It's a long and painstaking process, steering a drug through the preclinical phase of development. A promising drug candidate has plenty of potential when it leaves the discovery laboratory, but that's just the first step, and the statistics are against it. Only five of the 5,000 compounds that enter preclinical testing go on to human trials. And it takes a team with many different skills to create the drug, check for safety and scale it up for production.
During preclinical development, scientists carry out the process chemistry and scale-up, perform thorough toxicology studies, and sometimes decide on the drug's final formulation. In this phase, scientists contribute their technical and creative talents to move a promising candidate from the research lab into the clinic. In preclinical development, companies weed out drugs that are too cumbersome to produce, or that may be harmful, saving millions of dollars on wasted clinical trials.
Right place, right time
Preclinical development is a hot place to be. Organic growth, mergers, acquisitions and in-licensing are adding early-stage drug candidates to companies' pipelines. According to the American Chemical Society's annual survey, chemical-industry employment in the pharmaceutical sector grew slightly between 2000 and 2005. Although growth has stagnated since early 2004, job loss due to consolidation may be turning. Companies that shed staff after mergers are now hiring again, thanks to growth in their pipelines and movement towards later-stage compounds. And unlike manufacturing jobs, US preclinical development positions have yet to be outsourced abroad.
Moving a drug from discovery to preclinical stage means increasing its production from milligrams to kilograms. Doing so requires finding efficient ways to scale up. "In medicinal chemistry, you're simply interested in getting hold of the compound and you're not always bothered at this stage of the R&D process by how expensive the chemistry is," says David Nicholson, executive vice-president of research and development at Organon International in Roseland, New Jersey.
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The right mix: small firms need a collection of skills.
Scaling up production uses the talents of several types of chemist. Synthetic chemists devise scale-up processes, aiming to keep costs low. Analytical chemists characterize the new compound. And chemical engineers — most in demand at biotech companies — find the best ways to produce enzymes. All three types play critical roles on the road towards clinical trials.
The synthetic chemist asks critical questions about production, says Ken Batchelor, senior vice-president of GlaxoSmithKline's Center of Excellence for Drug Discovery: Metabolic and Viral Diseases. "Can the substance be produced in fewer steps, more quickly or with a greater yield?" Even when times are tight, there is always demand for highly skilled synthetic chemists.
Analytical chemists assess the compound and identify any impurities. Characterizing the product and assuring its quality are such important steps that there are sometimes as many analytical chemists and biochemists as there are process chemists, says Chuck Goochee, senior director of bioprocess research and development at Merck.
This phase also emphasizes the safety of chemical reactions, says Scott Biller, head of global discovery chemistry at the Novartis Institutes for BioMedical Research. Heat-producing, or exothermic, reactions, barely noticeable in discovery, can blossom into serious problems during development, where skilled process chemists with industry experience can trouble-shoot. And concerns over waste and environmental costs are prompting industry leaders to seek cleaner, more efficient ways to produce drugs (see Nature 440, 378–379; 2006).
Biological-based therapeutics such as proteins and monoclonal antibodies pose their own challenges in scaling up. In research settings, scientists use cell expression systems to produce small amounts of therapeutic molecules. But these methods have such low productivity that they're not commercially viable, so chemical engineers search for the best system to produce larger amounts.
Then they work with molecular biologists, biochemists and chemical engineers on the next stages: cloning, creating vectors, developing bioreactors for cell growth, and purifying and checking the protein products. The industry is relying more on computer-based technologies and '-omic' methodologies to weed out toxic compounds earlier in development, including using tests with computers, called biosimulation, to cut down on testing times and identify biological markers of toxicity (see Nature 428, 450; 2004).
Hitting the spot
Outsiders often overlook the importance of formulation on a drug candidate's passage through preclinical development. But without careful planning, a drug may not get to its site of action. Patch, pill or intravenous injection? Does it need to be protected until it gets to the intestine? At what pH is the drug most soluble? Will it be stable at a variety of temperatures for long periods? These are some of the questions that formulation scientists ask, to understand the physical properties of the drug, its target and intended market. They tend to be biochemists, physical chemists and scientists trained in pharmacy.
The right stuff: Kevin Stark, top, seeks team players; Ingelise Saunders looks for experienced all-rounders.
Scientific credentials remain the key to a career in industry, but hiring managers look for additional skills and experience from job applicants. "You need to be a team player, rather than an individual contributor," says Kevin Stark, senior director of strategic operations at Amgen. PhD or postdoc-level scientists should highlight any mentoring experience they've provided to young people, as they'll be expected to grow into that role within the company, often managing a team of up to five bachelor's or master's level scientists.
Ingelise Saunders, chief executive of ACE BioSciences, a Danish biotech whose pipeline includes prophylactic vaccines against traveller's diarrhoea, emphasizes experience (see Nature 433, 442; 2005). The company's size dictates this preference: with only ten people working in R&D, the vaccinologists she hires must be well-versed in animal models, adjuvants, immunology and data analysis, usually with a couple of years' experience at a scientific institution or in industry.
Larger companies may hire ten times more scientists with bachelor's and master's degrees than with PhDs or postdoctoral experience. For these young scientists, prior industry experience will catch the eye of any recruiter. Young scientists interested in entering drug development should look to internships, co-op placements or sandwich years to beef up their CVs (see Nature 439, 504–505; 2006). It's an opportunity to gain valuable experience and to decide whether this is the work for them. "It's a good way, even as undergraduates, to get a feel for what research is like in the pharmaceutical industry," says Biller.
As R&D becomes increasingly automated, these young scientists may be asked to contribute more brain power. Hiring managers are nearly unanimous: young scientists must learn to think, or they won't be prepared for a career in industry (see box). "They know the textbook stuff, but when you get into discussions and challenges and coming up with new ideas, they haven't been used to that," says Saunders.
Nicholson stresses that to succeed in industry young scientists must be keen to discover and develop drugs to treat disease. Batchelor agrees. "In industry you are completely focused on the discovery of a pharmaceutical product that will treat patients. In academia you worry if you can publish your paper in Nature."
Hit the lab running
"It used to be true in the chemical industry that you could only learn on the job," says Frank Douglas, who until August 2004 was head of the division of drug innovation and approval at Aventis Pharma. Douglas is trying to change that with the recent introduction of a programme offered by the Center for Biomedical Innovation at the Massachusetts Institute of Technology.
Although young, the programme has received positive feedback. One enthusiast is David Nicholson (below) of Organon International. "The course is geared to teach students to be focused on modern drug discovery," says Nicholson. "We need more of that type of course."
Backed by more than 20 years of experience in the drug industry and the enthusiasm of industry leaders, Douglas is bringing industry's past problems into the classroom. Every two weeks, he invites a senior scientist to present a real case of a failed drug.
"The students are challenged as a team to evaluate how they would use current technologies and methodologies that may not have been available at the time when the company was dealing with these issues," says Douglas.
Next year, he hopes to add a 'biopharm academy' for promising mid-level industry scientists.
"A common experience occurs when you put a high-potential scientist into a project-leader position," he says. "Initially they struggle because they are uncomfortable that they do not have the expertise either upstream or downstream of their own particular disciplines." The course will provide them with the broad overview, an understanding of the strategic issues, the framework and tools to become leaders, Douglas says.
H.H.