MEDICAL ISOTOPES TO
PROCEEDINGS OF A SYMPOSIUM
Nuclear and Radiation Studies Board
Division on Earth and Life Studies
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This activity was supported by contract DE-EP0000026/DE-DT0012738 between the National Academy of Sciences and the U.S. Department of Energy’s National Nuclear Security Administration. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project.
International Standard Book Number-13: 978-0-309-46627-1
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Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2018. Opportunities and Approaches for Supplying Molybdenum-99 and Associated Medical Isotopes to Global Markets: Proceedings of a Symposium. Washington, DC: The National Academies Press. doi: https://doi.org/10.17226/24909.
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JOINT SYMPOSIUM PLANNING COMMITTEES
Committee representing the National Academies of Sciences, Engineering, and Medicine
HEDVIG HRICAK, Chair, Memorial Sloan-Kettering Cancer Center, New York, New York
JACK L. COFFEY, Enigma Biomedical Group, Knoxville, Tennessee
EUGENE J. PETERSON, Los Alamos National Laboratory, Los Alamos, New Mexico
Committee representing the Russian Academy of Sciences
STEPAN N. KALMYKOV, Chair, Moscow State University
SERGEY V. YUDINTSEV, Institute of Geology of Ore Deposits, Petrography, Mineralogy, and Geochemistry, Russian Academy of Sciences
BORIS L. ZHUIKOV, Institute for Nuclear Research, Russian Academy of Sciences
Consultants to the Committee representing the Russian Academy of Sciences
BORIS F. MYASOEDOV, Scientific Council on Radiochemistry between Presidium of the Russian Academy of Sciences and the State Corporation “Rosatom”
YURI K. SHIYAN, Russian Academy of Sciences
OURANIA KOSTI, Study Director
RITA GUENTHER, Senior Program Officer
KEVIN D. CROWLEY, Director (until August 4, 2017)
TONI GREENLEAF, Administrative/Financial Associate
DARLENE GROS, Senior Program Assistant
NUCLEAR AND RADIATION STUDIES BOARD
GEORGE E. APOSTOLAKIS, Chair, Massachusetts Institute of Technology (emeritus), Cambridge
JAMES A. BRINK, Vice Chair, Massachusetts General Hospital, Boston
STEVEN M. BECKER, Old Dominion University, Norfolk, Virginia
AMY BERRINGTON de GONZÀLEZ, National Cancer Institute, Bethesda, Maryland
DAVID J. BRENNER, Columbia University, New York
MARGARET S. Y. CHU, M.S. Chu & Associates, LLC, Albuquerque, New Mexico
TISSA H. ILLANGASEKARE, Colorado School of Mines, Golden
CAROL M. JANTZEN, Savannah River National Laboratory, Aiken, South Carolina
NANCY JO NICHOLAS, Los Alamos National Laboratory, Los Alamos, New Mexico
HENRY D. ROYAL, Washington University School of Medicine, St. Louis, Missouri
DANIEL O. STRAM, University of Southern California, Los Angeles
WILLIAM H. TOBEY, Belfer Center for Science and International Affairs, Cambridge, Massachusetts
SERGEY V. YUDINTSEV, Russian Academy of Sciences, Moscow
CHARLES D. FERGUSON, Director
JENNIFER HEIMBERG, Senior Program Officer
OURANIA KOSTI, Senior Program Officer
TONI GREENLEAF, Administrative and Financial Associate
LAURA D. LLANOS, Administrative and Financial Associate
DARLENE GROS, Senior Program Assistant
The National Academies of Sciences, Engineering, and Medicine (The National Academies) and the Russian Academy of Sciences committees would like to thank the Department of Energy-National Nuclear Security Administration (NNSA) for sponsoring the study and especially NNSA staff members Mr. Jeff Chamberlin, Mr. Brett Cox, and Ms. Crystal Trujillo.
The committees also thank the International Atomic Energy Agency’s (IAEA’s) Departments of Nuclear Energy and Nuclear Sciences and Applications for cooperating with the two academies in organizing the July 17-18, 2017, symposium. Ms. Joanie Dix, Mr. Tom Hanlon, Ms. Frances Marshall, and Ms. Katarina Milosovicova provided assistance in the symposium preparation and logistical arrangements. Mr. Joao Osso significantly contributed to the successful organization of the symposium. The committees also wish to thank Mr. Christophe Xerri and Ms. Meera Venkatesh for providing a briefing on the agency’s activities related to nuclear applications the day after the symposium concluded and for supporting, together with Dr. Alexander Bychcov (Permanent Mission of the Russian Federation to the International Organizations in Vienna), a tour of the IAEA laboratories at Seibersdorf.
The committees are indebted to the symposium presenters and session moderators who spent the time and effort to share their experience related to molybdenum-99 production and supply. They are listed in Appendix A.
The committees extend special thanks to the staff of the National Academies for supporting this study. Study director Dr. Ourania Kosti took the lead for organizing the symposium and was primarily responsible for shaping the symposium proceedings. Dr. Rita Guenther, senior program officer, assisted with the proceedings review and publication. Dr. Guenther also skillfully managed the logistics of the committees’ meetings in Moscow, in close consultation with the Russian Academy of Sciences’ committee chair, Prof. Stepan Kalmykov. Ms. Toni Greenleaf and Ms. Darlene Gros provided valuable advice on the symposium logistics and managed the travel arrangements.
This Proceedings of a Symposium was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies in making each published proceedings as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the charge. The review comments and draft manuscript remain confidential to protect the integrity of the process.
We thank the following individuals for their review of this proceedings:
Alexander Bychkov, Permanent Mission of the Russian Federation to the International Organizations in Vienna
Michael Guastella, Council on Radionuclides and Radiopharmaceuticals
Robert Jubin, Oak Ridge National Laboratory
Galina E. Kodina, Burnasyan Federal Medical Biophysical Center of the Federal Medical-Biological Agency of Russia
Rostislav Kuznetsov, Research Institute of Atomic Reactors
Joao Osso, International Atomic Energy Agency
Parrish Staples, Department of Energy’s National Nuclear Security Administration (formerly)
Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the content of the proceedings nor did they see the final draft before its release. The review of this proceedings was overseen by Dr. Thomas J. Ruth, TRIUMF. He was responsible for making certain that an independent examination of this proceedings was carried out in accordance with standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the authoring committees and the National Academies.
The decay product of molybdenum-99 (Mo-99), technetium-99m (Tc-99m), is the most used medical isotope in diagnostic imaging worldwide. About 60-70 percent of the Mo-99 supplied globally is produced by irradiation of highly enriched uranium (HEU) solid targets in nuclear research reactors fueled by uranium. Irradiation causes uranium to fission [reaction: 235U(n,f)99Mo] and to produce a number of isotopes including Mo-99, iodine-131 (I-131), and xenon-133 (Xe-133). Efforts to reduce and ultimately eliminate HEU from targets irradiated for medical isotope production are under way as part of an international threat reduction goal. In the United States, the U.S. Department of Energy’s National Nuclear Security Administration (DOE-NNSA) is responsible for implementing the policy to reduce and ultimately eliminate HEU from civilian applications including medical isotope production.
Most Mo-99 in the world is supplied by companies in Australia, Belgium, Netherlands, South Africa, and, until recently, Canada.1 Except for Australia, these companies rely on research reactors that were built in the 1950s and 1960s, and often shut down for scheduled or unscheduled maintenance. In 2009 and 2010, Mo-99/Tc-99m shortages occurred when Canada’s NRU and Europe’s HFR reactors were simultaneously shut down for extended periods. Supply of Mo-99 and Tc-99m is particularly sensitive to reactor shutdowns because they cannot be stockpiled for future shortages due to their short half-lives.2
A number of additions to the Mo-99/Tc-99m supply chain are emerging in other countries, including the United States and Russia. The United States, although the biggest consumer of Mo-99, has not produced Mo-99 since 1989. Several projects are under way to establish U.S.-based production of Mo-99 from non-HEU sources. Russia consumes small amounts of Mo-99 but has been producing this medical isotope for decades to cover the country’s domestic demand and more recently for some exports of Mo-99 produced by irradiation of HEU targets. Since 2013, Russia has been increasing its Mo-99 production capacity and aspires to capture up to a 20 percent share of the global market. Details on Russia’s Mo-99 production plans and associated timelines have not been announced. On one hand, the sale of Russian-produced Mo-99 to global markets could help improve supply reliability. On the other hand, the sale of Russian HEU-sourced Mo-99 could interrupt the full adoption of current market and policy trends toward production of Mo-99 from non-HEU sources.
The 2016 National Academies of Sciences, Engineering, and Medicine report (NASEM, 2016) recommended that the U.S. government pursue opportunities for engagements between U.S. and Russian scientific and technical organizations to better understand Russia’s plans related to Mo-99 production. This recommendation led
2 The half-life of Mo-99 is 66 hours, and that of Tc-99m is 6 hours.
DOE-NNSA to ask the National Academies to host a symposium, with the objective of bringing together U.S., Russian, and other international experts to promote the establishment of working relations among global experts, especially U.S. and Russian experts, and a common understanding of global supply chain needs and requirements. The focus of the symposium was intended to be on Mo-99 production and to a lesser extent on other medical isotopes that are co-produced, for example, I-131 and Xe-133.
The symposium titled Opportunities and Approaches for Supplying Molybdenum-99 and Associated Medical Isotopes to Global Markets was held July 17-18, 2017, at the International Atomic Energy Agency (IAEA) in Vienna, Austria. It was co-hosted by the National Academies and the Russian Academy of Sciences in cooperation with the IAEA. The symposium featured a range of presentations3 on the topics listed in the statement of task (see Sidebar P.1). About 85 individuals from 17 countries participated in the symposium.4
The symposium was organized by a committee of U.S. experts appointed by the National Academies and a committee of Russian experts appointed by the Russian Academy of Sciences. The symposium organizing committees met four times over the course of the study. Two of these meetings were joint meetings with a quorum of U.S. and Russian committee members: in April 2017, in Moscow, Russia, to plan the symposium, and in July 2017, in Vienna, Austria, to hold the symposium and create an outline of the symposium proceedings. The third meeting took place in October 2017 in Washington, D.C., to finalize the symposium proceedings. That meeting lacked participation of Russian committee members due to the United States’ temporarily suspending issuance of visas in Russia.5 The fourth meeting took place in November 2017 in Moscow to receive comments on the symposium proceedings from the Russian committee.
This Proceedings of a Symposium was jointly authored by the U.S. and Russian symposium organizing committees and is published in both English and Russian. The committees are responsible for the overall quality and accuracy of the proceedings as a record of what transpired at the symposium. Although the symposium committees are responsible for the content of this proceedings, any views contained in the proceedings are not necessarily those of the committees, the National Academies, or the Russian Academy of Sciences. This proceedings does not contain findings, conclusions, or recommendations.
The proceedings is organized into seven chapters.
- Chapter 1 summarizes the July 17-18, 2017, symposium opening remarks from the IAEA, the National Academies, and the Russian Academy of Sciences.
- Chapter 2 provides an introduction of Mo-99/Tc-99m in nuclear medicine.
- Chapter 3 provides an overview of the current (as of July 2017) Mo-99 supply.
- Chapter 4 describes HEU- to LEU-sourced Mo-99 production conversion challenges and opportunities for research and development.
- Chapter 5 describes Mo-99 supply reliability.
- Chapter 6 describes prospects for future Mo-99 supply.
- Chapter 7 describes issues related to Mo-99 supply sustainability.
Each chapter summarizes information obtained during the presentations and discussions that took place at the symposium. The proceedings is intended for the reader with some prior knowledge on the Mo-99 supply chain and Mo-99/Tc-99m production methods. The joint committees suggest that non-expert audiences read the reports titled Molybdenum-99 for Medical Imaging (NASEM, 2016), Medical Isotope Production Without Highly Enriched Uranium (NRC, 2009), and 2017 Medical Isotope Supply Review: 99Mo/99mTc Market Demand and Production Capacity Projection 2017-2022 (OECD-NEA, 2017) for background information.
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|AIPES||Association of Imaging Producers and Equipment Suppliers|
|ANM||ANSTO Nuclear Medicine|
|ANSTO||Australian Nuclear Science and Technology Organisation|
|BARC||Bhabha Atomic Research Centre|
|CARR||China Advanced Research Reactor|
|CIIC||Canadian Isotope Innovations Corp|
|CNEA||Comisión Nacional de Energía Atómica (National Atomic Energy Commission)|
|CNNC||China National Nuclear Corporation|
|CRP||coordinated research projects|
|EMA||European Medicines Agency|
|EOB||end of bombardment|
|FCR||full cost recovery|
|HEU||highly enriched uranium|
|HLG-MR||High-Level Group on the Security of Supply of Medical Radioisotopes|
|IAEA||International Atomic Energy Agency|
|INVAP||Investigacion Aplicade (Nuclear Engineering International)|
|KAERI||Korea Atomic Energy Research Institute|
|KJRR||Kijang Research Reactor|
|MIPR||Medical Isotope Production Reactor|
|MURR||University of Missouri Research Reactor|
|NASEM||National Academies of Sciences, Engineering, and Medicine|
|NDA||New Drug Application|
|NNSA||National Nuclear Security Administration|
|NWMI||Northwest Medical Isotopes|
|OECD-NEA||Organisation for Economic Co-operation and Development’s Nuclear Energy Agency|
|PET||positron emission tomography|
|RAS||Russian Academy of Sciences|
|RIAR||Research Institute of Atomic Reactors|
|RMB||Brazilian Multipurpose Research Reactor|
|SCK•CEN||Belgian Nuclear Research Centre|
|SPECT||single-photon emission computed tomography|
|SPECT-CT||single-photon emission computed tomography-computed tomography|
|U.S. DOE||U.S. Department of Energy|
|U.S. FDA||U.S. Food and Drug Administration|
|U.S. NRC||U.S. Nuclear Regulatory Commission|
Anti-trust refers to government policy to prevent abuse of dominant position in the market or the existence of cartels (definition provided by Mr. Jan Velthuijsen, PricewaterCoopers).
Available production capacity is the maximum amount of molybdenum-99 (Mo-99) that can be produced or supplied on a routine basis (NASEM, 2016).
Breakthrough is the process of Mo-99 being co-eluted with technetium-99m (Tc-99m) from a technetium generator. The contamination of Tc-99m with Mo-99 can interfere with radiopharmaceutical production, reduce image quality, and expose patients to unnecessary radiation (NASEM, 2016).
Centralized nuclear pharmacy is a nuclear pharmacy contracted by hospitals/medical centers to produce and provide radiopharmaceuticals. Most of the nuclear pharmacies in the United States today are “centralized” nuclear pharmacies. The concept of centralized nuclear pharmacy is not widespread; most countries continue to use individual nuclear pharmacies.
Conventional molybdenum-99 production method refers to uranium fission production in a research reactor. Alternative molybdenum-99 production method refers to any other reactor- or nonreactor-based production method.
Elution is the process by which Tc-99m is obtained from technetium generators.
Full cost recovery is the pricing of services to recover the full cost of production of Mo-99 to ensure a sustainable supply.
Half-life (denoted as t1/2) is the time required for half of the atoms of a given radioisotope to decay to another isotope (NASEM, 2016).
High-Level Group on the Security of Supply of Medical Radioisotopes (HLG-MR, see https://www.oecd-nea.org/med-radio/security/) is a group established in 2009 by the Organisation for Economic Co-operation and Development’s Nuclear Energy Agency to examine the underlying causes of global Mo-99/Tc-99m shortages and recommend
actions to ensure adequate supplies in the future. The HLG-MR comprises approximately 40 experts representing the governments of 17 countries as well as from the European Commission and the International Atomic Energy Agency. The work of the HLG-HR was recently extended to the end of 2018.
Highly enriched uranium is uranium enriched in uranium-235 (U-235) to concentrations greater than or equal to 20 weight percent. HEU enriched to 90 percent or above is referred to as weapons-grade HEU. The primary concern with civilian utilization of HEU is its potential diversion by terrorists to make nuclear explosive devices (NASEM, 2016).
Highly enriched uranium-sourced Mo-99 production is a term used throughout this proceedings to indicate use of HEU targets to produce Mo-99. The use of HEU-fueled reactors for Mo-99 production is not addressed in this proceedings.
Low-enriched uranium is uranium enriched in U-235 to concentrations lower than 20 weight percent.
Neutron capture is a method to produce Mo-99 by irradiating natural or enriched Mo-98 targets and capturing a neutron (n) and transmuting to Mo-99 after emitting a gamma ray.
Outage reserve capacity is capacity maintained by irradiation facilities or processing facilities to allow rapid scale-up of Mo-99 production to meet demand when other irradiation or processing facilities shut down for scheduled or unscheduled maintenance. In recent years, Mo-99 suppliers have started to pay for the costs for maintaining the outage reserve capacity; this capacity is referred to as paid outage reserve capacity.
Six-day curie is the quantity used to price and sell Mo-99. It is the measurement of the remaining radioactivity of Mo-99 six days after the time of measurement.
Specific activity is radioactivity per unit mass, usually expressed as becquerel (Bq) per gram or curies (Ci) per gram (NASEM, 2016). Mo-99 produced by fission is of high specific activity, that is, more than 10,000 curies per gram (Ci/g). Mo-99 produced by neutron capture is of much lower specific activity, about 0.1-1 Ci/g.
Supply reliability refers to the current ability of the supply chain to deliver Mo-99/Tc-99m to meet demand.
Supply sustainability refers to the ability of the supply chain to continue long term to deliver Mo-99/Tc-99m to meet demand.
Uranium fission is a process to produce Mo-99 by irradiating U-235 targets.
Welfare is a term used in economics to describe the allocation of benefits (financial, health, other) between producers and consumers of a country. On the subject of Mo-99 production and supply, welfare can be transferred from one country to another, if the producing country subsidizes production by using taxpayers’ money and the Mo-99 is supplied to other countries in which patients are benefited without having to carry the full costs of the Mo-99/Tc-99m testing. In this example, the producing country loses welfare and the receiving countries gain welfare.