'Don we now sterile apparel ?'

Double-checking data, minimizing contamination and calibrating lab instruments are business-as-usual practices for most scientists.

But when the fruits of the laboratory are therapeutic products for patients, such quality and accuracy checks must surpass routine levels of stringency.

That's why Fred Hutchinson has built a $3 million, squeaky-clean, state-of-the-art shared resource for the manufacture of cell-based products aimed at improving treatment for diseases including leukemia, skin cancer and HIV infection.

The facility, scheduled to open in January, enables center investigators - already leaders in research to harness the power of human immune cells to treat these and other diseases - to deliver promising new and customized therapies more efficiently to patients with critical illnesses.

Located on E (basement) level of the Thomas Building, the 4,500-square-foot Cell Processing cGMP (for current good manufacturing practices) Facility allows for the reproducible production of human blood and immune cells that have been manipulated for therapeutic purposes. Such products must meet U.S. Food and Drug Administration standards which, said facility director Dr. Shelley Heimfeld, continue to undergo refinement.

Tight control

"These facilities and regulations were originally developed for drug manufacturers," he said. "Now, the FDA and granting agencies such as the National Institutes of Health have required that manufacture of therapeutic cell products be tightly controlled as well. Essentially, they are saying that such cells should be treated as if they are drugs."

Heimfeld, also an investigator in the Clinical Research Division and director of the center's Cellular Therapy lab, said Fred Hutchinson is one of only a handful of research institutions that have created this type of facility.

"This is still a very new area, and regulations and policies are still being defined," he said. "But there are now clear requirements for a special, separate facility with particular process control and highly trained staff. Ultimately, the FDA will conduct inspections of such facilities."

The facility will be used to produce any cell population that undergoes extensive laboratory manipulation, such as modification of its genetic material. Cells harvested from bone-marrow or stem-cell donors for routine transplant procedures do not fall into this category, Heimfeld said.

Examples of extensively manipulated cells, he said, might be:

• Blood cells from a patient with sickle cell anemia that have been engineered to contain a healthy version of the defective gene.
• The selection and expansion of populations of T cells that have specific virus- or cancer-targeting activity.

What distinguishes this type of manufacturing from standard drug production is that every cell product made in the facility is customized. Each patient typically receives a unique cell preparation made from his or her own tissue to prevent rejection by the immune system.

Center investigators sponsor 10 treatment clinical trials that involve products that will be manufactured in the new facility. Until now, these cell-based therapies have been produced off-site, a practice which increasingly became cost-prohibitive.

Therapeutic cell products are produced according to current good manufacturing practices (cGMP), a phrase that refers to FDA regulations that govern the safe manufacture of drugs, food and medical devices. "Current" reflects the changing nature of these guidelines as better practices and procedures are identified.

cGMP standards

For cell and tissue manufacturing, cGMP standards include establishing a dedicated space that is maintained with the highest levels of cleanliness and sterility. The center's facility was designed with a high-efficiency air filtration system and airlocks between internal rooms to prevent cross-contamination. All critical equipment is connected to emergency power and an alarm system that is monitored 24 hours a day. Digital automation systems continuously monitor and control access of personnel, lighting, incubator temperature and humidity and air pressure.

Access to the facility is strictly controlled and staff must don sterile gowns in a designated gowning area before entering any of the four laboratory suites.

Products manufactured in the facility must meet strict quality-control and -assurance guidelines, said Kim Stankey, manager of the facility.

"Quality control includes specific tests that a product must go through, such as those to assess sterility," said Stankey, who has worked with cell-based therapies for seven years in Dr. Stanley Riddell's Clinical Research Division laboratory.

"Quality assurance is essentially oversight of the whole manufacturing process, including calibration of machines and ensuring standardization of procedures such that each batch of a product performs similarly in tests."

In addition to Heimfeld and Stankey, the facility is staffed by:

• Beth MacLeod, who serves as manager of quality control and quality assurance
• Cody Sontag, who handles administration and budgeting
• Chris Heinonen, a computer analyst who oversees database management
• Three laboratory technologists.

Dr. Michael Linenberger of the Clinical Research Division, also an associate professor of medicine at the University of Washington and director of the National Marrow Donor Program Collection Center at the Seattle Cancer Care Alliance, serves as medical director. More staff may be added as use of the facility increases.

Interface with other resources

The Cell Processing Facility interfaces with three other shared resources, including the Cellular Therapy lab, in which blood-forming stem cells are prepared and stored for transplantation; Flow Cytometry, which performs sorting and analysis of cells; and the cGMP Biologics laboratory, which manufactures antibodies and other molecules.

As with other shared resources, services will be provided on a fee-for-use basis. The facility is also supported by funds from Fred Hutchinson's core grant from the National Cancer Institute, as well as grants awarded to center investigators whose research is intimately associated with the facility.

Initially, the new facility will support services for patients undergoing treatment at the Alliance and may also manufacture products for institutions that collaborate on center projects but do not have facilities of their own.

In the future, the facility may perform contract work for outside researchers.

Drop it, dunk it - this laptop will still work in new sterile lab

Tackling tough challenges is part of the job in Information Technology (IT), which oversees the center's complex and diverse computing environment.

But Joseph Flahiff, project manager, admits he initially was stumped by the unusual project proposed to him by staff of the Cell Processing (cGMP) Facility.

Like any other laboratory, the new facility's scientists rely on computers to store and process vast amounts of data. Yet the scrupulously clean environment that the lab must maintain requires subjecting all equipment to harsh sterilization.

"Everything in that laboratory needs to be kept sterile, including the computers," Flahiff said. "That means wiping down the computers several times a day with alcohol. We needed to find a computer that could withstand that kind of treatment."

Flahiff enlisted IT colleague Nancy Crase, telecommunications analyst, to seek advice from local biotechnology companies that also house "clean" labs.

"Nobody had dealt with this," he said. "Most facilities resort to recording data with pencil and paper."

Flahiff drew on his experience as an IT consultant to come up with an idea. Having worked with police departments on computing projects, he recalled seeing laptop computers designed to military specifications.

"These are resistant to sand and dust and are so resistant to impact that you can literally throw them," he said. "And they are waterproof. You can actually take them into the shower."

But the crucial requirement was to find a computer that could endure daily sterilization with alcohol.

Ultimately, Flahiff and Crase chose the Panasonic Toughbook. Several of the laptops - which are wireless, eliminating the need for sterilization of cables - are in use in the Cell Processing Facility.

Call it all in a day's work for IT.