Celia Henry
C&EN Washington

When people think of chemists in the pharmaceutical industry, they're generally thinking of organic chemists in discovery or development research. But organic chemists aren't the only ones employed by pharmaceutical companies. Analytical chemists are a vital part of drug development, from early discovery all the way to manufacturing.

Pharmaceutical companies need to know the identity and purity of compounds that they hope to turn into drugs. Analytical chemists provide this information using a range of techniques, such as chromatography, spectroscopy, and mass spectrometry. Scientists with a variety of backgrounds are filling these needs.

Analytical chemistry has traditionally been a service function within pharmaceutical companies. This is more true in drug development than drug discovery, where analytical chemistry is now being viewed as a more integral part of the process. Analytical chemistry groups used to reside in centralized facilities that provided services to all of research and development. In early drug discovery, analytical chemistry is now diffusing into the rest of the organizational structure.

Although analytical chemistry is assuming greater importance, a "QC mentality" persists, observes William E. Bowen, an analytical chemist and research fellow at Merck Research Laboratories, West Point, Pa. However, Bowen says, "I don't think [quality control is] what companies are expecting from their analytical departments. That's one of the roles that the analytical chemist fulfills, but that's not really what analytical chemists have to offer. We're probably selling ourselves short if we think that's all we should be doing."

Miller-Stein adjusts the electrospray ionization source of a mass spectrometer, which is used in quantitative analysis for drug discovery screening. [Photo by Bob Cimino, Merck & Co.]

Joseph A. Loo, a mass spectrometrist at Parke-Davis Pharmaceuticals--now Pfizer Global Research & Development --in Ann Arbor, Mich., describes his experience with the evolving role of analytical chemistry: "Originally, analytical chemistry was a core function, so there was a group called analytical chemistry that essentially served the entire research and development areas. As the need for analytical chemistry increased and as it started to have some real impact in a lot of different areas, it started to spawn out. Individual areas set up their own analytical groups."

Loo believes that this change helps analytical chemists better understand how they fit into the overall goals of the company. "It keeps us in touch with what is really important for the company. If we were just a core group and were huddled down in the basement where analytical chemistry, especially mass spectrometry, can often be found, we would have difficulty identifying the most important projects that we could impact positively," he says.

However, this diaspora of analytical chemists also has its downside. It is no longer enough for analytical chemists to understand analytical chemistry. They have had to expand their knowledge base. "In order to talk to biochemists and medicinal chemists, we need to speak their language," Loo says. "We've had to find ways to educate ourselves on the big-picture goals of science at a pharmaceutical company."

Another concern is that spreading analytical chemists throughout the company will limit their interactions with one another. "I've been in a lucky situation where I'm surrounded by a group of 20 analytical chemists," Loo says. "We can talk about issues relating to analytical chemistry that perhaps medicinal chemists would not care about and certainly would not understand. This reinforces our knowledge base in analytical chemistry. That could disappear once we start dissipating into the separate therapeutic groups."

Cynthia Miller-Stein, an analytical chemist in the drug metabolism group at Merck Research Labs , agrees that there are advantages to being in a centralized group, particularly the opportunity to learn from each other. "When one person overcomes an obstacle, we all benefit," Miller-Stein says. "If we're not interacting on a daily basis, it's harder to progress and keep up with the newest things."

Robert L. St. Claire, an analytical chemist at Triangle Pharmaceuticals in Durham, N.C., also considers these interactions important. "When you no longer have a formally defined analytical group, you really have service groups within specialty areas, and you don't have the option for cross-pollination technically," he says.

At Cambridge, Mass.-based Millennium Pharmaceuticals , the company is moving beyond the classical platform for analytical chemistry, according to Daniel L. Flynn, the senior director of chemistry. "To practice the type of drug discovery that we'd like to at Millennium, there are some other broader vision aspects of analytical chemistry that we're bringing on board," he says.

Analytical chemistry is becoming more prominent earlier in the drug discovery process. Historically, drug discovery has been a "linear exercise," Flynn says, that emphasizes potency and structure without as much initial concern about whether a compound will make a good drug. New in vitro assays are providing information about drug properties such as bioavailability and metabolism earlier in the discovery process. "If we can plan for these kinds of things up front and evaluate our compounds against a broad spectrum of assays in parallel with testing for potency," Flynn says, "I think we're going to be a game up on trying to decrease project team cycle time and to decrease attrition."

With "open-access" and "walk-on" instrumentation, some companies are giving the responsibility for more routine analyses back to the synthetic chemists. For example, Millennium has scattered nuclear magnetic resonance spectrometers and mass spectrometers around its campus. The centralized analytical group still maintains the instruments and trains people to use them. "But quite frankly," Flynn says, "we're making better use of people's time if we outsource some of the routine purity and structure ID analyses into the general community."

Automation and the open-access systems have made possible the transition away from centralized analytical services. "Nobody's spending a tremendous amount of time serving as a pair of hands," Flynn says. "Now, analytical chemists really feel as if they're not just performing service group functions. These people are dramatically impacting the path and success of project teams. The analytical chemistry group doesn't feel as if they're a 'silo' group that is relegated to the service-group mentality."

What does it take to be an analytical chemist in the pharmaceutical industry? Most people have an academic background in analytical chemistry. However, other types of preparation can serve just as well. Merck's Bowen doesn't look for a particular background, such as spectroscopy or chromatography. Instead, he says that the job candidate must be a "good scientist."

Bowen knows from firsthand experience that scientists with backgrounds other than traditional analytical chemistry can find a home in the discipline. He earned a Ph.D. in organic chemistry. He has been successful as an analytical chemist, but Bowen says that, at first, he "didn't think like an analytical chemist." After six years in the pharmaceutical industry, he feels that he still plays "catch up."

Bowen works with a group in drug development that includes spectroscopists, electrochemists, chromatographers, organic chemists, and physical chemists. This diversity of backgrounds is possible because even analytical chemists have a steep learning curve.

"Over the first three years, you're really on the steep slope of what it means to be an analytical chemist in the pharmaceutical business," Bowen says. "I think that's regardless of whether you come from an analytical background. We're actually quite successful in finding good scientists in the variety of disciplines--many of whom don't hold a Ph.D. in analytical chemistry--and having them work as analytical chemists. People may be selling themselves short if they don't feel that they would fit in or be interested in the field. I've found it to be a rewarding career."

Loo agrees that many people pick up analytical chemistry skills in ways other than formal training. "We have a lot of people here who are trained in other areas--physical chemistry, organic chemistry--whom I would call analytical chemists now. They didn't go through formal education with the intent of becoming an analytical chemist. But analytical chemistry is one area in which I believe you can pick up a lot of things just through experiences on your job."

Loo recommends that people thinking about going into analytical chemistry in the pharmaceutical industry do their homework. "They need to learn what goes on in a pharmaceutical company," he says. "It's to their advantage to know ahead of time what they might be getting into. I don't have any good ideas for getting this information, because it's not readily available. You don't just read a general book on the pharmaceutical industry to learn how companies operate and function. Every company is different."

St. Claire advises students who are considering going into the pharmaceutical industry to find out what the job entails. "When you go to a drug company, you'd better ask, 'What will I be doing? What do you see me doing in five years?' Typically, those areas that are more research focused, more non-GLP [good laboratory practices] focused, are going to be more challenging in the long term to the challenge-seeking doctoral-level people," he says.

Loo says students targeting the pharmaceutical industry as their main employment goal will have an advantage if they take introductory classes in areas outside of analytical chemistry, such as biochemistry, biology, or pharmacy. This tactic can give analytical chemists a head start in understanding the problems that their colleagues bring to them.

Positions for analytical chemists are available at all educational levels, probably more so than in other areas within the pharmaceutical industry. Loo says that, at Parke-Davis, the decision to hire a Ph.D. versus a junior-level scientist depends on the methods that are in place. "We generally require higher level scientists when we identify projects where perhaps we don't have the methods in place and we don't have anybody who would be willing or who can accept the responsibilities to manage the project. If we have a Ph.D. scientist in place with a developed process, but additional resources are needed to make this successful, then we tend to request B.S./M.S.-level scientists."

All the analytical chemists with whom C&EN spoke say that demand for analytical chemists is high. For example, Robert S. Rush, research manager of Amgen , says that "tracking people down and getting people with experience is problematic." He believes that analytical chemists are "in the driver's seat."

An Amgen scientist works at a flow cytometer.

Rush looks for people with previous industrial experience, a rather precious commodity. Such people are more likely to understand the regulations that the pharmaceutical industry operates under, such as good laboratory and manufacturing practices. "If they have experience where they've had major failures, they can see things coming at them, anticipate that there is going to be a problem, and take corrective action before it becomes a critical point. If they don't have that experience, then they have to go through it," he says.

"Nobody comes out of school with all the experience we're looking for or that we need," Rush says. "A lot of entry-level people are much more comfortable with the operation of the equipment and not necessarily with methods development and challenging the equipment. If we don't have good separations or we don't have good analytical methods, all this instrumentation is just going to sit there and wait until we get it."

Rush says an effective analytical group needs a good balance of Ph.D.-, M.S.-, and B.S.-level scientists. However, experience counts for as much as or more than the degree. "Personally, I would rather have somebody with a master's degree and 10 or 15 years of really good experience than a Ph.D. with four or five," he says. "When it gets down to making this equipment sing, it just takes experience, that's all."

Steve E. Unger, director of the bioanalytical/structural drug metabolism and pharmacokinetics unit at DuPont Pharmaceuticals , agrees that, at first, a scientist with a bachelor's or master's degree and several years of experience can outperform a freshly minted Ph.D. "It is usually after the first year or two that the entry-level Ph.D. really starts to exceed the individual with a B.S. or M.S. Ph.D. scientists need a year or two to work through an understanding of all the applications."

The best experience is industrial rather than academic, Unger says. He contends that few academic centers provide the exact experience DuPont is looking for in trace bioanalysis. "If we ask academic people to develop a multicomponent method to measure 20 or 25 drugs simultaneously at the picogram-per-milliliter level in plasma or to identify lots of metabolites, we find that people don't work at the pace that we do," he says.

Although B.S.-level scientists with experience are a precious commodity, Unger says that his group, which focuses on bioanalysis, tends not to hire new B.S.-degree graduates. "There's not a lot we would trust them to do. In that sense, we may be a little different than some groups within analytical sciences departments that might have work that is more straightforward and mundane."

Miller-Stein holds a bachelor's degree in clinical laboratory sciences, a program that mixes biology and chemistry. She says her background has been both a help and a hindrance. "It's helped me in the sense that I have a better understanding of physiological systems, plasma as a matrix, the type of thing that a straight chemistry major wouldn't necessarily have. As far as not having all of the traditional hard-core chemistry courses, that may have slowed me down a little bit."

Miller-Stein recommends that students who want to work in the pharmaceutical industry without going to graduate school participate in a cooperative education program. "You get to experience different disciplines in the field before you actually get into the field," she says. "You can get a feel for whether you like it or not." If a cooperative education program is not available, she suggests summer employment within the industry. "If you are exposed to the laboratory, [you can] make sure it's something you enjoy. Try to get as much exposure--whether it's volunteer or summer employment, whatever it takes to get in there and get that initial experience. Employers will see the type of work that you do and whether you're willing to learn, enthusiastic, motivated, careful, and organized."

Entry-level scientists will be spending their time at the bench, and their work will be carefully checked. "At the entry level, they get a lot of supervision and a lot of guidance as to how to set things up, how not to set things up, what to do, what not to do," Rush says. The higher the educational level and the greater the number of years of experience, the less supervision is needed. "If new hires have 10 or 15 years of experience, there's very little guidance. They actually are the experts in the area," he says.

When analytical chemists work in development or manufacturing, much of the job is routine. It becomes important that people not mind doing repetitive work. Miller-Stein points out that much of what she does in the drug metabolism group is routine. She says it is important that a person have "good refined skills, be able to do good consistent work, and not mind doing it."

"Although much of what we do could be classified as routine analysis, three or five years ago those analyses would have been considered pipe dreams," Loo says. "It's the fact that high-level scientists have developed these methods and made them more robust that has allowed them to be called routine analysis."

Pharmaceutical companies are trying to shorten their time to market, and analytical chemists are feeling the squeeze just like everybody else. "Automation and any methods to improve throughput and increase our capacity are in demand," Loo says. "Much of our research in analytical chemistry is devoted to increasing our throughput, making the analysis faster, so that we can make a quicker impact on the drug discovery time lines."

Amgen's Rush agrees. Analytical chemists are feeling pressure to focus on things that speed up the process, he says. "With high-throughput screening and high-throughput analysis, the numbers game pushes us pretty hard in terms of methods development and staying current."

Miller-Stein says the effort to reduce time lines has forced analytical chemists to be "smarter about the way they do things and to miniaturize to some degree." This philosophy is showing up in terms of more automation and the move to the ubiquitous 96-well microtiter plate format.

Improvements in throughput are giving analytical chemists the opportunity to work on new projects. "Because we're smarter about the way we're analyzing samples, because we're able to increase our throughput and decrease the turnaround time that we can deliver, we're getting involved in more studies that we may not have seen," Miller-Stein says.

Unger adds that compressed time lines have put more pressure on analytical chemists. "You learn how to do things in parallel," he says. "Chemists figured this out by accident. Unfortunately, we as analysts have been struggling to figure out how to catch up with them."

Miller-Stein believes that mass spectrometry has been vital in speeding the process. "If we didn't have mass spectrometry, I don't know that we would be able to speed it up all that much. There were limits that we had to deal with as analytical chemists," she says. "You could be as smart as possible about it or try to work things out as quickly as possible, but there were real time constraints. There were interferences that you had to work out."

Analytical chemists need to make sure that they are actually advancing the drug discovery and development process. "Where do you put the majority of your effort if you're an analyst?" Unger asks. "If you can be at critical points and expedite the process, you'll be seen as a very valued asset. If you're at critical points and you slow it down by sometimes wanting to do too much or the wrong studies or set the wrong procedures in place, you'll be seen as a detriment or bottleneck."

People need to ask, Unger says, "Am I really expediting this or am I just slowing the process down? Is the information that I'm providing at this stage of the project critical? If it's not critical, I'd better get out of the way, because there are other people who can provide critical data to move the project forward."

Analytical chemistry is crucial to the pharmaceutical industry. "You've got to characterize these things," Rush says. "That's what analytical chemistry does. That's not going to change. The only thing that's going to change, I suspect, is the arsenal of tools that we throw at it."

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