The process works as follows: the cyclotron accelerates hydrogen ions to a prerequisite energy, strips off the electrons to create a proton beam, and then directs this beam onto a thin target of enriched Mo-100. The protons collide with molybdenum nuclei and some of them cause it to transmute into Tc-99m (the proton beam energy is selected to optimize Tc-99m creation and minimize creation of other nuclides). Finally, the Tc-99m is extracted by dissolving the target and passing the solution through an ion-exchange column.
It's not a new idea – this method has been known for over 40 years – but, according to TRIUMF's Timothy Meyer, scaling up to efficient high-volume production requires the development and validation of several key processes.
"You need to show that the fabrication of the Mo-100 target is economical and reproducible, and that the accelerator can deliver sustained power levels in a reliable and efficient manner," he explained. "You also want to show that the separation and purification technologies meet regulatory guidelines for purity and clinical performance."
The TRIUMF team – known as CycloTech99 – is investigating Tc-99m production on three different types of cyclotron. The idea is to use existing hospital cyclotrons, which currently produce other medical isotopes, to produce Tc-99m and distribute it to local clinics. Such cyclotrons will need to be upgraded, in particular by adding a beamline that's capable of irradiating solid targets. "We're going to benchmark the price and performance of that upgrade process and how it varies on different cyclotrons," Meyer said.
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Importantly, says Meyer, the upgrade won't impinge upon the normal cyclotron operating cycle. "Most medial isotope cyclotrons don't run 24 hours a day, they produce PET isotopes with short half-lives at certain schedules during the day," he explained. "The strategy would be to irradiate Mo-100 overnight, and then transfer it to the laboratory in the morning to process the Tc-99m shipment for the day."
Cyclotron manufacturer ACSI is also working to optimize this method of Tc-99m production, and has teamed up with the Centre Hospitalier Universitaire de Sherbrooke in Quebec and the University of Alberta. The collaboration has already made progress in target and process development, with Curie amounts of Tc-99m created using existing cyclotrons at the two facilities.
Quality control tests have shown that the cyclotrons can produce clinical-grade Tc-99m. Research will now focus on developing cost-efficient production using ACSI's high-current 24 MeV cyclotrons. Similarly to TRIUMF, the ultimate aim is to establish a decentralized network of medium-energy cyclotrons capable of producing large quantities of Tc-99m.
Photoneutron focus
The other two teams - Prairie Isotope Production Enterprise (PIPE) and Canadian Light Source – are developing production methods based around an electron accelerator. Again, Mo-100 is used as the target, but in this case, photoneutron reactions create Mo-99 as the end product.
High-energy electrons from a linear accelerator are incident upon the Mo-100 target, usually via a metal filter that helps dissipate the heat from the electron beam and creates a beam of intense X-rays. The X-rays remove a single neutron from some of the Mo-100 atoms in the target – turning them into Mo-99.
"Right now, we're using a water-cooled tungsten converter in front of natural molybdenum samples," PIPE's Jeff Martin explained. He noted that the team is also considering direct electron-beam irradiation, but that this can create problems with heating. PIPE is also looking at a range of methods for extracting the radioisotopes from the irradiated target.
"The idea we're working the hardest on involves dissolving the molybdenum target in solution. The solution will also contain Tc-99m, which can then be separated via a solvent extraction technique," said Martin. "The advantage of this method is you get very little breakthrough of non-radioactive molybdenum, a heavy metal that you don't want to give to the patient."
Martin pointed out that PIPE plans to speed its production process to market by basing it mostly on commercially available technologies. The collaboration has already shipped Mo-99 twice to the Health Sciences Centre in Winnipeg. "They've dissolved and extracted Tc-99m and it looks like it works," added John Barnard, Acsion Industries' director of research and technology.
One challenge associated with both the accelerator- and cyclotron-based approaches is the cost of the Mo-100 targets. Mo-100 comprises less than 10% of naturally occurring molybdenum and currently costs over $1000 per gram. Thus Tc-99m manufacture must also involve reprocessing of the irradiated targets.
"Because you only activate a small part of the Mo-100 in each cycle, it has to be recovered and integrated into a recovery process, which is an added complication to the whole isotope use in hospitals," explained Barnard. "That is going to be challenging - whether you use cyclotron or accelerator."
Looking ahead
The teams now have 15 months to prove themselves. After that, successful technologies could be rolled out across Canada and then marketed worldwide, possibly exploiting industry partnerships private to help with licensing and commercialization. Time will tell which will scale the fastest and prove the most reliable and economical. Either approach would create a more distributed supply network that overcomes the vulnerabilities of the current supply chain.
In terms of practical implementation, the cyclotron-based method produces Tc-99m, which has a half-life of just six hours and must therefore be manufactured at or very near to clinical sites. This approach can, however, take advantage of a wide network of existing medical cyclotrons.
The electron accelerator approach creates Mo-99, which has a half-life of 66 hours and, as such, can be shipped. "One or two linacs could probably supply most of Canada," Barnard said. This method also benefits from being more similar to, and thus able to exploit, the existing Tc-99m supply chain based on shipping of Mo-99.
"The decision by the government of Canada to invest public funds in a technology development programme is quite bold," Meyer told medicalphysicsweb. "If it's successful, with a few of these technologies at scale within about 15 months, the government's strategy and its faith in the technical community will be validated."
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