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In 1999, chemists and biologists at what was then American Home Products embarked on an ambitious project to upgrade their company's medicinal compound storage and management system. The company's chemical library had been growing by leaps and bounds, thanks to a combination of library purchases, in-house synthesis by medicinal chemists, and acquisitions such as the 1994 purchase of American Cyanamid. But keeping track of the compounds--used for screening against disease targets--required 20 people, and still the staff was having trouble keeping up with screening demands. Wyeth executives knew they had to standardize and automate the maintenance of their compound collection. At the same time, they were looking for alternatives to the complex robotic systems chosen by some drug industry competitors that had a head start in the automation process. Today, American Home Products is known as Wyeth, and John E. Morin, director of high-throughput screening, and his colleague Dominick Mobilio, director of cheminformatics, are owners of what they believe is the state-of-the-art system for compound storage and retrieval. Their system, fully up and running for three months now at Wyeth's laboratories in Pearl River, N.Y., incorporates two breakthrough compound management technologies: a custom-built process for dissolving dry compounds in dimethyl sulfoxide (DMSO) and a compound storage and retrieval setup based on the unlikely concept of pneumatic tubes. A walk-through of Pearl River Bldg. 222 with Morin and Mobilio reveals the vestiges of Wyeth's old storage system: a cavernous room of aging freezers once filled with rack upon rack of dissolved compounds that needed to be retrieved by hand. It was this system that Morin and Mobilio--working together across two normally separate and sometimes squabbling drug company functions--were determined to rethink. Before broaching the storage problem, however, they tackled the means by which Wyeth created DMSO solutions of its compounds. They were using the industry standard of dissolving them in test tubes and pipetting the resulting solution into open-air deep-well plates. But DMSO is highly hygroscopic, and, according to Mobilio, researchers at Wyeth and other firms were learning the hard way that exposed solutions rapidly absorb atmospheric water and oxygen. Wyeth's response was partnering with Advent Design Corp. to modify an industrial "pick and place" device--used to make everything from cellular phones to ball bearings--to work under an atmosphere of nitrogen gas. The customized system, which took six months to design and another year to build, flushes dry compounds with nitrogen before dissolving them in DMSO that has itself been distilled in nitrogen. The solution is pipetted into inch-long bar-coded polypropylene vials that are then capped and assembled in 8-by-12 racks. The Advent system passed site acceptance tests in December 2001, and Wyeth spent the next six months processing some 350,000 compounds from its 1 million-plus compound library. Morin and Mobilio, meanwhile, continued to explore their options for the storage and retrieval of their newly dissolved compounds. Polypropylene breathes, so keeping the compounds inert required an external nitrogen atmosphere during vial storage. However, according to Morin, many of the traditional vendors of storage and retrieval equipment weren't interested in developing a nitrogen-atmosphere system. Those who were interested proposed very big solutions--both in physical size and price. At a loss, Wyeth scientists were considering fixes as extravagant as a nitrogen-filled storage room that would be accessed by technicians in space suits. Then, in 2000, TTP LabTech, a British engineering design company, developed a storage system it called comPOUND. ComPOUND is an 8-foot-high storage freezer that holds up to 100,000 vials in a stack of disklike carousels that can be blanketed in air or nitrogen. Rather than using a robotic arm to "cherry pick" vials, as most competing systems do, comPOUND lines up its carousels and pneumatically funnels the desired vials into racks through built-in channels. TTP claims that comPOUND can retrieve any desired vial within an average of five seconds and fill a 96-vial rack in eight minutes. For Wyeth, a drawback of comPOUND was that researchers must manually pick up assembled racks through a small door, an unwanted extra step before screening preparation. TTP's response: comPILER, a rack assembly and screening prep device that collects vials from comPOUND via pneumatic tubes much like those used 50 years ago in banks and department stores to deliver mail. Competing assemblers such as the Haystack retrieval system from the Automation Partnership--recently installed at Merck and Amgen--use robotic arms to gather racks of compounds. But compound handling at -20 ºC presents challenges for robotic systems, including ice formation and lubricant freezing. TTP's pneumatic system, in contrast, has few moving parts--"automation without the anthropomorphic arm," Morin says. Visitors to the compound-handling room at Wyeth's screening resources lab can watch vials of frozen solution whiz out of comPOUND, travel overhead through long transparent tubes, and rocket down to a landing pad in comPILER. There, assembled racks are slowly thawed on a warming track. Next, a centrifuge spins the racks, removing liquid that may have splashed onto the vial caps. The caps are removed, and the vials are flooded with argon, which is heavier than air and keeps the solutions oxygen- and moisture-free. -------------------------------------------------------------------------------- "We try not to be tech-heads. As much as we love these machines, they are just tools in the drug discovery process." -------------------------------------------------------------------------------- AN ADJACENT plate-management device made by TekCel then pipettes about 5 µL of solution from each vial onto a well on a 384-well plate. The vials are topped off with argon, recapped, and sent back to storage, never having left the inert atmosphere. Completed plates are transported via an internal track to adjacent TekCel PlateServer/PlateStore modules where they are sealed and stored under inert atmosphere. They are eventually transferred to nearby high-throughput screening labs--which have themselves been upgraded with the TekCel modules. Morin and Mobilio are obviously proud of their new tools. Yet they claim not to be overly enamored of the gadgetry. "We try not to be tech-heads," Morin says. "As much as we love these machines, they are just tools in the drug discovery process." In addition, the system is a work in progress. For example, the scientists want to close a gap in which compounds are briefly exposed to air during the transfer from vials to plates. And Wyeth is still developing software to help automate certain manual aspects of its compound management system. But with the help of their new storage and retrieval system, Wyeth scientists are approaching the pharmaceutical industry standard of retrieving and screening 500,000 compounds a month in at least five parallel screens. "This system is what we needed to reliably accomplish that," Morin says. |
| UPDATE | 05.03 |
| COMPANY | Wyeth |
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