A Place Like No Other

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By Nicole Resnick

There's a relatively new tenant on the western edge of the neighborhood known as the University of Wisconsin-Madison campus, and in the short time since opening its doors to the public, the Waisman Clinical BioManufacturing Facility (WCBF) already has to play an important role in the growth of local, national and even international industry.

Located in the north tower of the Waisman Center at the western edge of the UW campus alongside UW Hospital and Clinics, the WCBF provides a unique resource not only to its university partners but also to the state of Wisconsin.

"Our focus is to assist our customers in transferring early stage discoveries from the lab into a clinical trial," says John Keach, business development manager of the WCBF.

As a facility that specializes in efficiently transitioning research into clinical trials, the WCBF decreases the time and cost associated with this stage of development. "We serve as the bridge between the lab and the clinic, and we help university and outside investigators understand what they need to do to make this leap," he says.

Like a Maze
Occupying almost 10,000 square feet of space, the interior of the WCBF strikes the first-time visitor as a maze of high-tech laboratories. Each of the six "suites" is separated from its neighbors to create a series of discrete, controlled areas. But that is precisely the point. With names such as the "microbial products suite," the "mammalian cell processing suite" and the "aseptic filling suite," each laboratory was designed to fulfill a specific job with 100 percent accuracy, sterility and accountability. There is no room for error when it comes to manufacturing drug therapies for human disease.

As a state-of-the-art "clean-room" facility, the WCBF provides manufacturing and testing services to academic researchers and industry partners for a broad range of pharmaceuticals. The facility operates under the U.S. Food and Drug Administration current Good Manufacturing Practice guidelines to manufacture biological pharmaceuticals for early-stage human clinical trials.

Several features of the WCBF contribute to the unique nature of the facility. It was designed and built with the sole intention of providing the services it currently provides. So, as Keach points out, unlike many other academic clean room and manufacturing facilities in the U.S., the WCBF is not a "retro-fit" design.

Moreover, the WCBF is the only academic facility of its kind that is multi-use, or can accommodate mammalian cell (such as human and mouse), bacterial cell and aseptic fill capabilities. Most institutions that offer anything comparable are usually equipped to deliver only one, rather than all, of these services.

The Value of Being Non-Profit
There is an economic factor that sets the WCBF apart from its competitors: It is a nonprofit institution.

This facility, as a nonprofit, is able to allow more companies to move ahead into Phase I [clinical trials]," says Derek Hei, director of the WCBF and former director of biomedical engineering at Cerus Corp. in California. "Demonstrating proof of concept in Phase I trials allows companies to generate clinical data and gain more funding to support future development."

Hei says the WCBF contributes a tremendous resource to new companies because typically, in the past, investigators had to rely on partnerships with big pharmaceutical companies to move forward with promising new biotherapeutics.

The bottom line of being a non-profit, as Keach sees it, is that it puts the WCBF at an advantage because it can usually beat any commercial manufacturer on price. The savings in costs it offers can be especially attractive to young startup companies. The downside, however, is that the facility doesn't earn the additional money or profit margin that easily allows it to remain cutting-edge in training, methodology and internal research and development, and has had to find other ways to remain cutting edge.

"That's the aspect of being nonprofit that's affected us the most," he says.

Yet Keach points out that once he gets potential clients in the door to visit the facility, they usually come away quite impressed. The challenge lies in persuading clients to first approach the door. As a university-affiliated institution, the WCBF does not naturally attract as many industry clients as Keach would like.

The Challenge is in the Perception
"We still struggle to overcome the challenge of being perceived as an academic facility," says Keach. "There is an impression that academic facilities focus on academic research needs, rather than quality production and manufacturing."

Keach is actively working to alter this perception, and he recognizes the need to do more outreach. "We need to get the message out that while we may be at a university, we're staffed with industry experienced people," he says.

He also emphasizes how the WCBF — because it does not have to worry about a profit margin — engenders a more collaborative and collegial relationship with its customers, allowing more give and take.

"We can be more open with customers about what the real cost is — something they don't typically find with commercial manufacturing facilities," he says.

There's no doubt that the efforts by the WCBF team are paying off. The facility recently took on several new long-term projects and now is operating at near 100 percent capacity. In the past six months business has surged, and the WCBF now boasts a list of customers that includes biotech companies on the West Coast (both the San Diego and San Francisco areas), as well as in Seattle, Aurora, Colo., Washington D.C., and Kensington, Md. Keach says the WCBF is close to signing with another four to six companies, including two more in the Madison area.

In a recent press release, a new partnership between the WCBF and a Vancouver, British Columbia, company called Protox Therapeutics was announced. As Protox geared up to begin Phase I clinical trials of its No. 1 drug, PSA-PA1, used for the treatment of localized prostate cancer, the company turned to the WCBF for the large scale manufacturing of the drug.

Said Tom Buckley, chief scientific officer of Protox, in the press release, "WCBF appears to be most suited to produce our lead product in development within our budget and timelines."

On-Campus Partnerships
As WCBF makes progress connecting with clients nationwide, it continues to provide valuable services for some of the most groundbreaking medical research taking place on the UW campus. One of the first such partnerships formed was with a team of researchers from the UW School of Veterinary Medicine's Department of Surgical Sciences, which is investigating ways to improve human organ transplantation.

Led by Jonathan McAnulty and Christopher Murphy, the research effort focuses on the role of trophic factors in the process of transplantation. Trophic factors are a mixture of molecules normally found in the blood that allow organs to remain viable and functional once they are transplanted into recipients.

McAnulty, Murphy and their colleagues initially used a dog model of transplantation to identify a combination of factors that, when added to a specialized organ preservation solution, improved the quality and length of time that kidneys could be preserved until transplantation into a recipient animal.

Next comes the leap from the successful dog model to human subjects. After honing in on the optimal combination of trophic factors, the researchers designed a Phase I clinical trial to be conducted at UW Hospital. The key step in the process is the large-scale production of the trophic factors that are guaranteed pure enough for human use. This project is currently under way.

"The Waisman Center has been very advantageous for us to collaborate with, and they were helpful upfront in putting together an FDA proposal," says McAnulty.

Other benefits of working with the WCBF, says McAnulty, include its convenient location (walking distance from the veterinary school) and the faculty's push to move the project along without letting it stagnate. He also is impressed by the level of knowledge and professionalism exhibited by the group at the facility.

"It's a big step moving from the lab research phase of a project to clinical use, and they have brought a lot of added value to the process," he says. "If we get past Phase I, and I'm confident we will, we'll be looking to do Phase II/III trials, and we look forward to working with them."

Attracting Top-Notch Researchers
The existence of a facility as valuable as the WCBF even may serve as extra incentive offered by the UW to bring top-notch researchers to the campus. An example of this phenomenon was the hiring of world-renowned neural stem cell researcher Clive Svendsen. Recruited from Great Britain several years ago, Svendsen moved his research program, including several of his laboratory staff, to Madison to join the Waisman Center.

Svendsen says that the promise of the WCBF — which was a mere skeleton of a building at the time when he first came to visit the UW-Madison campus — largely influenced his decision to accept the position here.

"A facility like this was required to bring the work with my neural stem cells to patients; this was a mechanism for generating cells that could be FDA approved," he says. "The facility was an enormous draw."

Since setting up shop at the Waisman Center, Svendsen has accomplished his goals of producing banks of neural stem cells and then scaling them up through the WCBF. Under the keen technical guidance of the facility's staff, they're ready to be used as a source of tissue for transplantation for treating ALS and Parkinson's Disease.

"Derek [Hei] has been instrumental in working with the FDA to put together packages to begin using them in clinical trials," says Svendsen. "His knowledge has been invaluable."

Federal Agencies Are Also Partners
Another source of projects for the WCBF is federal research at agencies such as the National Institutes of Health. According to Hei, the facility has nearly completed a five-year long, $2 million contract with the National Institute of Arthritis and Musculoskeletal and Skin Diseases to become a national supplier of specialized cells used in therapeutic skin cell research. Effective treatment of burns, for example, relies heavily on being able to grow large-scale quantities of skin in the lab — a clinical challenge that continues to pose many problems.

The WCBF's contract with the institute also is significant because of the growing emphasis on the concept of skin gene therapy, says Hei.

"The idea is to grow sheets of cells [containing a therapeutic gene] and then transplant them onto a patient — kind of like a living version of the Nicoderm patch," he says.

Hei is hopeful that this partnership will lead to more work with the NIH in the future, especially in the realm of embryonic stem cells. "This is a big area we hope to move ahead with in collaboration with Dr. Jamie Thomson [UW stem cell scientist] and the WiCell investigators at the UW."

Small Markets Pose Another Challenge
For now, there are other hurdles to overcome if the WCBF is to establish itself as a leader in its specialized field of services. Keach says, the challenge lies in the relatively small local and regional market from which the facility can draw clients. Until now, the WBCF struggled to operate at maximum utilization, most likely because there are not enough local companies that are at the point of needing to scale up and manufacture large molecules for clinical use.

Yet Keach is continuing to increase awareness by targeting those companies that may have a specific need for a facility such as the WCBF sometime in the future. Hei does his part by offering his expertise and advice, as well as keeping the lines of communication open with potential companies in the Madison area.

"We want to make sure that these companies know that we're here and that we can answer some questions and help provide some input — even if they end up not using our facility," he says.

The ups and downs of establishing the WCBF makes for an exciting ride, yet Hei is determined not to compromise one of the founding missions of the WCBF. The facility was built for the purpose of manufacturing therapeutics designed for treating rare diseases, or "orphan drugs," which may not be as economically attractive and often don't merit the funding that more common diseases receive.

"These may not provide enough of an economic incentive to get pharmaceutical companies interested, but with the help of WCBF, investigators can still manufacture therapeutics which will eventually help people," he says.

As Hei points out, that is one of the reasons why the Waisman Center was created in the first place.

"When dealing with mental retardation and other related diseases often the causes are rare. Gene-based therapy for treating them is one of the great hopes," he says. "The Waisman Center is here to support the development of promising new therapeutics, even for rare disorders."