The article by Bénard et al. in this month’s issue of The Journal of Nuclear Medicine (1) is an important work, showing the feasibility of producing large quantities of 99mTc on a biomedical cyclotron and extraction of the 99mTc from the target material, converting it to a chemical form suitable for conventional compounding of nuclear medicine drugs. The authors state “with some modifications of existing cyclotron infrastructure, this approach can be used to implement a decentralized medical isotope production model. This method eliminates the need for enriched uranium and the radioactive waste associated with the processing of uranium targets.” The recent planned and unplanned shutdowns of nuclear reactors producing 99Mo highlight the need for alternative production methods, necessitating a review of the current state ofSee page 1017
99Mo/99mTc production and the potential alternatives moving forward to ensure a steady, uninterrupted supply of 99Mo/99mTc for decades to come.
CONVERSION EFFORTS FROM HIGHLY ENRICHED URANIUM (HEU) TO LOW-ENRICHED URANIUM (LEU)
Currently, 85%–95% of the world’s 99Mo is produced using HEU. The United States is the world’s primary supplier of HEU, which has an enrichment of 93%. The U.S. Department of Energy’s National Nuclear Security Administration has, with cooperation from all of the current commercial producers, set a goal of total conversion from HEU to LEU by 2016. ANSTO (Australia) and NTP Radioisotopes (South Africa) already use LEU for their 99Mo production. Mallinckrodt (The Netherlands) and IRE (Belgium) are in the process of shifting their 99Mo production from HEU to LEU and plan to have the conversion complete by the end of 2015. The AECL (Canada) has decided to exit the market, stating that the cost of maintenance and conversion to LEU production at the Chalk River reactor is too high for staying in the market. AECL currently provides 31% of the world’s 99Mo; alternative production methods will be needed.
ALTERNATIVE PRODUCTION OF 99Mo
There are currently 3 companies working on alternative production methods for 99Mo: Babcock & Wilcox, SHINE Medical Technologies, and NorthStar Medical Radioisotopes.
Babcock & Wilcox has suggested a series of small, subcritical liquid fuel reactors with LEU solution to produce 99Mo. The 99Mo is extracted from the LEU solution and can be used with the existing 99Mo/99mTc generator model. This project is currently suspended, as Babcock & Wilcox is seeking a new partner.
SHINE Medical Technologies uses a subcritical reactor and deuterium–tritium beam line to bombard an LEU solution with neutrons. SHINE has shown that the 99Mo can be extracted from the LEU solution with high efficiency and is in the process of building its production facility. SHINE expects its facility will be able to meet half of the U.S. demand for 99Mo.
NorthStar Medical Radioisotopes uses the 100Mo(γ,n)99Mo production route with an electron linear accelerator (LINAC) to produce the necessary high-energy γ rays. This technology has been demonstrated on a small scale, and commercial-scale testing is in progress. Additionally, NorthStar has partnered with the University of Missouri Research Reactor to irradiate 98Mo targets in a conventional research reactor setting. Both methods produce low-specific-activity 99Mo that requires the use of new generator technology to produce 99mTc.
All 3 of these companies are in the process of receiving approval to build their radioisotope production facilities. Each of these facilities should be able to meet about half of the U.S. demand for 99Mo, assuming expected normal available capacity is met.
PRODUCTION OF 99mTc DIRECTLY USING CYCLOTRONS
The direct production of 99mTc on a biomedical cyclotron was pioneered by Beaver and Hupf in 1971 (2), using the 100Mo(p,2n)99mTc reaction. Over the years, there has been further development on target development and cross-section measurements (3–5). However, the inexpensive and plentiful supply of fission-fragment 99Mo provided disincentive for groups to move forward with 99mTc production on a biomedical cyclotron for wide-scale distribution. The recent global 99Mo supply shortages have renewed an interest in 99mTc production on biomedical cyclotrons, and recent publications have been assessing the feasibility of cyclotrons producing 99mTc on a large scale (6–8).
Recent work has shown the peak cross section for 100Mo(p,2n)99mTc to be approximately 15 MeV (9), which is within the range of many biomedical cyclotrons being used to produce 18F-FDG. Therefore, a move toward cyclotron-based production of 99mTc could potentially use an existing network of cyclotrons and would not require investment in new cyclotrons at many sites.
The authors have developed a robust method for target production and handling system for transfer of targets to and from the cyclotron and separation/purification hot cell. High-purity 99mTc is produced and isolated from the target material, providing 99mTc that can be used with existing 99mTc-based radiopharmaceutical kits.
CHALLENGES FOR CYCLOTRON-BASED 99mTc PRODUCTION
Although the authors have shown the feasibility of 99mTc production on a biomedical cyclotron, there are many challenges that need to be addressed in order to establish a network of cyclotrons for this production.
Irradiation of the targets ranged from 100 to 240 μA of beam current for durations ranging from 85 min to 6.9 h. These parameters present both technologic and logistic challenges. The high level of beam current is not currently feasible for most cyclotrons currently in operation and would require technologic modifications or upgrades. Additionally, many of the cyclotrons are being used for 18F-FDG production from late evening to early morning and will not be available for 99mTc production because of target availability or beam current constraints. This logistic challenge can be solved if enough 99mTc can be produced during off hours (i.e., 12 pm to 10 pm) such that even with decay there is sufficient quantity the next morning.
Another challenge is the differing rules between traditional nuclear medicine drugs and PET drugs. For example, most (if not all) of the biomedical cyclotrons used for PET drug production in the United States have their facilities set up in compliance with 21 CFR 212 or USP <823>, which is current good manufacturing practice for PET drugs. Part of the PET drug facility may be set up to comply with USP <797> in order to dispense the bulk PET drugs into prescription doses. 99mTc is not a PET drug, so the production, separation, and purification of 99mTc would need to be done in compliance with 21 CFR 210, 21 CFR 211, and USP <797>.
Given both the technologic and the logistic issues and the differing current good manufacturing practice regulations, it is more than likely that separate 99mTc production facilities will be constructed rather than using existing PET drug production facilities. This, of course, increases the infrastructure costs associated with direct production of 99mTc on a cyclotron.
Finally, one must take the distribution distance into account. One of the reasons that 99mTc has gained such a large foothold in nuclear medicine is due to the complementary half-lives of the parent–daughter generator. The 66-h half-life of the 99Mo parent allows for easy, worldwide distribution of generators on a weekly basis. Nuclear medicine clinics do not need to be near the 99Mo producer. Use of cyclotron-based production of 99mTc will require nuclear medicine clinics to be within a reasonable transportation distance of the production facility because of the 6-h half-life of 99mTc. Cyclotron-based production of 99mTc is therefore much more feasible for larger urban locations or areas with strong transportation networks and would present a great challenge for lower-population-density areas of the world.
CONCLUSION
Cyclotron-based production of 99mTc has been proven feasible and could be part of a solution for a steady, uninterrupted supply of 99Mo/99mTc. There are significant challenges that must be overcome in order to use a network of cyclotrons for 99mTc. None of the challenges is insurmountable, but economic factors will play a role.
Regardless of method (B&W, SHINE, NorthStar, direct cyclotron production of 99mTc), there will need to be significant investment in infrastructure to ensure diversity in providing 99Mo/99mTc for the greater nuclear medicine community and avoiding the shortages that have affected the nuclear medicine community over the past several years. More than likely it will be a combination of these different methods along with conventional reactor methods that will provide 99Mo/99mTc for the nuclear medicine community in the decades to come.
DISCLOSURE
No potential conflict of interest relevant to this article was reported.
Footnotes
Published online Apr. 28, 2014.
- © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
REFERENCES
- Received for publication March 10, 2014.
- Accepted for publication March 14, 2014.
