An Mo-99 generator that produces Tc-99m and vials for elution of Tc-99m to prepare radiopharmaceuticals. Courtesy Covidien Radiopharmaceuticals

With the current world shortage of molybdenum-99 (Mo-99) and the aging of the research reactors that produce this vital precursor of the technetium-99m (Tc-99m) used in about 80 percent of nuclear medicine procedures, two American companies have come forward with unique concepts for producing this isotope. Advanced Medical Isotope Corp. (AMIC), in Kennewick, Wash., is proposing to create Mo-99 using compact systems similar to the proton linear accelerator it is now using to produce fluorine-18. Meanwhile, Lynchburg, Va.-based Babcock and Wilcox Technical Services Group, which operates nuclear facilities throughout the U.S., has teamed with Covidien Ltd. of St. Louis, one of only two U. S. manufacturers of the Mo-99/Tc-99 generators, to develop production of Mo-99 in a series of compact liquid fuel reactors.

AMIC proposal

AMIC is exploring six different solutions to the isotope shortage, according to Robert Schenter, PhD, chief science officer. The one that is furthest along involves working with scientists and researchers at the University of Missouri to make Mo-99 in a compact fission system.

"Our expertise is in compact systems to make medical isotopes," Dr. Schenter explained to ADVANCE in an interview last fall. "We already have a proton LINAC compact system in Kennewick, where we are making fluorine-18 and PET isotopes. We are also going to be making indium isotopes in Buffalo, N.Y. on a cyclotron, so our expertise is compact systems to make all major therapeutic and diagnostic isotopes."

An advantage of the University of Missouri device is that it uses electrons that hit a target, creating gammas that in turn produce neutrons, so the device can be turned off and on as needed, he said. At the time of the interview, however, the device had not yet produced any Mo-99.

Another option under consideration is the use of a compact neutron generator developed at the Lawrence Berkeley National Laboratory in California.

"What the Berkeley people have done is miniaturize a fusion device down to smaller than room size, where you make high energy neutrons," Dr. Schenter said. "These neutrons then hit a target and the target produces Mo-99, with no fission products. It is a faster process." (For more on this system, visit http://ndt.net/article/wcndt2004/html/htmltxt/706_leung.htm.)

This January, AMIC announced that it was partnering with the U.S. Department of Energy (DOE), through the Pacific Northwest National Laboratory, on a two-year project with the Kharkiv Institute of Physics and Technology in the Ukraine. The project's goal is to develop and bring to market a compact system using the Alternative Method for Producing Medical Isotopes being developed at the Kharkiv Institute. This method will generate an intense neutron beam under controlled conditions to produce neutron-rich medical isotopes.

While individual compact systems would not produce as much Mo-99 as the current research reactors in Europe and Canada, their smaller size and lesser cost would allow several to be stationed around the U.S. producing the isotopes closer to potential users, Dr. Schenter said.

The ability to site multiple small systems in various areas of the country will also be useful for the production of carbon-11 (C-11), an important PET isotope with a short (20.3 minute) half-life that is being used to label radioisotopes under research for imaging prostate cancer and Alzheimer's plaques.

According to a company spokesperson, the high production rates of the LINAC in the Kennewick facility may make it possible to ship C-11 within an 80- to 100-mile radius of the LINAC production facility.

Partnering for production

Although close proximity to users would reduce the amount of isotopes lost by decay during shipping, any Mo-99 thus produced will either need to be shipped to the Covidien facilities in St. Louis or the Lantheus Medical Imaging facilities in N. Billerica, Mass. These are the only FDA-approved Mo-99/Tc-99m generator manufacturers in the U. S.

This January, Covidien announced that it had signed an agreement with Babcock and Wilcox (B&W) Technical Services Group to develop technology to make Mo-99.

"What attracted us to B&W is their specialty in providing nuclear energy and technical services around nuclear energy products," said Dale Simpson, BS, manager of research and development for Covidien. Thus, they have expertise in dealing with government licensing and regulations, Simpson said. Covidien brings its expertise in the radiopharmacy business and dealing with FDA approval processes. The company has also been purifying Mo-99 from targets irradiated at the NRG facility in Petten and shipping that material to its facilities in St. Louis.

The patented B&W Aqueous Homogeneous Reactor, which can produce the Mo-99 medical isotope using low-enriched uranium targets. courtesy Babcock and Wilcox Technical Services Group

The proposed isotope production facility would make Mo-99 and other fusion isotopes in an aqueous homogeneous reactor (AHR), also known as a solution reactor. This reactor uses low-enriched uranium (LEU) for both fuel and target, rather than the high-enriched uranium (HEU) now used in producing medical isotopes, addressing the concerns that last month prompted the National Academy of Sciences to issue a report urging medical isotope providers to switch from HEU to LEU to produce medical isotopes.

In addition, virtually all of the commonly used reactors use the uranium fuel in solid form and also use solid targets, which produce the fission products once the uranium reaches a critical mass. The AHR uses uranium fuel salt dissolved in acid and water.

The interesting part of the liquid criticality device is that when the criticality occurs, fission gases form little bubbles that reduce the reactivity and so the reaction tends to shut down until the bubbles dissipate, said Evans Reynolds, ME, program manager for B&W's medical isotope production system.

"It is self-limiting, which is an inherent safety feature," Reynolds said. Also, each AHR produces only about 200 kilowatts of power, while a research reactor produces about 45 thousand kilowatts (45 megawatts) and power reactors produce about a thousand megawatts. "Each of these reactors is in the neighborhood of 2 feet in diameter and 4 feet tall and works at atmospheric pressure. It also operates at 80 degrees centigrade, so there are no high temperatures to worry about."

Another safety feature is that it does not use solid targets, similar to those used in current reactors. After irradiation, those solid targets have to be extracted from the reactor and dissolved in acid to recover the isotope products. The targets then become HEU radioactive waste, with more than 99 percent of the uranium still in the target, Reynolds explained.

The AHR, however, does not use a solid target, as the Mo-99 is extracted directly from the liquid fuel, where it is stripped of the Mo-99 and other usable products. The fuel is then returned to the reactor, where it is periodically refreshed with small amounts of uranium to keep the chemistry right. This process continues for the life of the machine - about 25 years. As such, there is minimal radioactive waste accumulation, since many of the other products of fission, including I-131 and Xe-133, are also useful. It also allows skipping one part of the solid target Mo-99 process, because the Mo-99 is already dissolved in the acid and ready for processing into the generators.

And, unlike other methods proposed to produce Mo-99, the AHR uses existing technology that has been used in the U.S. and Russia for many years.

"It is just a matter of refining existing technology and making sure it passes commercial viability tests," Reynolds said.

Current plans are to install four of the systems in the initial facility. The modular nature of the systems can allow for expansion within the facility or to other areas of the world as the need arises, Reynolds said.

"What we have discussed in the past is that each one of these 200 kilowatt machines would be capable of about 1,000 six-day curies a week, and the U. S. demand is 5,000 to 6,000 six-day curies a week, Reynolds said. "Even allowing for some inefficiency in delivery, it should comfortably handle about 50 percent of the U. S. market."

Unfortunately for those impacted by the current shortage, Reynolds estimates it will take between five and six years before this system is up and running.

Once it is in service, however, the modular nature of the system will help in stabilizing the Mo-99 supply. If one of the modules fails or needs maintenance, the others would still be running. The company has not finalized the site for the facility, but any site in the Eastern U.S. would be closer to St. Louis than Covidien's current suppliers in Europe.

 "I think the combination between B&W strengths and our strengths is definitely a plus for this project to be successful," Simpson concluded. "A key benefit of the agreement is that it diversifies our supply and gives us a U.S. base of supply. It is also environmentally friendly, because it generates less waste than the current processes, and it obviously supports the non-proliferation efforts of HEU to LEU conversion."

Joyce Ward is senior technical editor at ADVANCE. She can be reached at jward@advanceweb.com.