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C&EN Washington

Strategies such as combinatorial chemistry are speeding up the discovery portion of the new-drug timeline and pumping more candidates into the development pipeline. The flood of compounds entering the development stage--of which only an estimated 10% will make it to market--requires process chemists to separate the drugs from the duds quickly while expending minimal resources on candidates destined for failure. Process chemists are responsible for devising efficient, safe, and economic routes for synthesizing drugs. These scientists serve as the bridge between the discovery and the manufacture of pharmaceutical compounds (see page 35).

The demand for process chemists is higher than ever as discovery groups reap the fruits of their efforts. "A number of companies, such as SmithKline Beecham, are seeing dramatic growth in this area--it's the only way to better position themselves to deliver their products to market more quickly," says Joseph R. Flisak, associate director for synthetic chemistry at SmithKline Beecham, King of Prussia, Pa. "We have built an aggressive process chemistry group here. Our development pipeline is promising, and we need to deliver these products to market as fast as we can. We will need more qualified chemists to handle the development of these compounds."

David Askin, a senior investigator for process research at Merck Research Labs, Rahway, N.J., agrees that the demand for process chemists is increasing with the growing complexity of the molecules in the pipeline. "Our department is in the process of expanding because the discovery area is expanding," he says. "We have to be able to keep up with the increased number of compounds coming into development."

The prospects for process chemists are very good, with more openings than qualified candidates, says Jo Ann Wilson of Ligand Pharmaceuticals in San Diego. As a smaller pharmaceutical company, Ligand does not have its own manufacturing facility. Therefore, it needs process chemists who already understand the challenges of working at scale. "We tend to look more for chemists who already have that kind of experience or who come from a large pharmaceutical company or another chemical industry that does scale-up," she says.

Bristol-Myers Squibb, Princeton, N.J., accelerates the development timeline by engaging in "prospective process chemistry." As discovery chemists find promising classes of compounds, process chemists are working to develop better synthetic routes before a specific candidate is identified, according to David M. Floyd, vice president for discovery chemistry. "We'll take prospective process research as far as we can if we think there's a drug candidate on the horizon," he says. As Bristol-Myers Squibb increases its productivity in discovery, Floyd says, the need increases for all the components of the company--including process chemistry--that translate those discoveries into candidates.

Some companies, such as Eli Lilly & Co., Indianapolis, are still at the stage of expanding their discovery groups. According to Sandy Sifferlen, manager of U.S. recruiting at Eli Lilly, the company is in a "growth mode." This growth in the discovery area will fuel future expansion of process chemistry. She expects the company's needs to be at both the senior (Ph.D.) and associate (B.S./M.S. degree) levels.

In addition, process chemistry is growing at companies that provide services to the pharmaceutical industry. "We are seeing a lot of companies both in the U.S. and in Europe that are what I call service companies to the pharmaceutical industry and are providing building blocks or research services such as contract process research and development," says Trevor Laird, chief executive of consulting firm Scientific Update in Mayfield, England, and editor-in-chief of Organic Process Research & Development , published jointly by the Royal Society of Chemistry and the American Chemical Society. "You've got companies all over the U.S. that are expanding, mostly by doing process chemistry."

One such company is Albany Molecular Research, Albany, N.Y., which provides services to a wide variety of pharmaceutical companies--from large companies needing extra capacity to virtual companies without facilities. Harold Meckler, vice president for chemical development, expects that as the company continues to expand, it will hire at the same rate it has for the past few years. He believes the outsourcing of R&D by the pharmaceutical industry is only beginning. According to Meckler, Albany Molecular offers process chemists the opportunity to work on a wider variety of problems than they would working for a pharmaceutical company.

What are all these process chemists doing? A recently published book, "Process Chemistry in the Pharmaceutical Industry," provides a detailed look at the types of problems process chemists are solving. The book, edited by Kumar G. Gadamasetti, now senior director of chemistry development at Axys Advanced Technologies in South San Francisco, contains a dozen case studies from around the pharmaceutical industry detailing the challenges posed by specific syntheses.

Process chemistry is often mistakenly believed to be simply reaction scale-up. As Steve King and Todd McDermott, both process chemists at Abbott Laboratories, Abbott Park, Ill., describe it, scaling up the chemistry is the goal but not the focus of their day-to-day activities. "You've got to know everything about the reactions you're going to scale up," McDermott says. "Everything we're doing is to enable us to scale up the reaction safely and efficiently."

"Process chemists are charged with developing the best chemical route to the particular drug candidate," Askin explains. "The goal is to make it in one step, at 100% yield, from starting materials that are free, basically. We usually don't achieve that, but that's what we're always shooting for."

"Process chemistry is state-of-the-art chemistry applied to the synthesis of a specific target molecule," Flisak says. "That molecule gets defined by the medicinal chemist, and then the process chemist will find the most efficient way to make that molecule so we can do all of our trials here and also make the compound on a large scale."

Although synthetic organic chemists are involved in both drug discovery and process chemistry, the strategies differ in the two areas. "In discovery, you try to get a compound as quickly as you can, and you don't worry about how much it costs to make it because, if it turns out to be useful, you'll know with a small amount," says chemistry professor Ronald Breslow of Columbia University, a synthetic organic chemist who has consulted for pharmaceutical companies for nearly 40 years.

Discovery chemists must use flexible synthetic strategies so they can make a variety of target molecules, Flisak says. Often they don't know ahead of time what the final product will be. In contrast, process chemists "know where we're going to end up," Merck's Askin says. "Consequently, we'll frequently start toward that objective from a totally different direction, since we have the advantage of knowing the precise molecular structure of the target."

"People who love synthesis or who love trying to figure out how a reaction occurs so they can make it better" are particularly well suited for process chemistry, Breslow says. Because medicinal chemists are trying to "outsmart nature," biological knowledge is more important for discovery chemists than for process chemists. In fact, the process chemists C&EN spoke with eschewed discovery work because the necessary biological study was a distraction from their true love--chemistry.

Process chemists can focus purely on chemical research and on "refining and perfecting the art of organic synthesis," Askin says. They often have the opportunity to discover chemical reactions. Someone may propose a new reaction that avoids an intermediate and "then go into the lab and make that reaction work," Askin says. For just that reason, Breslow, in a foreword to the book "Process Chemistry in the Pharmaceutical Industry," characterized process chemists as "working at the forefront of chemistry."

Process chemists evaluate the medicinal chemistry synthesis to see if any parts of it can be used for the scale-up. Initial quantities of the drug candidate required for testing might be synthesized using the medicinal chemistry route, but that route can rarely be used for full-fledged scale-up. "We're very happy to throw out their entire synthesis," King says. "We're also very happy to use what we feel are the good parts. We need to make a good decision based on the science."

After the first few kilograms necessary for laboratory tests have been made, process chemists work to improve the synthesis, possibly following a completely different strategy from the medicinal chemists. "We're just dealing with one target, so we can focus all our energy on the best way to construct that molecule," Flisak says.

Devising the synthetic route is often a team effort--the more complex the molecule and the synthesis, the more people who are likely to participate. The route is broken down into separate steps, with a different chemist working on the different steps. "In the project I'm working on, I need to work out two of the six or seven steps that are going to be in the final sequence," McDermott says. "I'm responsible for making sure that those reactions work and that they're ready to scale up when we need to scale them up."

At some point, the process must be handed over to chemical engineers, who play a large role in the actual scale-up of the synthesis. "Our role in R&D is twofold," says Karen Larson, a chemical engineer at Merck Research Labs. "One is to provide drugs to continue the ongoing clinical and safety studies. Our second role is to make sure that we provide manufacturing with a good, reproducible, robust process."

At Merck, chemical engineers are involved from the time that the amounts of material needed exceed those that can be easily made at a bench scale. They are involved until the handoff to the manufacturing facility. Larson says: "Our final milestone is when the whole research team--that's the process chemists, the analytical chemists, and the chemical engineers who have all worked on this project--goes to the manufacturing site and demonstrates the process to the manufacturing team. We're literally teaching them how to run the process. We often say that this is our 'final exam.' "

One challenge for process chemists is making sure that they don't squander resources on the majority of drug candidates that fail. "You can spend a lot of effort on early-stage molecules--do some really interesting chemistry, scale it up, and possibly make a few kilos," Laird says. "Then the drug dies for reasons that are totally out of the process chemist's control."

"Many companies have adopted the strategy of evaluating compounds quickly and efficiently in early development to answer the basic question: Is this likely to be a drug?" Gadamasetti says. "Expending 90% of resources on the 90% of projects that fail is the extreme this strategy seeks to avoid."

Process chemists at Merck demonstrated just how fast a drug can be developed with Crixivan, a human immunodeficiency virus protease inhibitor. "We literally launched the drug out of the pilot plant while construction on the factory was still being completed," Askin says. "This was all the more remarkable in that Crixivan is the most complex drug substance we have ever produced here by total synthesis." They accelerated development by applying chemistry developed for an earlier drug candidate that had been abandoned. The development time for Crixivan, from start to product registration, was a mere four years--"still a record for Merck and maybe for the industry as well," Askin says. Thus the knowledge gained from failed candidates can still be applied productively.

Such a rapid development time raises the bar for future candidates. However, Askin points out, "not every program is going to be like Crixivan, because Crixivan had unusual resources and we took unusual risks with that particular program because of the really critical human need and tragedy going on."

In addition, automation is expediting the task of developing drugs rapidly. "We have a very huge robotics program going on [at SmithKline Beecham], which helps us screen chemical reactions more quickly," Flisak says. "Years ago, when we did not have robotics or reaction screening, we had to run each of these reactions by hand. With robotics, you can run 12 reactions at once."

Some people are worried that the compressed development times and concomitant time pressures will leave process chemists without "thinking time." Process chemists are so busy that they "don't have time to think and time to read and keep up with what's going on," Laird says.

However, the process chemists C&EN interviewed make a point of keeping up with the literature. "I encourage my staff to keep current on the literature," Wilson says. "We try to do whatever we can to make that easy for them," including purchasing online editions of journals. Other chemists, such as McDermott, scan the literature on their own time. "I have a significant number of journals that I subscribe to and keep up with," he says.

Breslow believes that, despite the time pressures, freedom to innovate is essential. "Where the mistake would come is in a place where the time pressure was so great that there was no time for creativity. That would be a terrible waste of the opportunity to use somebody's real imagination," he says.

Process chemists must be able to work on a team that includes more than just synthet-ic chemists. They work closely with analytical chemists, chemical engineers, environmental chemists, and regulatory affairs specialists. For example, Flisak's group at SmithKline Beecham was responsible for the development of the compound carvedilol, marketed as a treatment for congestive heart failure under the trade name Coreg. When the compound was going to be launched, the group had to transfer the technology to the manufacturing site in Cork, Ireland. "[We] had to get this whole team together to do this transfer as one cohesive unit. It's very exciting to be involved with something like that," Flisak says.

Process chemists also face the challenge of keeping the manufacturing costs down. Wilson recounts an experience at Ligand Pharmaceuticals: "There was a process that we had basically taken from medicinal chemistry and without very much work scaled up to meet the needs of a clinical program. The process worked fine. However, the per-kilogram cost of the drug was pretty high. We realized that was not going to be acceptable in the long term if this compound were to go to market." By optimizing the process, they were able to cut significantly the cost of producing the drug.

Several chemists agree that the most rewarding part of being a process chemist is seeing chemistry that they developed work at scale. "One of the best feelings I had," Flisak recalls, "was doing the manufacturing handover when you're working at the manufacturing site on a 500- to 1,000-gal scale and seeing a couple of hundred kilos of product crystallize out before your eyes. What's even more rewarding is knowing that drug is going to make it to market, and you're going to help make people's lives better because of that." Wilson says that, even after years in the field, seeing chemistry run at scale is still a "big wow."

McDermott compares the experience of seeing a reaction run at scale to running reactions in graduate school: "In my natural product synthesis, I made a couple of hundred [milligrams] of one product and maybe a few [milligrams] of another. Obviously, the chemistry is good, but it's much more satisfying to have good chemistry and end up with a large jug of material at the end of the day."

The most frustrating part of being a process chemist in the pharmaceutical industry is the paperwork that comes with working in a highly regulated industry. At small pharmaceutical companies such as Ligand, the process chemists are directly involved with regulatory agencies. In the larger companies, the process chemists provide information for regulatory affairs departments that act as liaisons to regulatory agencies.

People interviewed by C&EN were attracted to process chemistry for a variety of reasons. "My Ph.D. adviser and my postdoctoral adviser really pushed process chemistry," Flisak says. "They thought that all the very clever chemists ended up in process chemistry."

McDermott's adviser also advocated process chemistry. "That's not always the case. A lot of academic people don't really appreciate what happens in process chemistry," McDermott says.

King was drawn to process chemistry because he's "a chemist through and through." Medicinal chemistry involves too much biology to satisfy him. He says, "Although I think biology is a fascinating topic, I want to spend my time studying chemistry. The time spent studying biology is a diversion from that."

Wilson knew when she finished graduate school that she wanted to work in the pharmaceutical industry because "the most interesting chemistry" is found there. Then she needed to choose medicinal or process chemistry. "It was clear to me that I wanted to do process chemistry because I believe that process chemistry requires a good understanding of chemistry--understanding mechanisms of reactions and how the chemistry works. For the process chemist, the goal is actually the chemistry itself," she says.

Pharmaceutical companies are looking for process chemists at all educational levels, but particularly those with doctorates. Chemists interviewed for this article agree that the best preparation for a career in process chemistry is an advanced degree in either synthetic or physical organic chemistry.

"I don't think industry really wants the universities to try to teach process chemistry. They'd prefer it if the chemist got a good all-around education," Laird says. "At the moment, I think it's more up to industry to take the chemists from the Ph.D. programs and educate them in the way they want."

Wilson agrees that graduate work in synthetic chemistry is essential. "We have considered candidates in the past whose graduate research has focused on bioorganic chemistry or even physical organic chemistry, but I believe the ideal candidate will have extensive experience in synthetic organic chemistry and the laboratory skills that come with graduate work in synthetic chemistry." She says Ligand requires candidates without advanced degrees to have previous industrial experience.

McDermott recommends a diverse background that has involved running a variety of reactions. "People who have run a lot of reactions but have also done some methodology work are set up pretty well to do good process chemistry. A methodology project forces you to think about the little details," he says. However, just running reactions isn't enough. "People can make molecules and do reactions without really thinking about it too much. We clearly want someone who has shown they can think about the chemistry," he adds.

According to King, a postdoctoral appointment used to be vital to finding a position in the pharmaceutical industry at the Ph.D. level--but not anymore. In the nine years that he has been in the industry, he has seen the percentage of Ph.D.-level scientists with postdoctoral experience fall significantly. "A postdoc is becoming less and less of a requirement to get a good job with a good pharmaceutical company," King says.

The long-term prospects for process chemists look good, Laird says. "The chemical entities are becoming much more complex, so it means there's more work for the chemists to do. On the other hand, the regulatory authorities are demanding much more information about the process itself. Again, that means more work for the chemists. I can't see that situation changing."

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