Nobel Prize for green chemistry.

Says Walt Stalzer, vice-president of project management at Ricerca Biosciences LLC (Concord, OH, www.ricerca.com), "If you don't think about green from the beginning, you may be painted into a corner and never get around to doing it. A lot of this is 'do the right thing at the right time,' which is the key to putting together a good process."

Colleague Paula Lorence, vice-president of business development at Ricerca, agrees. "There's a lot of processes out there for which green wasn't the focus when they were put in place, she says. "So now, they're having to deal with it and minimize the negative."

The first steps in green API manufacturing could be as simple as reducing the number of reactions and isolations required to produce a given molecule. Fewer steps mean less solvent to recover and dispose of. The second step is to replace volatile solvents and reagents with those that are better for the environment. Stalzer provides an example: "You'd normally choose the hydrocarbon-based solvent because you won't have to deal with controlling the chlorinated solvent, which is difficult to do and not environmentally friendly," he says.

Companies should also create an organized plan for developing environmentally friendly processes. Bristol-Myers Squibb (New York, NY, www.bms.com) has instituted a "Green Chemistry Program" that encourages scientists to think about minimizing environmental hazards when developing new compounds. The company uses a "process greenness scorecard" in its education and training and in every step of a compound's development to rate the impacts of certain reagents and solvents on its processes. "It's certainly something that we're excited about and it's something beneficial to do," notes Brian Harrison, senior director of manufacturing technology and API at Bristol-Myers Squibb. "We chart the greenness of every process that comes through."

In addition, companies should consult with a variety of environmental chemistry specialists (both in the commercial and academic research fields) who can identify the best ways to make a process greener. "You should be in touch with the insiders in the industry so that you know what researchers are working on. Otherwise, you have limited access to it," points out Brock University (St. Catharines, ON, Canada, www.brocku.ca) chemistry professor Tomas Hudlicky, PhD.

Roche Colorado and Pfizer (New York, NY, www.pfizer.com) use a team approach to discuss green chemistry for this reason. "We start off a process by forming a team that has a mix of chemists, process engineers, and analytical research personnel to give us our eyes and ears," explains Les Harris, principle process development engineer at Roche Colorado. "We're allow ideas to flow within the team—ideas for which pure chemists may not have the perspective of what can be possible with engineering and for which engineers may not have the perspective of what an alternative synthesis may be. We get a cross-fertilization of ideas."

The Pfizer green chemistry team, says Russ Linderman, director of the research API group (Groton, CT), also educates the company's chemists about solvent alternatives. "We've been very effective at looking at methods to reduce solvent use and make more optimal solvent selections even very early in the discovery process," he explains.

Big Pharma gives the green light

Better catalysts and less solvent. Pharmaceutical chemists agree that decreasing the number of synthesis steps is one of the most important ways a company can make its process greener. But sometimes, this is easier said than done. To achieve this goal, many companies focus on catalysis.

Pfizer redesigned the commercial manufacturing process of sertraline, the API in its "Zoloft" antidepressant drug. The company streamlined a three-step process into a single step by using a more selective palladium catalyst in the reduction step. According to the company, this step reduced the formation of impurities, eliminated the need for reprocessing, and significantly cut the amount of necessary raw material.

The company also substituted more benign solvents for the combined process. "We moved to ethanol, methanol, and ethylacetate. We also increased concentrations and eliminated two isolations in the four-step process. This reduced the solvent use from 2300 to 250 L/kilo of active product. It was nearly a 10-fold reduction in solvent usage, which translates into a similar volume of waste solvent that must be recovered or disposed of," says John Keith, vice-president of environmental health at Pfizer (New York)."This represented over a decade worth of improvements, but the process of looking for improvements is ongoing." Pfizer worked closely with the US Food and Drug Administration to approve the new process.

Biorenewable sources. Other companies are finding creative ways to make use of biorenewable sources. For example, the source of paclitaxel (the active ingredient in Bristol-Myers Squibb's "Taxol" blockbuster anticancer drug) is the Pacific yew tree, an environmentally protected and slow-growing tree that takes more than two hundred years to mature. To harvest the substance, one needed to strip off the tree's bark, a process that eventually killed the tree. "As you can imagine, this wasn't a very environmentally friendly way of studying and using this molecule," notes Harrison.

To reduce the environmental impact, Bristol-Myers Squibb developed a method of using a biorenewable source and plant cell fermentation to produce the drug. "We took leaves and twigs from trees, which didn't damage the tree permanently. We extracted a component from that source. It wasn't the final reactive material, but we then used some synthetic steps," explains Harrison. The semisynthetic process also presented environmental hazards, though, requiring 11 chemical transformations and 7 isolations, which called for 13 solvents and 13 organic reagents, according to the US Environmental Protection Agency (EPA).

The company improved this process further by developing a novel plant cell fermentation process, which reduced the number of solvents required. In the cell fermentation stage of the process, taxus cells are grown in an aqueous medium in large fermentation tanks under controlled temperatures and pressures."I think there's a trend towards the greater use of enzymes which can be used in aqueous media. The manufacturing process is greener as you are using an aqueous bioprocess instead of chemical reactions," says Harrison. Scientists extract paclitaxel directly from plant cell cultures, purify it by chromatography, and isolate it by crystallization. Bristol-Myers Squibb received the 2004 Alternative Synthetic Pathways Award from the EPA for these changes to the production process.

Solvent database. Manufacturers have standard solvent-recovery operations, relying mainly on distillation (often preceded by decantation of aqueous layers and filtration and separation of solids). Pfizer and Roche are also fostering solvent recovery by developing a database of information about solvent mixtures that help chemists develop environmentally safe processes.

"It includes information about the properties of solvents, advocates solvents that have lower safety concerns, and offers guidelines about the feasibility of solvent substitutions and concerns that can inhibit solvent recovery," says Keith of Pfizer.

Roche's Harris explains, "It gives a facility the ability to quickly evaluate a mixture and see how easy it is to separate, what are the economics of the separation, and that allows it to identify priorities for green manufacturing."

Collaborating with suppliers. Though drug makers strive to reduce solvent use, there will typically be some waste. Roche Colorado partners with its suppliers to either recover and return solvent to the company or re-sell it to another industry that may be able to use it. Some waste can also be recovered and recycled for energy. In addition, the company returns packaging for raw materials back to suppliers for recycling.

What can green do for you?

Getting experimental green chemistry projects from the research environment into the industrial world requires a brave corporate guinea pig. And that necessitates a powerful incentive. One university researcher recalls a senior Big Pharma executive saying: "I don't care if I can recycle my catalyst, but I've got to get it out of my product. If you can furnish me with a new way to get it out of my product, I can afford to try the new method."

To convince industry to use novel, environmentally friendly methods, university scientists are working to develop win–win propositions, offering manufacturers more efficient processes that save money and are better for the environment. "It isn't enough to be benign. You have to give people another reason to want to use it," stresses Charles Eckert, PhD, a professor in Georgia Institute of Technology's School of Chemical and Biomolecular Engineering and director of the Specialty Separations Center (Atlanta, GA, www.gatech.edu). "It's either better economics, it yields a better product, it's better for regulations, it cuts down on waste because the cost of waste disposal is going up...or all of these factors."

By giving manufacturers their cake and letting them eat it too, university scientists believe their green chemistry techniques will gain industry acceptance. Says Eckert, "There are barriers for the integration of university green chemistry projects into the pharmaceutical industry. But, the first inroads will be when nothing else works or when nothing else works as well."

Switchable solvents. During the multiple reactions required to produce a specific molecule, process developers change the solvent several times according to the polarity required for each given step. A Georgia Tech research team is working to simplify this procedure by altering the solvent's polarity in situ rather than replacing the solvent itself. Their "switchable solvents" change polarity in response to specific changes in heat, light, and pH. The new class of solvents could enable chemists to perform multiple reactions in one pot. "What we're trying to do is to change the nature of the solvent just by applying carbon dioxide gas," explains Charles Liotta, PhD, Georgia Tech's vice provost for research and graduate studies and Regents professor of chemistry.

In a recent Nature paper, the group proves it can take a relatively nonpolar, oily compound and make it ionic (1). When carbon dioxide is bubbled through the liquid mixture at one atmosphere of pressure, it redistributes the charge to ionize the liquid. This solvent can be converted back to its original nonionic state by bubbling nitrogen through it, which removes the weakly bound carbon dioxide molecule. The process is done at room temperature, but can be accelerated by raising the temperature to 50 °C.

The technique could be applied to the use of ionic liquids, substances that interest researchers because they have no vapor pressure and don't cause air pollution. But the industry has hesitated to use ionic liquids because they require a complicated and expensive separation process. The Georgia Tech researchers believe the separation can be done easily with their technique. In addition, says Liotta, the process is suitable for asymmetric or chiral compounds and separations.

Pfizer's Linderman says of ionic liquids, "Ultimately, cost is a factor. There are some interesting factors in terms of the toxicity of their biodegradation. As new efforts are including the full gamut of ionic solutions, we'll see more potential applications."

"Causing phases to change and causing molecules to change is where we think the future of chemical reactions will be," says Eckert. "I think this type of thinking is going to furnish all types of opportunities for a variety of manufacturers of high value-added chemicals to do things in a more benign fashion."

Nano-and microtechnology. Researchers at Cornell University (Ithaca, NY, www.cornell.edu) also are working on reducing multistep reactions to one pot. "To achieve this kind of telescoping, the industry needs to develop new tools and new intellectual constructs," says D. Tyler McQuade, PhD, green chemistry specialist and chemistry professor at Cornell.

According to McQuade, organic chemistry is too often thought of as discrete steps that must be put together. "We need to think of chemistry as a system. We need to think about reactions as a system, and we need to learn how to integrate reactions with respect to each other," he stresses. Rather than thinking of reactions as an assembly line, McQuade's group is using microreactors to synthesize molecules in one step and improve yields.

Though microreactors aren't new to the pharmaceutical industry, the group has improved on traditional designs. To reduce clogging, a common problem with stacked-plate microreactors, the group uses tubes. "The clogging essentially makes the reactors useless. You have to take them apart and clean them. It can really be devastating," he says. "By having tubes, we can improve the process. We can take two fluids together that form a solid and we can make it in our device without clogging," says McQuade.

In addition, the group is experimenting with nanoencapsulation. The goal is to separate the molecules that are undergoing the chemical reactions from other molecules. The group makes a porous polyamide protective shell around catalytic nanoparticles, which keeps the catalyst's chemical properties intact. Changing the pore sizes can exclude certain molecules from getting to the catalyst but enables reactants and end-products to flow out.

Different nanocapsules might perform each of the many steps required to make a drug by combining many capsules in one pot to reduce waste. "What we're trying to do to mimic nature's brilliance is to take different encapsulated catalysts and put them in sequence within the channels of a microfluidics device," McQuade told the National Cancer Institute in an interview. According to McQuade, the technique should enable scientists to produce more or less drug by varying the amount of catalytic microfluidic devices.

Biological methods. Minimizing waste from chemical reactions is a common goal of green-thinking chemists. But, researchers from Brock University aren't just minimizing waste; they are converting it into desirable pharmaceutical compounds.

The group, led by Hudlicky, focuses on the oxidation of aromatic compounds that have halogens. Bromobenzene is oxidized in a relatively large-scale fermentation and produces a chiral compound. "From that compound, other complex products can be made that are sort of building blocks," says Hudlicky. Residual waste from this process can be disposed of in municipal sewers because several steps are performed in water with bacteria commonly found in soil.

The group has successfully recycled byproducts into analgesic, anesthetic, and antitumor products that treat cancer, bioinfection, and diabetes. According to Hudlicky, the researchers have supplied their compounds to companies such as Sigma-Aldrich.

Under development at Rice University (Houston, TX, www.rice.edu) is another biologically based, green production method. The group uses a genetically engineered strain of Escherichia coli that produces succinate, a common solvent. "Succinate is a high-priority chemical that the US Department of Energy has targeted for biosynthesis," said process codeveloper George Bennett, professor and chair of the department of biochemistry and cell biology at Rice, in a statement in an official press release. "Succinate's also a priority because some bacteria make it naturally, so we have a metabolic starting place for large-scale fermentation."

The researchers added genes to boost the bacteria's natural succinate production and deleted four other genes that interfere with succinate production. These two complimentary methods increase the yield and speed of succinate production.

AgRenew Inc. (Manhattan, KS) began testing the production method at industrial scale in August.

Parallel and continuous processing. A growing area of interest that has university roots is parallel process development. This concept enables scientists to run many experiments at one time, rather than doing each one sequentially. "This provides a much easier way to maximize the amount of data and come up with the very best reaction conditions to minimize the environmental impact of the process you are developing," explains Erickson of Roche.

Continous reactions, which aim to eliminate batch processing, also have generated a lot of interest. These reactions may be done in very concentrated solutions, which vastly reduces the solvent usage. "It's an inline method that uses flow-through equipment," says Keith of Pfizer. "It's used to do reactions, isolations, or drying and eliminates and reduces handling operations. You can have multiple steps in line so you can reduce the number of isolations." Though many companies use this technique for various applications, it is not yet used to manufacture APIs.

Pfizer's Linderman says that flow systems could be suitable for hard-to-scale-up oxidation processes. "With flow systems, you could accelerate discovery by being able to have more robust technology along those lines," he says.

Uncertainty about the environmental movement

Green chemistry is still a fairly new field and like most developing areas, it is facing a time of uncertainty. In short, scientists don't have a clear idea of what exactly consistitutes "green" and what makes for "efficiency."

"As we move forward, there will be a lot of driving forces to improve chemical processes. I think we'll begin to see what is truly valuable and what is not. I don't think we're there yet," notes Cornell's McQuade.

For example, some chemists have touted the success of supercritical carbon dioxide as a green solvent, but others believe it takes too much energy to generate. In addition, some scientists believe that using water as an organic solvent improves efficiency, but according to one industry observer, "Purifying water is extremely expensive. It's a cost in terms of dollars, and environmentally, it's a huge tax on energy." Moreover, one scientist called fluorophase chemistry—a method for isolating a compound with minimal amounts of solvent— a red herring because "it's hard to get out of the environment. There aren't any mechanisms for organisms to degrade fluorocarbons." Others believe this chemistry is more benign than traditional chemistry.

Brock University's Hudlicky agrees that there is a lack of consensus about the parameters of green chemistry. "Once you start asking questions, a lot of the principles in green chemistry are not as green as you might imagine," he says.

As in many fields, money is a concern for those who are experimenting with new green chemistry projects. In particular, funding is hard to find for certain types of projects such as biological methods for green manufacturing, that aren't popular among US research groups, but are in full swing in Canada and Europe. Rather, new catalytic methods are at the center of the environmental movement in the United States. One industry observer says, "In the United States, there is just total inattention to using plants or bacterial enzymes in green chemistry." He also points out that major funding institutions such as the National Institutes of Health tend not to provide as much funding to these areas. "People who attempt certain green methods in the United States would be destroyed for lack of funding," he asserts. "There are lots of examples of people who just quit and were run out of the business."

Despite these challenges, green chemists are hopeful that their work will be accepted because it is so valuable for the manufacturing industry. Says Eckert, "Green chemistry isn't a cure-all and I'm not saying it works for everything. It should be in the bag of tricks. It should be a tool that's available to the people designing processes."

Reference

1. P.G. Jessop et al., "Green Chemistry: Reversible Nonpolar-to-Polar Solvent," Nature 436, 1102–1102 (25 Aug. 2005).