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Biotech's New Economy plant

THE BALTIMORE SUN

FREDERICK - Deep inside a spotless biopharmaceutical plant off Interstate 70, Marco A. Cacciuttolo is performing one of the daily rites of a soldier in Maryland's New Economy. He is getting dressed for work, something he does several times a day.

Cacciuttolo has a doctorate in biochemical engineering. He oversees the college-educated MedImmune Inc. workers who daily tend to the delicate nurturing of a living soup from which, after a matter of weeks, a vaccine will be harvested.

Balanced on one leg, he hunches over coveralls that he has just ripped from a plastic bag stored on a shelf in a small anteroom. The trick, he tells a visitor, is to get the coveralls on without letting any part of them touch the ground. Doing so might allow tiny particles of dirt into the sealed area in which MedImmune's Synagis vaccine is being produced, something that could ruin it. Synagis fights a respiratory infection in infants.

"You grab the wrist and the knee," he says. "Then you do the same for the other side."

Keeping its vaccine contaminant-free is a virtual obsession at MedImmune, a biopharmaceutical manufacturer the state champions as a prime example that its efforts to make Maryland a powerhouse of drug production are bearing fruit. The effort has been the subject of much hand-wringing over the past decade, with critics lamenting that the state had so far failed to turn its concentration of biotech research jobs - many of them at government laboratories such as the National Institutes of Health - into a foundation for companies that make biological drugs.

MedImmune built its $50 million plant with the help of $13 million in state and local incentives, a package that persuaded Gaithersburg-based MedImmune, which was being wooed by Cleveland, to build its first plant in the state. The plant won Food and Drug Administration approval in December.

Other Maryland biotech companies that are significantly expanding manufacturing this year include Human Genome Sciences Inc., which makes experimental gene-based drugs, and contract manufacturer BioReliance Corp., both in Rockville. But even with these successes, the state's figures show that Maryland has ground to make up if it wants to achieve significant job growth in the industry. Maryland had fewer jobs at biotechnology companies in 1998 - the last year for which figures were available - than it did in 1993, according to a study released this month by the state Department of Business and Economic Development.

Private industry employment, including biotech manufacturing, peaked at 18,304 jobs in 1993, dropped nearly 19 percent over the ensuing three years to bottom out at 14,847 in 1996, and then rebounded to nearly 16,000 two years later, according to the study.

Department Secretary Richard C. Mike Lewin called the job figures in his department's report "improbable at best" and said they didn't include jobs at bioinformatics companies such as Celera Genomics Group, which was formed in 1998 to use computers to map the human genome. All told, the department has assisted biotech companies that created an estimated 2,300 jobs over the past two to three years alone, Lewin said.

Report author Fereidoon "Fred" Shahrokh, a department economist, said jobs lost when companies such as American Type Culture left the state, and increased efficiencies at existing companies, might explain the decline.

While it is far from clear how the number of jobs could drop so precipitously while the number of biotech companies in the state rose (from 319 in 1988 to 510 two years ago, according to Shahrokh), MedImmune is an example of how companies can eliminate the need for more jobs by improving productivity. The company was designing an increase in manufacturing capacity at an estimated cost of $50 million to $80 million when it made breakthrough improvements in its existing manufacturing processes, said James F. Young, executive vice president of research and development.

"Because we made the improvements, we don't need to do that," he said of a plant expansion.

Edward A. Goley, vice president in charge of the Frederick plant, said MedImmune's scientists found ways to optimize conditions for the cells in its nutrient-laden soup, leading them to produce more of the vaccine.

"We're talking about living systems," Goley said, explaining that the vaccine-producing cells have respiratory rates and must get the right amounts of food, oxygen and space to grow and divide. "It's like growing up in the country vs. New York City."

The plant also illustrates why the state has targeted biotech for growth: It has produced high-paying jobs.

MedImmune employs about 170 people on its Frederick campus, including warehouse workers and administrators - about 20 more than it initially estimated.

The majority live in the Frederick area and are college-educated and salaried. MedImmune declines to discuss what it pays workers, but the Frederick County Office of Economic and Community Development estimated in December that the plant would have an annual payroll of about $10 million. It also said it believed that salaries would average $68,000 a year, with hourly workers making $34,000.

A trip inside MedImmune's plant shows just how different the biopharmaceutical work is from manufacturing jobs in traditional industries such as steel-making.

MedImmune's 90,000-square- foot building in Frederick is two plants in one, divided down the middle by a broad, gray-floored hallway that workers can enter only after they have walked through a locker room to put on scrub suits.

Red doors on one side lead to production space for drugs made from plasma, such as CytoGam, which is designed to fight infection in certain organ transplant patients. MedImmune has applied to the FDA to produce a portion of that drug for the market in Frederick, meaning it could soon be expanding again. On the other side of the hall, green doors lead to its cell culture plant, where Synagis is made in the soup.

Inside the anteroom, Cacciuttolo has finished putting on the coveralls along with a rubber-soled set of knee-high cloth boots, also pulled from a bag, and a mask covers his mouth and goatee.

"Once we cross this line, we can't go back" without having to change clothes again, Cacciuttolo says just after pulling on his second boot and stepping to the "clean" side of the room, over a line taped to the floor. Then he guides his similarly gowned visitors deeper into the plant through a specially sealed door.

The filtered air inside is free of 99.997 percent of the particles in outdoor air. Pressure differences blow the clean air out, rather than the dirty air in, as he opens the door.

Another small room with a circular, padlocked freezer is the first stop. Inside, stored in liquid nitrogen at temperatures as low as minus 190 degrees centigrade, are tiny vials filled with small white pellets used to seed MedImmune's living soup. Each vial contains 10 million cells that will come to life when warmed in a water bath at 37 degrees centigrade (MedImmune's water is pure enough to safely be injected into a human body) and deposited in a small, flat flask filled with MedImmune's proprietary pink nutrient mix.

The company created the cells in a lab, in part by combining synthetic bits of a mouse gene with bits of a human antibody gene. The combination is designed to produce the antibody - which MedImmune has dubbed Synagis - that fights respiratory syncytial virus in infants without causing the body to reject the medicine as foreign.

But the cells that spit out Synagis are sensitive. They grow only when in a certain proximity to each other. So MedImmune's gowned workers first deposit the cells in a small, flat flask filled with its pink medium and place it in an incubator. As the cells grow and multiply, they are transferred to a larger "spinner" flask that gently rocks them, and finally into a series of increasingly larger bioreactors, R2D2-shaped vats in which the cells are coddled, fed amino acids, rocked and warmed.

On this afternoon, in MedImmune's Bioreactor Hall C109, three workers watch over the cells, monitoring items such as temperature and acidity levels. They mark every reading on a dizzying array of FDA-required quality-control sheets that are checked by other MedImmune workers to ensure accuracy. The place has the look of a high-tech beer fermentation hall, with pipes running in and out of the gleaming vats and records flashing on personal computers.

To determine if the cells are multiplying readily, production technician Jeffrey Anderson turns a series of valves on the 250-liter bioreactor and drains a small sample into a plastic bottle. Then he walks briskly into an adjacent room where fellow worker Thomas Barnhart sits before a microscope.

By looking at a drop or two of the sample on a gridded slide, Barnhart can eyeball the number of live cells per grid, using it to estimate how many cells are in the vat. When the number hits a certain threshold, the entire 250 liters will be transferred into a larger bioreactor. The hall's largest bioreactor is a 2,500-liter vessel that is more than a story tall and produces thousands of vaccine doses per batch.

After 22 days in that vessel, the contents will be sucked through one of the pipes to another place in the plant, where the cells will be separated from the antibodies amid air that is even cleaner than that in Bioreactor Hall. Later, at a contract manufacturer, the liquid will be freeze-dried and deposited in vials that contain one dose of the drug each and sell for $900.

From start to finish, the process - including packaging - will take about nine weeks.

"You've got to be 100 percent, seven days a week, 24 hours a day dedicated," Anderson says about his job, noting that a mistake in pH or temperature could ruin a batch. "If an alarm goes off and you're at home eating a hamburger, you've got to get in a car" and head in.

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