Why is the US still dependent on foreign medical isotope production?
The United States currently does not have any large-scale commercial production of the isotope molybdenum-99 (Mo-99) used for nuclear imaging. It is critical to more 40,000 U.S. diagnostic nuclear imaging exams each day, representing about 80% of all diagnostic molecular imaging procedures.
Instead, the U.S. supply chain relies on foreign isotope reactors, which are the cause of somewhat regular shortages of the most widely used radiotracers.
With another unexpected shutdown of the high-flux reactor (HFR) in Petten, Netherlands—a primary supplier of Mo-99—the U.S. nuclear imaging programs are bracing for radiotracer shortages very soon. In early 2022, the Dutch reactor underwent an unplanned outage that disrupted the supply chain of Mo-99 and Lu-177 for months, and that was far from the first time such an outage occurred. The new shortage will likely resurrect calls for establishing a critical domestic supply of Mo-99.
The U.S. Department of Energy's (DOE) National Nuclear Security Administration (NNSA) created a program to help get domestic isotope production off the ground after the last string of isotope shortages in the 2010s. The DOE awarded tens of millions of dollars in grants to help fund the development of U.S.-based, low-enriched uranium reactors for domestic isotope production. However, years later, the five companies that received millions in federal dollars are still not producing any Mo-99. The last commercial production of isotope in the U.S. ended in 1989.
History of isotope shortages spurred calls for U.S. Mo-99 production
The current and 2022 shutdowns of the Petten reactor were both due to its age. It is 63 years old and faces ongoing maintenance issues that leave open concerns about stable supply. This was the same issue that prompted numerous shutdowns of the Chalk River reactor in Ontario, Canada, which previously supplied the majority of U.S. Mo-99. That reactor, built in 1957, was shut down in 2016 due to a string of serious maintenance issues blamed on the aging reactor’s infrastructure.
The U.S. isotope production comes from foreign reactors located in Europe, South Africa and Australia. Others are located in China and Egypt. Mo-99 has a half-life is 2.75 days so it cannot be stockpiled to help alleviate shortages. It lasts long enough for it to be transported to the U.S. for processing into technetium-99m (Tc-99m) used in SPECT radiotracers. Tc-99m has a half-life of just 6 hours so it must be produced in fresh batches at regional radiopharmaceutical companies and distributed to medical imaging centers daily. This makes supplying and transporting the isotopes a fragile process.
National security also plays a role in federal interest in isotope production
Calls for domestic isotope production and the federal funding were spurred not only by shortages, but also concerns about national security.
Prior to 2021, foreign reactors were using highly enriched uranium (HEU) fuel sources, which the U.S. was exporting to support isotope production. HEU can also be used to build nuclear bombs, which was seen as a potential national security threat.
The DOE NNSA created a program to help fund the development of U.S.-based, low-enriched uranium (LEU) reactors for domestic isotope production to reduce U.S. dependence on foreign sources. The primary isotope reactors converted over to LEU by 2021. So, the DOE certified in December 2021 there was enough global supply of Mo-99 from LEU sources, which triggered a ban on further U.S. exports of HEU for foreign medical isotope production.
The American Medical Isotopes Production Act of 2012 directed DOE/NNSA to implement a technology-neutral program in cooperation with private companies. Congress appropriated $40 million for these awards in 2018, and $20 million in 2019, and directed the DOE to competitively award cooperative agreements. NNSA was to fund each agreement at $15 million and require each awardee to provide $15 million of matching funds.
Of the five companies given awards, only one—NorthStar—started production, though that was quickly halted.
Where are we now with domestic production Mo-99?
NorthStar received more than $109 million from the NNSA to develop and commercialize a LEU isotope production system, which was cleared by the U.S. Food and Drug Administration (FDA) in January 2021. Later that year, NorthStar built a new reactor facility to produce Mo-99 in Beloit, Wisconsin.
The NNSA said in November 2022, NorthStar was supposed to be capable of producing enough Mo-99 to meet approximately 20% to 40% of the U.S. demand. NorthStar expected to complete start-up and regulatory submissions before the end of 2023.
NorthStar used its technology to set up a production line at the Missouri University Research Reactor, which operated from 2018-2023, and helped supply some Mo-99 during the last U.S. shortage caused by the Dutch reactor shutdown in 2022. However, the company ended production because of increasing costs and being unable to compete with the lower-cost competition from subsidized foreign reactors. At the time when NorthStar made the announcement about shutting down Mo-99, the Society of Nuclear Medicine and Molecular Imaging (SNMMI) said in a statement the closure would have no impact Mo-99 supply and would not create any shortages, illustrating the continued U.S. dependence on less expensive foreign supplies.
NNSA’s cooperative agreement with NorthStar was terminated at the company’s request, said Max Postman, director of the NNSA's Office of Reactor Conversion and Uranium Supply, at an Oct. 9 NNSA Mo-99 stakeholder meeting. The company has since refocused its efforts to produce the therapeutic radioisotopes copper-67 (Cu-67) and non-carrier-added actinium-225 (nca Ac-225), using the same equipment developed for Mo-99 production.
The news of NorthStar pulling out of the Mo-99 production business because it was not profitable likely had a cooling effect on investors wanting to put money into similar projects. This may have been an influencing factor for why several other startup companies that also partnered with the DOE NNSA have not progressed to the production stage
Northwest Medical Isotopes LLC, based in Corvallis, Oregon, is a startup that partnered with the NNSA to produce Mo-99. It received Nuclear Regulatory Commission (NRC) approval to put out a request for proposal (RFP) to construct its reactor and manufacturing facility in May 2018. The company also received about $7 million in tax abatements from Boone County, Missouri, for the manufacturing center in Discovery Ridge Research Park in Columbia, Missouri.
In August 2019, Northwest Medical Isotopes was also awarded $30 million for a 50/50 cost share Cooperative Agreement from DOE NNSA, which was to support RPF final design and the NRC operating license application submission. The company had opened its NRC operating license application and had its final RFP design finished by the fall of 2020. However, the company website has not been updated since 2020, and the chief operating officer listed left the company that same year.
Eden Radioisotopes LLC, based in Albuquerque, New Mexico, was another startup company NNSA partnered with in 2019. In August 2023, the company formally notified the U.S. Nuclear Regulatory Commission of its plans to submit license applications to construct and operate its medical isotope production facility near Eunice in New Mexico.
Niowave Inc. in Lansing, Michigan is another company that signed on for cooperation with NNSA. It received a $15 million federal grant in 2019 to start Mo-99 production and established an isotope manufacturing business that uses a superconducting electron accelerator with radio-frequency microwaves to accelerate electrons. However, the cooperative agreement was terminated by mutual decision, Postman said. The vendor does appear to have operational Mo-99 production listed on their website though.
SHINE Technologies based in Janesville, Wisconsin, also signed a cooperative agreement with the NNSA, which Postman said is the sole remaining cooperative agreement partner with the NNSA.
"We have plans to satisfy more than half the world’s demand through the company’s mass production facility, The Chrysalis, which is currently under construction in Janesville, Wisconsin," the company’s website states.
New federal incentives being offered
Postman said Congress appropriated $50 million in new funding for Mo-99 cooperative agreements to help expedite stable domestic production of the isotope. Following an independent merit review, NNSA reallocated $32 million in funding to the SHINE cooperative agreement in June 2024.
The federal government recognizes that subsidized reactors overseas have a price advantage, so Postman said the Centers for Medicare and Medicaid Services (CMS) proposes replacing the add-on payment given for using Tc-99m produced in reactors that do not use HEU with a new add-on payment related to domestic Mo-99 production. He said this will be starting in 2026.
Postman said the NNSA expects to decide on additional allocations of the newly appropriated Mo-99 funding by early 2025.
Dave Fornell has covered healthcare for more than 17 years, with a focus in cardiology and radiology. Fornell is a 5-time winner of a Jesse H. Neal Award, the most prestigious editorial honors in the field of specialized journalism. The wins included best technical content, best use of social media and best COVID-19 coverage. Fornell was also a three-time Neal finalist for best range of work by a single author. He produces more than 100 editorial videos each year, most of them interviews with key opinion leaders in medicine. He also writes technical articles, covers key trends, conducts video hospital site visits, and is very involved with social media. E-mail: dfornell@innovatehealthcare.com