Isotope Crisis: New Technologies Primed for Post-Chalk River Production

Continued shutdowns at research reactors throughout the world have created shortfalls in essential medical isotope supply for several years. One of the world’s top suppliers, the National Research Universal (NRU) reactor facility in Chalk River, Ontario, Canada, is scheduled to close its doors in the fall of 2016. As stakeholders scramble to prevent an all-out crisis in isotope supply, a few new technologies have experts encouraged, but still uneasy.

Last November, after a brief closure, the Atomic Energy of Canada Limited’s (AECL) NRU facility in Chalk River resumed production of molybdenum-99, colloquially known as moly. This is the all-important parent element needed to procure technetium-99m, which accounts for the vast majority of worldwide medical isotope demand. The news came shortly after another announcement that the Dutch Petten High Flux Reactor, another major producer of medical isotopes, would close its doors temporarily for up to three months. The SAFARI-1 reactor in Pelindaba, South Africa, a producer of up to 25 percent of world supply, was also closed due to an unexpected leak. This came shortly after three reactors were concurrently closed in May of last year. The Chalk River facility had closed its doors for an entire year in 2009 and a morass of closures in 2007 and 2008 meant an impossibly high percent of the global demand was periodically left unmet. To provide a snapshot, every year the nuclear medicine community performs an estimated 30 million imaging studies, according to the European Nuclear Society. Thousands and thousands of nuclear medicine procedures had to be canceled as a result.

This musical chairs of shutdowns has been a scourge for the nuclear medicine community for the past 10 years and it is no wonder. It is well known that the dinosaurs used to meet global demand are on average 50 years old and well beyond the intended lifespan of their design.

The status quo

A few hulking research reactors that figure into the worldwide market for medical isotopes dot the landscape from continent to continent—six reactors to be exact. These are the Canadian NRU Chalk River facility and the Petten reactor in The Netherlands, which collectively supply 100 percent of North American demand of molybdenum and about 80 percent of total global need. The others are the OSIRIS reactor in France, the BR-2 in Belgium, the before-mentioned SAFARI-1 and the OPAL in Australia. There are other research reactors throughout the world producing medical isotopes or currently under production, but mostly for domestic supply.

The single most important news for the world isotope market is the announcement that the Chalk River reactor will be decommissioned in 2016, and to add pressure, other reactors are expected to shut their doors permanently within the next five years, including the OSIRIS and High Flux Reactor. Obviously, the heat is on to provide solutions for what could be a devastating shortfall in medical isotope supply if new technologies do not step up. There has been some well-publicized jockeying to set new lines of production in motion that have so far been less than successful, including the AECL’s Maple reactor project that is now discontinued and a no-go partnership between Babcock & Wilcox and Covidien for Aqueous Homogeneous Reactor (AHR) technology using low-enriched uranium (LEU). The later would have reportedly produced as much as half of global demand. Still in the works is a South Korean facility scheduled to open sometime in 2016 and a platform is moving forward in Russia for world distribution. Argentina and China also may bring new facilities to the global supply network (Nature. 11 Dec 2014).

The European Nuclear Society also has deemed the relatively new FRM-11 reactor in Munich a possibility for moly recovery, but a supply chain would have to be worked out for these targets.

Johan Verzijlbergen, president of the European Association of Nuclear Medicine, and professor of nuclear medicine at Erasmus University in Rotterdam, The Netherlands, says that after Chalk River is shuttered in October 2016, the Belgian BR-2 also is scheduled to shut down for more than a year to switch from highly enriched uranium (HEU) to LEU targets. The rest of the producers will have to strike a very delicate balance until new projects come online. Any unplanned closures could be catastrophic to patient care.

“The effect of a shutdown of one of the reactors will result in shortages in North and South America, part of Asia and less severe in Europe,” warns Verzijlbergen. “The shutdown will affect many nuclear medicine diagnostic procedures. The impact will be worst in oncologic and cardiac diagnostic procedures.”
Epicenter in the Americas

Liable to feel the pinch the most, North America and particularly the United States needs to focus on solutions based close to home. Peter Herscovitch, MD, PhD, incoming president of the Society of Nuclear Medicine and Molecular Imaging (SNMMI), asserts that European efforts are not enough to secure North American supply. “For patients to receive the best medical care, it is essential that a reliable supply of molybdenum-99 (Mo-99) be available in the United States. SNMMI highly appreciates efforts from outside the U.S. to stabilize Mo-99 supply, but this is a stopgap measure.”

The U.S. National Nuclear Security Administration (NNSA) has been supporting the development of four modes of moly supply that provide an alternative to HEU targets associated with nuclear arms proliferation. Herscovitch says the goal of developing a stable commercial supply must be nearing completion, because fiscal year 2015 funding for this initiative has been reduced. “However, it is not at all certain that the goal will be achieved within this timeframe.”

Shiny new possibilities

Centralized reactor approaches are not the only solution for this long-term challenge. A few of these new projects center on rather decentralized technology. But first, a review of conventional production. Uranium-235 targets are usually irradiated in a research reactor. Downstream production of moly from these targets takes place in a handful of facilities throughout the world. The decayed element, technetium-99m can then be prepared using generator kits produced by major radiopharmaceutical suppliers such as Covidien, GE, IBA Molecular and Lantheus through their supply chain of distribution centers. The supply chain needs to be a well-oiled machine, because molybdenum has a half-life of 66 hours, and technetium, only about six hours.

Alternatives to this mainstay include production with a Subcritical Hybrid Intense Neutron Emitter (SHINE), developed by a company of the same name based in Monona, Wis. This operation requires LEU to be irradiated by neutrons from a proprietary technology, not a research reactor. A facility is expected to open its doors in 2016 and a long-term supply and distribution deal was just struck with GE Healthcare and announced April 3.

“There are no modern technologies making medical isotopes today,” says Greg Piefer, PhD, founder and chief executive officer of Shine Medical Technologies. “Our process actually uses a particle accelerator—a much newer technology, to make neutrons and that eliminates the need for this external reactor. As such, it has tremendous cost and safety advantages over the old fashioned way of making isotopes.”

Another difference between conventional production and Shine’s method is that the latter uses liquid instead of solid targets and this makes it easier to extract the molybdenum and reuse the target with much less nuclear waste production.

Here are some of the other U.S. Department of Energy-backed options: The AHR technique that was presented and subsequently failed to take shape; another method called neutron capture that involves taking natural molybdenum-98 targets and exposing them to the core of power reactors to create moly-99 targets—however the radioactivity of these targets is much weaker and would require completely different logistics and generator infrastructure; other efforts by Hitachi and GE use the University of Missouri’s research reactor to irradiate naturally occurring molybdenum; and a company called NorthStar, in Madison, Wis., has been engaging in dual technologies—one very similar to Hitachi’s and another using high powered linear accelerators to bombard molybdenum-100 to “knock out” neutrons, but both create the low-specific activity moly that will require an overhauled generator supply chain, explains Piefer. Yet another company, Northwest Medical Isotopes based in Corvallis, Ore., announced in early May that it plans to open a new facility in Columbia, Mo., in close proximity to the University of Missouri research reactor, to supply 50 percent of U.S. need of molybdenum from targets shipped in from a network of research reactors. Northwest also purports that no change in supply chain is necessary.

Canadian Efforts for Decentralization

Meanwhile, TRIUMF, Canada’s national laboratory for particle and nuclear physics has been working on proton-based linear accelerators that run on electricity and magnetism for production of isotopes. This is a non-neutron and reactorless approach that can supplement moly supply. This technology, as is, can supply a city the size of Vancouver, B.C. It is also scalable and can be made smaller or developed in higher-powered accelerators to supply a larger area. There are about 900 cyclotrons in the world, says Paul Schaffer, PhD, head of the nuclear medicine division at TRIUMF. Of these, about 450 cyclotrons are capable of being retrofitted with this technology for local supply with zero nuclear waste. Every little bit helps.

“In North America, I do believe that we are susceptible to a disruption in supply,” says Schaffer. “At a national nuclear safety administration meeting last April there were a number of minds that gathered in Chicago to discuss the situation. What was clear was that there is a surplus capacity of moly-99 in the world today, but what is not clear is how that supply has matured over the past year, nor is it clear regionally or geographically how that supply would be distributed.”

Verzijlbergen projects that all of the new projects will probably cover total global demand. “Nevertheless, there is no outage reserve capacity left and all the abovementioned projects need to be effectively started.”

In the meantime, all are watching as the end of an era of old research reactors passes quietly into the chronicles of bygone technology. The innovations and diversification of the coming years will look nothing like nuclear medicine’s longtime reliance on a largely unreliable supply.