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  1. From Our Perspective

From Our Perspective: FDA’s Role in Helping a Critical Medical Isotope Meet Sufficient Supply in the US for First Time

By: Joseph Rajendran, M.D. (Medical Doctor), FASNC (Fellow of the American Society of Nuclear Cardiology), FACNM (Fellow of the American College of Nuclear Medicine), Medical Officer, FDA (U.S.Food and Drug Administration), CDER (Center for Drug Research and Evaluation), OND (Office of New Drugs), OSM (Office of Specialty Medicine), DIRM (Division of Imaging and Radiation Medicine)

Photo of Joseph Rajendran, M.D.

FDA’s Commitment Helps to Provide Benefits to Drug Supply Chain, National Security

Recently FDA’s Center for Drug Evaluation and Research (CDER) and the U.S. Department of Energy’s National Nuclear Security Administration (DOE/NNSA) recognized that the U.S. has reached a sufficient supply of molybdenum-99 (Mo-99) produced without highly enriched uranium (HEU). Mo-99 is an important radioactive isotope used in medical imaging to detect cancer and other potentially fatal conditions. With a half-life of only 66 hours, Mo-99 decays rapidly and cannot be stockpiled.

Through FDA and DOE/NNSA combined efforts, Mo-99 is now sufficiently produced from low enriched uranium (LEU) for medical imaging. This means the U.S. no longer needs to send HEU to nuclear reactors in other countries to produce Mo-99. As such, the U.S. has banned sending HEU overseas for the purpose of medical isotope production, further advancing national security objectives. HEU is a proliferation-sensitive material that, if diverted or stolen, could be used to make a nuclear weapon. NNSA works to minimize the civilian use of HEU, through conversion of facilities from HEU to LEU. DOE/NNSA’s Mo-99 Program historically assisted global Mo-99 production facilities in converting to non-HEU processes and supports the establishment of domestic supplies of Mo-99 without the use of proliferation-sensitive HEU.

Achieving a sufficient supply of Mo-99 produced without the use of HEU was a result of collaboration among FDA, DOE/NNSA, U.S. national laboratories, foreign government partners, and the commercial Mo-99 industry. An additional aim of this collaboration is to diversify the production methods and to establish a domestic source of Mo-99. As a result, in 2018, FDA approved the first non-uranium process for the production of Mo-99, providing the U.S. medical community with a domestic source of technetium 99metastable (Tc-99m).

What is Mo-99? How is it used in medical imaging?

Mo-99 is the essential precursor for Tc-99m -- the most widely used radioisotope in medical diagnostic imaging. Isotopes are parts of an element that have the same number of protons but different numbers of neutrons. Medical isotopes are used by health care professionals to diagnose and treat health conditions such as heart disease and cancer. The production of medical isotopes is achieved by using two overarching technologies: nuclear reactors and particle accelerators (linear accelerators, cyclotrons).

Mo-99 is used to produce the Tc-99m generator, which provides Tc-99m on demand. Medical imaging uses different technologies to view the human body to diagnose and monitor medical conditions.

The essential medical radioisotope, Tc-99m, is used in approximately 80 percent of nuclear diagnostic imaging procedures, or over 40,000 medical procedures in the U.S. every day. Tc-99m is used in nuclear pharmacies to radiolabel drugs that target various tissues in the body. The finished Tc-99m labelled product is injected intravenously and imaged to help diagnose heart disease, evaluate the spread of cancer, study organ structure and function, and perform other important medical applications, including the cardiac “stress test” that measures the blood flow to the heart. The process of Mo-99 production also creates iodine-131 and xenon-133. These isotopes are used in the treatment and diagnosis of thyroid disease, cancer treatment, lung diseases and other conditions in adults and children.

Medical radioisotopes, including Tc-99m, I-131 (Iodine 131) and Xe-133 (Xenon 133) are regulated as drugs. CDER and NNSA have been working with manufacturers to build a domestic supply chain, to advance and diversify commercial production technology, and to shift the production methods from HEU to LEU and non-uranium sources.

Why could we not produce Mo-99 domestically until recently, and why was that a problem?  

For decades, the U.S. had no capability to produce Mo-99 domestically. The Mo-99/Tc-99m generator was created in New York in the 1950s. The Atomic Energy Commission produced and supplied Mo-99 from its nuclear reactors in Tennessee and New York until 1966 when the U.S. decided to stop government production and switch to commercial sources. After years of private sector production, the final domestic facility producing Mo-99 was shut down and decommissioned in 1989.

As a result of this situation, the U.S. had to export HEU to foreign medical isotope producers, which used the material to produce Mo-99 for medical diagnostic use in the U.S. and global markets. Mo-99 has a short half-life, quickly breaking down into elements that are not usable for medical imaging, which prevents the ability to build reserves of the medical isotope. Relying solely on outside sources for such a critical isotope had risks, and in 2009, the world experienced a global shortage of radiological imaging isotopes when two reactors responsible for up to 70% of the world’s supply of Mo-99 unexpectedly shut down and remained offline for 18 months. The shortage resulted in delays for critical medical procedures. Clinicians had to shift to alternative isotopes, potentially exposing patients to higher doses of radiation with less optimal testing methods or delaying the procedures altogether until the drug became available.

What was CDER’s role in increasing domestic production of Mo-99?

CDER’s role is to advance innovative technologies for increasing domestic production by providing expert advice during the development phase of the product and assessing the quality of the product prior to approval and during the post-marketing phase.

After the 2009 global shortage, Congress passed the American Medical Isotope Production Act of 2012 (AMIPA) which directed federal agencies to take a number of steps, including phasing out the export of HEU for production of medical isotopes over seven years and supporting the domestic production of Mo-99 without the use of HEU by non-federal entities. In addition to supply chain stability, AMIPA serves to advance national security goals by minimizing the use of proliferation-sensitive HEU in medical isotope production.

FDA nuclear chemists, microbiologists, engineers, and a broad range of scientists and medical professionals from both CDER and FDA’s Center for Devices and Radiologic Health provided important scientific and technical expertise throughout the development of this innovative technology. 

The first example is the 2018 FDA-approved NorthStar Medical Radioisotopes, LLC’s process to produce the first domestic supply of Mo-99 in nearly thirty years, as well as the first non-uranium production method, using Mo-98 as the starting material. NorthStar’s Radiogenix system is a unique system for producing Tc-99m which aims to achieve a stable and secure supply of this critical radioactive imaging product. FDA worked with the manufacturer to make sure the process of producing Tc-99m meets all the pharmaceutical and microbiological quality standards that we have for all drug products.

This was a positive development for America’s infrastructure and innovation. We are continuing to assist progress on development of additional technologies. For example, we approved the use of Mo-99 produced by the global suppliers using LEU. Novel technology is needed to diversify and secure a domestic supply of Mo-99 to meet patient needs and to also contribute to enhanced national security.

We will continue to partner and collaborate with DOE/NNSA to further strengthen the US supply of non-HEU-based Mo-99.

What does the future hold for CDER in working to supply and stabilize medical radioisotopes?

We hope to approve additional novel technology to produce medical radioisotopes. Doing so will help stabilize the supply of Mo-99 and other radioisotopes such as I-131. We are also encouraging domestic development of new technologies for Mo-99 production.

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