In recent years, however, these reactors have suffered from several maintenance and repair outages. In an effort to mitigate likely shortages caused by the expected shutdown in 2016 of the AECL National Research Universal reactor in Chalk River, the Canadian government has allocated $35m to four projects developing new ways of producing Tc-99m. The two-year Non-reactor-based Isotope Supply Contribution Program (NISP) is designed to advance accelerator-based technologies, either by producing Tc-99m directly with proton cyclotrons or producing Mo-99 via a photo-neutron reaction. In 2012 Canada's Isotope Technology Acceleration Program (ITAP) also earmarked another $25m for the further development of alternatives to existing isotope-production technologies.

Participants in these programmes include Vancouver-based TRIUMF (Canada's national laboratory for particle and nuclear physics); Advanced Cyclotron Systems Inc. (ACSI) of Richmond, British Colombia; as well as the Canadian Light Source (CLS) in Saskatoon and the Prairie Isotope Production Enterprise (PIPE) in Winnipeg. The ultimate goal is to achieve a more diverse and secure supply of Tc-99m, with less reliance on nuclear-reactor-based production.

Cyclotron-based systems

Both the TRIUMF and ACSI projects use cyclotrons to create isotopes by accelerating hydrogen ions and bombarding them into non-radioactive materials. ACSI has developed a series of techniques to create cyclotron-produced Tc-99m – known as CycloTec – and, in partnership with a number of Canadian universities, research centres and hospitals, has created the Canadian National Cyclotron Network, which brings together technetium-producing cyclotrons to ensure a sufficient supply of CycloTec and other medical isotopes throughout Canada.

In 2012 scientists at TRIUMF also pioneered two methods for producing Tc-99m using molybdenum-100 (Mo-100) targets and medical cyclotron-based accelerator technology. Melissa M Baluk – TRIUMF's strategic planning and communications co-ordinator – explains that the team used a handful of cyclotrons already in use by healthcare centres across Canada to develop an "upgrade kit" that could be retro-fitted onto the various brands of cyclotrons. The kit includes the production of Mo-100-coated solid cyclotron targets and target-handling hardware, as well as dissolution and purification chemicals.

"This model enables daily, decentralized Tc-99m production for Canada," says Baluk. "We have demonstrated that cyclotrons in Vancouver, London and Hamilton have sufficient capacity to supply their respective hospital catchments with Tc-99m. A cross-Canada network of Tc-99m-producing cyclotrons can thus be developed at a more reasonable cost than funding or replacing a reactor."

According to Baluk, the benefit of using a cyclotron is that these machines already exist in health units, hospitals and universities across the country and around the world. "An added benefit is that Canada is home to two manufacturers of cyclotrons and they have successfully tested this model for Tc-99m production," she says.

Baluk also reveals that at the British Columbia (BC) Cancer Agency, the ITAP consortium has achieved the "significant milestone" of demonstrating large-scale production of Tc-99m using a cyclotron manufactured at ACSI. The 10 curie production yield satisfies around 50% of the daily demand of a metropolitan area such as Vancouver.

"The technology is now ready for clinical testing and is moving forward to obtain regulatory approval for routine use in patients with a target date of 2016," Baluk adds.

The Medical Isotope Project facility at the CLS, located at the University of Saskatchewan, is the first of its kind anywhere in the world, and uses an innovative particle accelerator to produce Mo-99 isotopes. Late last year, CLS scientists announced the first shipment of medical isotopes produced in its dedicated linear accelerator (linac).

As CLS's director of accelerators, Mark de Jong explains, the process uses a small high-power industrial electron linac to produce a flux of high-energy X-rays through bremsstrahlung radiation. The X-rays strike a target of enriched Mo-100, in the process knocking out a neutron from the nuclei of some of the target atoms to produce Mo-99. After several days of irradiation at the CLS facility, the target is extracted at the Winnipeg Health Sciences Centre's Radio-Pharmacy Department and dissolved to let the Tc-99m, which arises from the decay of Mo-99, be more easily extracted.

"The main advantage of this method is the complete avoidance of any use of uranium or fission, with all the problems that arise from both volatile short-lived isotopes as well as disposing of the long-lived radioactive waste," says De Jong. "The electron linear accelerator is small enough to be located close to where the Mo-99 is required, possibly even within major hospitals, reducing losses via decay during shipping. In the current fission-based production, more than 80% of the Mo-99 produced has decayed before it reaches the hospitals."

According to De Jong, the pilot production facility that the CLS team has built is intended for "real-world" commercial applications once the processes involved, including Mo-99 production, target dissolution and Tc-99m extraction, have been approved by Health Canada. "Eventually, the facility should produce enough for the hospitals serving a population of more than two million people," he adds. However, De Jong also points out that a few "significant technological issues" must be overcome before other commercial applications can be developed, mostly related to the engineering of the targets "to handle as much power as possible".

Another major issue in the roll-out of the technology is the fact that the CLS system mixes Mo-99 with Mo-100, so that the "specific activity" (radioactivity per unit mass of radionuclide), measured in gigabequerels per gram, is reduced by a factor of around 10,000 compared with Mo-99 created via reactor-based fission. "As a result, none of the processes currently used, from the reactor to the hospital radio-pharmacy, can be used with linac-sourced Mo-99," says De Jong. "This makes the linac Mo-99 quite revolutionary for the current suppliers, and makes the business case more difficult."

The other photo-neutron production project being funded – in addition to the CLS proposal – is run by PIPE, a non-profit organization created by the Winnipeg Regional Health Authority through its Health Science Centre, alongside Acsion Industries and the University of Winnipeg. "Acsion's core technology is the linear accelerator, which was used to prove the concept of producing Mo-99 in a different fashion," explains Acsion chairman David Walker. "We have since been working among the three partners to expand on this proof of concept and prepare for regulatory approval."

The PIPE method uses high-power electron-beam accelerators to produce intense X-ray beams of the appropriate energy to excite Mo-100 nuclei and convert them to Mo-99, through a process called photo-disintegration. According to John Barnard, senior technical specialist at PIPE, the advantages of the new method stem from recent technological advances that enable the availability of reliable high-power electron accelerators of the correct energy, at a reasonable cost.

"The result is capital costs for production facilities [that are] a tenth to a hundredth that of new reactors and lower facility operating costs, [as well as] no need to use fission weapons-grade materials and no long-lived radioactive waste to manage," Barnard says.

Although the PIPE system has not yet been used in a real-world commercial or healthcare application, the company's president Chris Saunders reveals that it will be within the next two years. "We are currently at the prototype production stage and have started approval trials," he says. "There are similar developments in the US and Europe among entrepreneurs, governments and scientists who understand the technology's relevance based on their work in related fields."

US initiatives

In addition to the variety of innovations under way as part of the Canadian NISP initiative, a number of technologies are also being developed in the US. One interesting example is the Wisconsin-based firm SHINE Medical Technologies, which has developed a method of creating Mo-99 using an inexpensive linac.

According to Katrina Pitas, vice-president of business development at SHINE, the process begins with the creation of deuterium ions, which are accelerated using a simple 300?kV DC accelerator before colliding with a tritium gas target. The neutrons created in this process then leave the target chamber and enter a low-enriched uranium salt solution, where they cause fission of the uranium – with Mo-99 produced in the solution as a fission product. After an irradiation cycle is complete, the solution is drained through a special column that preferentially adsorbs the molybdenum, which is then rinsed from the column and purified, before being tested and packaged.

Pitas says that there are several advantages to this process, including the fact that it eliminates the very high capital and operating costs, as well as the large quantity of radioactive waste, associated with using a nuclear reactor. "Because it uses fission to produce the Mo-99, the end product is basically indistinguishable from the Mo-99 produced today. Because our facility will have eight operating devices, rather than just one reactor, failure of a single machine need not result in supply disruptions," she says.

Pitas reveals that the base accelerator technology has already been used in one non-healthcare-based application with what she says are great results.

"The uranium target has been tested with a different accelerator technology at the national labs, also with great results," she adds. "The two demonstrated pieces will come together in our manufacturing facility in Wisconsin and begin producing commercial products in early 2018. The biggest challenge we have faced and still currently face is financial."

Also based in Wisconsin, NorthStar Medical Technologies is working on a neutron-capture method to produce Mo-99 from the stable Mo-98 isotope. According to James Harvey, senior vice-president and chief science officer at NorthStar, the process is performed by adding one neutron in a nuclear-reactor core. The company plans to use the Missouri University Research Reactor located in Columbia, Missouri, with production starting in late 2015.

By 2017, NorthStar also expects to perfect an electron-accelerator photon-transmutation method, which removes a neutron from the stable Mo-100 isotope to produce Mo-99.

Harvey says that photon transmutation will be performed using electron accelerators at the firm's facility in Beloit, Wisconsin, in 2017. In this process, electrons are converted to high-energy gammas, or bremsstrahlung, which eject a neutron from the molybdenum-100 nucleus. "Both NorthStar processes produce an extremely benign waste stream that is easily dealt with and disposed of in accordance with all regulatory requirements, at a fraction of the costs of the uranium-related waste stream," Harvey says.

• This article originally appeared in the Physics World Focus on Medical Imaging.