Molybdenum-99 for Medical Imaging
Committee on State of Molybdenum-99 Production and Utilization and
Progress Toward Eliminating Use of Highly Enriched Uranium
Nuclear and Radiation Studies Board
Division on Earth and Life Studies
A Report of
THE NATIONAL ACADEMIES PRESS
Washington, DC
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This activity was supported by Grant No. DE-PI0000010/DE-DT0007382 between the National Academy of Sciences and the U.S. Department of Energy, 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: 978-0-309-44531-3
International Standard Book Number-10: 0-309-44531-0
Digital Object Identifier: 10.17226/23563
Cover: Technetium-99m, the decay product of molybdenum-99, is the most widely used radionuclide for medical imaging. The images on the cover were produced during a myocardial perfusion imaging (MPI) study using technetium-99m to assess blood flow to heart tissues (courtesy of Henry D. Royal, Washington University School of Medicine). The series of tomographic images at the top are produced during the stress portion (either exercise or pharmacological) of the test and the images at the bottom during the rest portion. The center image (referred to as a bulls-eye image) combines multiple images taken at stress or rest (in this case at rest) to assess myocardial perfusion defects. The black area of the bulls-eye image corresponds to areas of abnormal myocardial perfusion. The patient was diagnosed with a myocardial infarction (i.e., heart attack).
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Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2016. Molybdenum-99 for Medical Imaging. Washington, DC: The National Academies Press. doi: 10.17226/23563.
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COMMITTEE ON STATE OF MOLYBDENUM-99 PRODUCTION AND UTILIZATION AND PROGRESS TOWARD ELIMINATING USE OF HIGHLY ENRICHED URANIUM
S. JAMES ADELSTEIN, Chair, Harvard Medical School, Boston, Massachusetts
THOMAS J. RUTH, Vice-Chair, TRIUMF, Vancouver, British Columbia, Canada (emeritus)
LIN-WEN HU, Massachusetts Institute of Technology, Cambridge, Massachusetts
JOSEPH C. HUNG, Mayo Clinic, Rochester, Minnesota
ROBERT T. JUBIN, Oak Ridge National Laboratory, Oak Ridge, Tennessee
EMMETT B. KEELER, Pardee RAND Graduate School, Santa Monica, California
GERALD L. KULCINSKI, University of Wisconsin–Madison
JASON S. LEWIS, Memorial Sloan Kettering Cancer Center, New York, New York
KATHRYN A. MORTON, University of Utah, Salt Lake City
EUGENE J. PETERSON, Los Alamos National Laboratory, Los Alamos, New Mexico
TOR RAUBENHEIMER, SLAC National Accelerator Laboratory, Menlo Park, California
HENRY D. ROYAL, Washington University School of Medicine, St. Louis, Missouri
FELICIA L. TAW, Los Alamos National Laboratory, Los Alamos, New Mexico
Staff
KEVIN D. CROWLEY, Study Director
OURANIA KOSTI, Senior Program Officer
TONI GREENLEAF, Administrative and Financial Associate
DARLENE GROS, Senior Program Assistant
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NUCLEAR AND RADIATION STUDIES BOARD
ROBERT C. DYNES, Chair, University of California, San Diego
JAMES A. BRINK, Vice Chair, Massachusetts General Hospital, Boston
GEORGE E. APOSTOLAKIS, Massachusetts Institute of Technology (emeritus), Cambridge
DAVID J. BRENNER, Columbia University, New York
MARGARET S. Y. CHU, M.S. Chu & Associates, LLC, New York, New York
TISSA H. ILLANGASEKARE, Colorado School of Mines, Golden
CAROL M. JANTZEN, Savannah River National Laboratory, Aiken, South Carolina
MARTHA S. LINET, National Institutes of Health, Bethesda, Maryland
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
Staff
KEVIN D. CROWLEY, 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
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Acknowledgments
The successful completion of this study would not have been possible without the cooperation and assistance of many organizations and individuals. The committee would especially like to acknowledge and thank the following organizations and individuals for their support:
Department of Energy’s National Nuclear Security Administration (NNSA), which sponsored the study and provided information on the agency’s activities to establish domestic production and support international production of molybdenum-99 for medical use without highly enriched uranium. The committee would especially like to thank Jeffrey Chamberlin, Rilla Hamilton, Peter Karcz, Randy Howell, Thomas Hanlon, Tim Evans, and Crystal Trujillo. Rilla Hamilton served ably as the agency’s liaison to the committee and was effective in coordinating NNSA’s response to the committee’s many requests for information.
Department of Energy’s Office of Environmental Management: Theresa Kliczewski and Hitesh Nigam for providing information on the uranium and lease take-back program.
Other federal agencies involved in establishing molybdenum-99 production that provided information on their regulatory processes and activities. The committee thanks Eric Duffy, Food and Drug Administration; Daniel Duvall, Centers for Medicare & Medicaid Services; and Steven Lynch, U.S. Nuclear Regulatory Commission.
U.S. National Laboratories: Argonne National Laboratory (ANL), Los Alamos National Laboratory, Oak Ridge National Laboratory, Savannah River National Laboratory, and Y-12 National Security Complex, which provided information on the NNSA-supported research and development for establishing domestic production of molybdenum-99 for medical use without highly enriched uranium (see Appendix C). The committee wants to especially thank George Vandegrift, Sergey Chemerisov, and Amanda Youker, ANL, for coordinating the national laboratories’ presentations and the site visit of a small group of committee members to ANL.
Organisation for Economic Co-operation and Development-Nuclear Energy Agency: Kevin Charlton provided information on global supply and demand for molybdenum-99 for medical use and responded to many committee questions.
Current molybdenum-99/technetium-99m supply chain participants for providing information and supporting site visits of small groups of committee members. The following individuals coordinated the organizations’ responses and site visits: Roy Brown, Mallinckrodt Pharmaceuticals; Scott Claunch, Cardinal Health Pharmacy; Chris Critch and Phil Larabie, Nordion; Tina Eboka, NTP Radioisotopes; Ira Goldman, Lantheus Medical Imaging; Adrian Paterson and Mark Alexander, Australian Nuclear Science and Technology Organisation; Shannon Quinn, Atomic Energy of Canada Limited; Marc Robillard, Canadian Nuclear Laboratories; Bertrand Stepnik, AREVA; Alexander Tuzov, Research Institute of Atomic Reactors; and Jean-Michel Vanderhofstadt, Institut National des Radioéléments.
Potential domestic molybdenum-99 suppliers and supporting institutions for providing information on their production technology and schedules. Special thanks to Carmen Irene Bigles, Coquí RadioPharmaceuticals; Ralph Butler, University of Missouri Research Reactor Center; Richard Coats, Eden Radioisotopes; Terry Grimm, Niowave; Carolyn Haass, Northwest Medical Isotopes; James Harvey, NorthStar Medical Radioisotopes; Gregory Piefer, SHINE; John Saurwein, General Atomics; and Kirk Sorensen, Flibe Energy.
International Atomic Energy Agency (IAEA): Joanie Dix for hosting a group of committee members at the October 2015 IAEA meeting on global capabilities for the production and manufacture of molybdenum-99 targets.
Council on Radionuclides and Radiopharmaceuticals: Michael Guastella for assisting with planning the site visit of a group of committee members to Cardinal Health.
Other speakers and invited participants at the committee’s information-gathering meetings. These individuals are too numerous to be listed here. Their names are provided in Appendix C.
Other individuals and organizations who provided information and support for this study: John Harisson and Steve Ebdon-Jackson, Public Health England; Rostislav Kuznetsov, Research Institute of Atomic Reactors; Jun Lee, Korea Atomic Energy Research Institute; Bernard Ponsard, Belgian Nuclear Research Center; Julian Preston, United Nations Scientific Committee on the Effects of Atomic Radiation; and Tokushi Shibata, Japan Radioisotope Association.
The committee also thanks staff at the Nuclear and Radiation Studies Board (NRSB) of the National Academies of Sciences, Engineering, and Medicine (the Academies) for organizing and facilitating this study. Study director Kevin Crowley and senior program officer Ourania Kosti organized the committee meetings, assisted the committee with report writing and review, and provided valuable technical and policy insights. The chair and vice-chair of the committee complement the study director and senior program officer on the skill and dedication they brought to oversight of the far-flung site visits and to midwifery of the final report. Toni Greenleaf and Darlene Gros managed the logistics of the meetings, report review, and publication. Senior program officers Rita Guenther from the Academies Committee on International Security and Arms Control and Jennifer Heimberg (NRSB) escorted a small group of committee members to the site visits in Russia.
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Reviewer Acknowledgments
This report has been 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 institution in making its published report as sound as possible and will ensure that this report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We thank the following individuals for their participation in the review of this report:
Carolyn J. Anderson, University of Pittsburgh
Cynthia E. Atkins-Duffin, Lawrence Livermore National Laboratory
Ronald Cameron, Ron Cameron Consulting Ltd.
Margaret S. Y. Chu, M.S. Chu & Associates, LLC
Jeffrey A. Clanton, Vanderbilt University
Richard V. Coté, Atomic Energy of Canada Ltd. (retired)
Cathy S. Cutler, Brookhaven National Laboratory
Victor A. Ferrari, University of Pennsylvania
Michael M. Graham, University of Iowa Carver College of Medicine
Mitchell Meyer, Idaho National Laboratory
Julia M. Phillips, Sandia National Laboratory (retired)
Thomas Rockwell Mackie, University of Wisconsin–Madison
John P. Schiffer, Argonne National Laboratory
Orhan H. Suleiman, Food and Drug Administration (retired)
Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the conclusions and recommendations of this report, nor did they see the final draft of the report before its release. The review of this report was overseen by Michael L. Corradini, University of Wisconsin–Madison, and Fred A. Mettler, Jr., University of New Mexico School of Medicine (professor emeritus). They were responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were considered carefully. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.
Contents
1.1 Statement of Task for Present Study
1.2 Strategy to Address the Study Task
2 Medical Isotope Production and Utilization
2.4 Production of I-131 and Xe-133
2.5 Overview of Mo-99/Tc-99m Supply Chain
3 Global Production of Molybdenum-99 and Future Prospects
3.1 Mo-99 Supply Chain Participants
3.2 Prospects for New Mo-99 Supplies
3.3 Recent Supply Interruptions
4 Progress Toward Establishing Domestic Production of Molybdenum-99 and Associated Medical Isotopes
4.1 DOE-NNSA Cooperative Agreement Projects
4.2 Other Projects for Domestic Production of Mo-99
4.3 Domestic Production of I-131 and Xe-133
4.4 Progress Toward Establishing Domestic Production of Mo-99
4.6 Findings and Recommendations
Appendix 4A FDA Regulatory Submission Process
5 Progress in Eliminating Highly Enriched Uranium and Remaining Obstacles
5.1 American Medical Isotopes Production Act
5.3 Irradiation Facility Conversion
5.4 Processing Facility Conversion
5.7 Assistance from Other Organizations
5.8 Findings and Recommendations
6 Molybdenum-99/Technetium-99m Historic and Projected Demand
6.1 Global Demand for Mo-99/Tc-99m
6.2 Domestic Demand for Mo-99/Tc-99m
6.3 Future Global Demand for Mo-99/Tc-99m
6.4 Future Domestic Demand for Mo-99/Tc-99m
6.5 Domestic Demand for I-131 and Xe-133 and Future Projections
7 Molybdenum-99/Technetium-99m Supply
7.1 Future Available Supply Capacity
7.2 OECD-NEA Analysis of Mo-99 Supply and Demand
