3
Molybdenum-99/Technetium-99m Supply

The focus of this chapter is on the supply of molybdenum-99 (Mo-99) and technetium-99m (Tc-99m) for medical diagnostic imaging. The chapter provides a description of the global supply of Mo-99, the supply of Tc-99m in the United States, and Mo-99/Tc-99m supply chains. The information provided in this chapter is used to address the availability clause of the second charge in the statement of task for this study (see Sidebar 1.2).

PAST PRODUCTION OF Mo-99 IN THE UNITED STATES

Although there is currently no commercial production of Mo-99 in the United States, this was not always the case. Prior to 1989, Cintichem, Inc. produced Mo-99 for the U.S. market using a 5 MWt (megawatt thermal) research reactor located in Tuxedo, New York. This reactor was shut down when tritium contamination of surface waters adjacent to the reactor site was confirmed. A decision to decommission the reactor was subsequently made after a risk-benefit study carried out by Cintichem’s parent company, Hoffman-LaRoche, determined that its continued operation was not justified. Cintichem offered to arrange a long-term supply agreement with the other North American supplier, the Canadian company Nordion (later MDS Nordion), to supply Mo-99 to U.S. technetium generator manufacturers (Amersham [now GE Healthcare], Mallinckrodt, and DuPont1).

1

Of these three, only Mallinckrodt continues to supply technetium generators to the U.S. market.



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3 Molybdenum-99/Technetium-99m Supply T he focus of this chapter is on the supply of molybdenum-99 (Mo-99) and technetium-99m (Tc-99m) for medical diagnostic imaging. The chapter provides a description of the global supply of Mo-99, the sup- ply of Tc-99m in the United States, and Mo-99/Tc-99m supply chains. The information provided in this chapter is used to address the availability clause of the second charge in the statement of task for this study (see Sidebar 1.2). PAST PRODUCTION OF Mo-99 IN THE UNITED STATES Although there is currently no commercial production of Mo-99 in the United States, this was not always the case. Prior to 1989, Cintichem, Inc. produced Mo-99 for the U.S. market using a 5 MWt (megawatt thermal) research reactor located in Tuxedo, New York. This reactor was shut down when tritium contamination of surface waters adjacent to the reactor site was confirmed. A decision to decommission the reactor was subsequently made after a risk-benefit study carried out by Cintichem’s parent com- pany, Hoffman-LaRoche, determined that its continued operation was not justified. Cintichem offered to arrange a long-term supply agreement with the other North American supplier, the Canadian company Nordion (later MDS Nordion), to supply Mo-99 to U.S. technetium generator manu- facturers (Amersham [now GE Healthcare], Mallinckrodt, and DuPont1). 1 Ofthese three, only Mallinckrodt continues to supply technetium generators to the U.S. market. 

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 MEDICAL ISOTOPE PRODUCTION WITHOUT HIGHLY ENRICHED URANIUM In response to growing concerns about medical isotope availability, Congress created2 the Isotope Production and Distribution Program and gave it the responsibility for ensuring a stable supply of isotopes, includ- ing medical radioisotopes, in the United States. In 1991, the Department of Energy (DOE) was funded by these three domestic technetium genera- tor manufacturers to study the feasibility of using its facilities to develop a domestic supply of Mo-99 and associated fission products. As a result of this feasibility study, DOE purchased the rights to Cintichem’s Mo-99 production technology3 and associated equipment in 1991. Initially, DOE planned to produce Mo-99 using the Cintichem technology at the Omega West Reactor (OWR) and the Chemistry and Metallurgy Research (CMR) hot cell facilities at the Los Alamos National Laboratory. However, in De- cember 1992–January 1993, a leak in the primary cooling system piping of that reactor was determined to be contributing to tritium contamination of the groundwater beneath the reactor facility. After detailed analysis, DOE decided in mid 1993 to shut down the reactor. From mid 1993 until early 1995, DOE evaluated other alternative facili- ties for Mo-99 production. An Environmental Impact Statement (DOE, 1996a) prepared during 1995 evaluated these alternatives, and in 1996 DOE issued a Record of Decision (DOE, 1996b) that selected the CMR facility at Los Alamos for target fabrication and the 2 MWt Annular Core Research Reactor (ACRR) and associated hot cell facilities at Technical Area V at Sandia National Laboratories as the preferred alternatives for Mo-99 production. From late 1996 until mid 1999, DOE made capital investments and supported operating costs of the Sandia nuclear facili- ties to develop a Mo-99 production capability. DOE costs ranged from $20 million to $50 million, depending on whether facility operating costs were included as part of the Mo-99 project costs. DOE issued an Expression of Interest (EOI) in 1999 to gauge com- mercial interest in further development of this Sandia production initiative. There was initial industrial interest in learning about the Sandia production capability. However, knowledgeable Mo-99 producers concluded that San- dia production of Mo-99 was not economically competitive with then-exist- ing commercial Mo-99 production. The yield of Mo-99 (in terms of curies per gram of uranium-235 [U-235]) using the Cintichem technology in the 2 Public Law 101-101. The program was managed by the Office of Nuclear Energy within the Department of Energy (DOE). 3 Cintichem used an acidic dissolution process (now referred to as the Cintichem process) to produce Mo-99 from irradiated highly enriched uranium (HEU) targets. An improved version of this process is currently being developed for use on low enriched uranium (LEU) targets by Argonne National Laboratory. It is referred to as an LEU-modified Cintichem process or sometimes just modified Cintichem process.

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 MOLYBDENUM-/TECHNETIUM-m SUPPLY Sandia facilities was about 65–80 percent that from other major producers, thus making it unattractive to the industrial sector. One of the outcomes of the production initiative was the participation of an Albuquerque-based small business, Technology Commercialization International (TCI), in the DOE EOI information meetings. This company had existing supply arrangements for isotope distribution from Russian isotope production facilities and was interested in alternative technologies for Mo-99 production and distribution. TCI and the Kurchatov Institute, along with Argonne National Labora- tory, were funded to evaluate a Kurchatov Institute solution-based reactor concept for Mo-99 production. This initiative proceeded through demon- stration of production of Mo-99 samples, and these samples were evalu- ated for product quality and product yield. However, TCI was not able to sustain this initiative after the conclusion of DOE funding, and ultimately the company decided to terminate its isotope production initiatives. All of TCI’s business operations were terminated just as this National Academies study was initiated. Another U.S. company (Babcock & Wilcox) is now try- ing to commercialize the solution-reactor technology as discussed elsewhere in this chapter. CURRENT Mo-99 SUPPLY Between 95 and 98 percent of the world’s supply of Mo-99 is produced by just four organizations (NNSA and ANSTO, 2007), all of which use HEU targets: MDS Nordion, Mallinckrodt, Institut National des Radioéléments (IRE), and Nuclear Technology Products Radioisotopes (Pty) Ltd. (NTP) (see Table 3.1 and Figure 3.1). These companies are referred to as large- scale producers in this report because they supply more than 1000 6-day curies4 (see Sidebar 3.1) of Mo-99 per week to the market on a routine basis. Two of these companies (MDS Nordion and Mallinckrodt) supply all of the Mo-99 used in the United States under normal operating conditions. These companies routinely purchase Mo-99 from each other and from the other two large-scale producers to help maintain supply reliability. The remaining world supply of Mo-99 is provided by a small number of organizations that make Mo-99 primarily for indigenous or regional use. The committee refers to these organizations as regional producers in this report. These producers supply considerably fewer than 1000 6-day curies per week, collectively producing only about 5 percent of the world supply 4 The committee uses curies instead of the equivalent international standards (SI) unit, Becquerel, in this report because this unit is used and understood by the isotope production community. Curies can be converted to Becquerel by multiplying by 3.7 × 1010.

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 MEDICAL ISOTOPE PRODUCTION WITHOUT HIGHLY ENRICHED URANIUM TABLE 3.1 Principal Large-Scale and Regional Producers of Mo-99 Percent of Percent of Primary Supply World Supply U.S. Supply of Mo-99a of Mo-99a Mo-99 Producer Country Regions MDS-Nordion Canada North America, South 40 60 America, Europe, Asia Mallinckrodt United States, North America, Latin 25 40 Netherlands America, Europe, Middle East IRE Belgium Europe 20 0 Africa, Australiaa NTP South Africa 10 0 Other Argentina, South America, Pacific- 5 0 Australia, Asia, Russia Russia NOTE: Percentages are estimates and vary depending on global reactor production schedules. aThese percentages include production of Mo-99 by ANSTO. However, ANSTO shut down its production in January 2007 and has been purchasing Mo-99 while it converts its processing facilities to use the CNEA-developed LEU-based Mo-99 production process. SOURCE: Supply quantities from Bonet et al. (2005). FIGURE 3.1 Large-scale global production of Mo-99 and supply to the U.S. market. NOTE: Arrows indicate only the major flows of Mo-99. There are secondary flows among producers that are not shown on the figure.

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 MOLYBDENUM-/TECHNETIUM-m SUPPLY SIDEBAR 3.1 6-Day Curies Mo-99 is priced and sold based on units of radioactivity (or activity) calibrated to a certain future time. Time calibration is necessary because of radioactive decay. The unit of activity used by Mo-99 producers to price and sell this isotope is the unit curie (Ci), which is equal to 37 billion disintegrations per second. Most producers, and all large-scale producers, calibrate the sale price to the number of curies present in a shipment of Mo-99 6 days after it leaves the producer’s facili- ties. This quantity is referred to as 6-day curies. The 6-day curie concept is schematically illustrated in the figure below, which shows the buildup and decay of Mo-99 during target irradiation, processing, and shipping. During the 5- to 7-day period of irradiation in the reactor (left side of figure) Mo-99 builds up in the target and eventually approaches a maximum as Mo-99 production is balanced by Mo-99 loss to radioactive decay. Mo-99 contin- ues to be lost to radioactive decay after the targets are removed from the reactor, and some additional losses are incurred during target processing because of process inefficiencies (middle of figure). The amount of Mo-99 available for sale as 6-day curies (right side of figure) is only a fraction of the isotope present in the targets at the end of bombardment (EOB) by neutrons in the reactor. The current global demand for Mo-99 is about 12,000 6-day curies per week. To produce this quantity of isotope, producers would need to irradiate enough U-235 targets to obtain about 77,000 curies of Mo-99 in the targets at EOB (left side of figure). About 54,400 curies of Mo-99 will be recovered from processing these targets, assuming a Mo-99 recovery efficiency of 90 percent (Chapter 2) and a processing time of 1 day (Table 3.4). The 12,000 6-day curies represent about 17 percent of the Mo-99 present in the targets at EOB. The weekly global demand for Mo-99 can be supplied by the fission of about 2 g of U-235. The 54,400 curies of Mo-99 available at the end of target processing would have a mass of about 0.11 g. This mass of Mo-99 is about the amount con- tained in a cook’s “pinch of salt.” The remainder of the U-235 ends up as waste. 71,100 Ci EOB 54,400 Ci available for shipping 80 60 Ci 10% loss during 40 target processing 12,000 6-day Ci 20 0 Target irradiation Target Calibration time for (7 days) processing 6-day Ci (1 day) Time Sidebar 3-1-2

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 MEDICAL ISOTOPE PRODUCTION WITHOUT HIGHLY ENRICHED URANIUM of Mo-99. At least two of these producers are contemplating an expansion of their supply capabilities as is discussed elsewhere in this chapter. The short half-life for Mo-99 (66 hours) prevents it from being stock- piled for use, so Mo-99 producers must schedule the production of this isotope to meet projected demand. Producers make Mo-99 at the rate at which they can sell it, so it is reasonable to assume that Mo-99 supply is equal to Mo-99 demand, particularly when averaged over periods when there are no production or distribution disruptions. Industry supply and demand estimates for Mo-99 are usually expressed as weekly quantities, probably because this isotope is produced on a con- tinuous basis to meet demand. The committee follows this industry conven- tion in this report and expresses supply quantities in terms of -day curies per week. Several estimates of the global and U.S. supply for Mo-99 have been published (e.g., Bonet and Ponsard, 2005; von Hippel and Kahn, 2006; NNSA and ANSTO, 2007). The committee is unable to verify the accuracy of these estimates because Mo-99 producers do not publicly disclose their production data. The most recent and likely the most reliable5 of these estimates is provided in NNSA/ANSTO (2007). According to that report, the 20066 production of Mo-99 for medical diagnostic imaging (Chapter 2) was approximately 12,000 6-day curies per week; 2006 production for the U.S. market fluctuated between about 5,000 and 7,000 6-day curies on a weekly basis. This range reflects variations in both supply and demand in the U.S. market over the course of the year and may also reflect uncer- tainties about the actual supply and demand quantities. According to a representative of MDS Nordion, growth in 2006 supply has been “flat to single digit growth levels” since 2006 so “this range can be used to reflect demand/supply for this entire time period.”7 CURRENT Mo-99 PRODUCERS All of the organizations that currently produce Mo-99 utilize government-owned research or test reactors to irradiate targets, and some use government-owned facilities for target processing and Mo-99 recov- 5 The committee judges that this is the most reliable currently available estimate because it is based on a workshop that was attended by three of the four global Mo-99 producers, includ- ing the two producers that supply the U.S. market, as well as several regional producers. All of these producers had an opportunity to provide information for this conference report. 6 Publicly available supply and demand estimates for Mo-99/Tc-99m are usually at least 1–2 years old. Producers do not divulge current information. 7 Jill Chitra, MDS Nordion, written communication with study director Kevin Crowley, November 26, 2008.

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 MOLYBDENUM-/TECHNETIUM-m SUPPLY ery. Table 3.2 provides information about these reactors as well as other reactors that could be used to produce Mo-99 in the future. The principal producers are described briefly in the following sections, starting with the large-scale producers and followed by the regional producers, each in alphabetical order. Large-Scale Producers Mallinckrodt (Netherlands) Mallinckrodt produces approximately 40 percent of the U.S. supply of Mo-99 and about 25 percent of world supply depending on global reactor production schedules. Production is carried out at the Petten site in the Netherlands in a joint venture with the Nuclear Research and Consultancy Group (NRG), the site operator. Production began in late 1998. Mo-99 is produced using uranium-aluminum alloy dispersion targets (Table 2.2). The targets are irradiated in the High Flux Reactor (HFR), which is located at the Petten site, the Belgian Reactor II (BR2), which is located in Mol, Belgium, and the Osiris reactor, which is located in Saclay, France. After irradiation, the targets are processed in a Mallinckrodt-operated facility at the Petten site. That facility contains 10 hot cells, only 5 of which are apparently required to produce Mo-99. The process wastes are shipped off site for storage.8 IRE (Belgium) IRE produces approximately 20 percent of the world supply of Mo-99 depending on global reactor production schedules and provides Mo-99 to the U.S. market through MDS Nordion and Mallinckrodt. It has been pro- ducing Mo-99 since 1979 at its site near Fleurus, Belgium. HEU targets are irradiated in three reactors:9 HFR, BR2, and Osiris. The irradiated targets are transported in shielded casks on trucks to the IRE facility for processing. IRE has a dedicated bank of hot cells for target processing, a backup set of processing hot cells, and a third set of hot cells that are used intermittently for processing of strontium. 8 Information on the number of hot cells in the facility, the number of hot cells used to produce Mo-99, and waste disposition can be found at http://ie.jrc.ec.europa.eu/publications/ brochures/HFR%20brochure.pdf and http://www.wmsym.org/abstracts/2001/25/25-5.pdf. 9 IRE also utilized a fourth reactor in Germany (FRJ-2) until it was shut down in 2006.

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 MEDICAL ISOTOPE PRODUCTION WITHOUT HIGHLY ENRICHED URANIUM TABLE 3.2 Research, Test, and Isotope Production Reactors for Mo-99 Production Reactor Reactor Name Location Owner Category Reactors Used by Large-Scale Producers of Mo- NRU Chalk River, Canada AECL Research HFR Petten, Netherlands European Commission Test BR2 Mol, Belgium Centre d’Etude de l’Energie Nucleaire Test (SKC-CEN) Osiris Saclay, France Commissariat à l’Énergie Atomique Research (CEA)/CEN-Saclay SAFARI-1 Pelindaba, South Nuclear Energy Corporation of South Research Africa Africa (NECSA) Reactors Used by Regional Producers of Mo- RA-3 Buenos Aires, CNEA Research Argentina OPAL Lucas Heights, ANSTO Research Australia WWR-TS Obninsk, Russia Karpov Institute of Physical Chemistry Research Existing Reactors That Could Be Used for Mo- Production MURR Columbia, Missouri, University of Missouri Research USA G.A. Serpong, Tangerang Badan Tenaga Nuklir Nasional Research Siwabessy (West, Java) (National Nuclear Energy Agency) MPR ETRR-2 Inshas, Egypt Atomic Energy Authority of Egypt Research RP-10 Peru Instituto Peruano de Energía Nuclear Research RECH-1 Chile Comisión Chilena de Energía Nuclear Research MARIA Poland Institute of Atomic Energy Test TRIGA II Romania RAAN Test Pitesti HANARO S. Korea Korea Atomic Energy Research Test Institute JMTR Oarai, Ibaraki-ken, Japan Atomic Energy Research Test Japan Institute

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 MOLYBDENUM-/TECHNETIUM-m SUPPLY Max. Maximum Power Commissioning Annual Days of Target (MWt)a Date Operation Fuel Type Type Mo-99 Producer 135 1957 315 LEU HEU MDS Nordion 50 1961 290 LEU HEU Mallinckrodt IRE HEUb 100 1961 115 HEU Mallinckrodt IRE 70 1966 220 LEU HEU Mallinckrodt IRE HEU (45%)c 20 1965 315 HEU NTP 10 1968 230 LEU LEU CNEA LEUd 20 2007 340 LEU ANSTO 15 1964 190 HEU (36%) HEU Karpov Institute of Physical Chemistry HEUb 10 1966 339 LEU 30 1987 147 LEU LEU 22 1997 294 LEU LEU 10 1988 104 LEU 5 1974 48 LEU 30 1974 140 HEU (36%) 14 1979 84 LEU 30 1994 252 LEU 50 1968 182 LEU continued

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0 MEDICAL ISOTOPE PRODUCTION WITHOUT HIGHLY ENRICHED URANIUM TABLE 3.2 Continued Reactor Reactor Name Location Owner Category Reactors That Are Not Yet Operating But That Could Be Used for Mo- Production Maple Chalk River, Canada reactors Jules Cadarache, France Horowitz Reactor Pallas Petten, the Netherlandsh Medical Lynchburg, Virginia, Isotope USA Production System aReactor power is not a measure of a reactor’s Mo-99 production capacity. In general, capacity depends on neutron flux and the number of targets that can be irradiated simultaneously. bReactor will be converted to LEU when suitable fuel is available. cIn the process of converting to LEU. dLEU-based isotope production scheduled to begin in 2009. eReactors have been shut down. See Chapter 10. MDS Nordion (Canada) MDS Nordion provides approximately 60 percent of the U.S. supply of Mo-99 and approximately 40 percent of world supply depending on global reactor production schedules. MDS Nordion has provided 100 percent of the U.S. supply of Mo-99 on several occasions over the past several years. It obtains raw Mo-99 stock from Atomic Energy of Canada Limited (AECL), a Canadian government-owned Crown Corporation,10 under a revenue- sharing agreement. AECL is responsible for target fabrication, target irradia- tion, and target processing to recover a solution containing Mo-99, as well as the management of wastes from these processes. AECL fabricates pin-type targets (Table 2.2) from HEU obtained from the United States and irradiates those targets in the National Research Universal (NRU) reactor (Table 3.2) at the Chalk River site in Ontario, Canada. The targets are processed at the Chalk River site in a single bank of hot cells. Process wastes are stored at the site. The separated Mo-99 is shipped by truck to MDS Nordion’s plant in Ottawa for purification and preparation for distribution. 10 MDS Nordion was originally part of AECL but was privatized in 1991.

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 MOLYBDENUM-/TECHNETIUM-m SUPPLY Max. Maximum Power Commissioning Annual Days of Target (MWt)a Date Operation Fuel Type Type Mo-99 Producer e HEUf 10 LEU LEUg 100 2014 (est) LEU? Mallinckrodt IRE 30–80 2016 (est) 300 (est) LEU LEU? Mallinckrodt IRE 0.20 per 5 years from 350 (est) LEU LEU B&W unit funding fHEU was used in the original design. gReactor may start up with 27 percent HEU if high-density LEU fuel is not available. hAnticipated location. A final decision on the site for this reactor has not been made. SOURCES: Reactor data from IAEA (2000, Series No. 3-Nuclear research reactors of the world) and discussions with reactor operators. NTP Radioisotopes (South Africa)11 NTP, a subsidiary of the South African Nuclear Energy Corporation (NECSA), produces about 10 percent of the world supply of Mo-99 and provides backup supplies to the U.S. market. It produces Mo-99 from uranium-aluminum dispersion targets (Table 2.2) fabricated in South Africa using 45 percent HEU of domestic origin. The targets are irradi- ated in the Safari-1 reactor (also fueled with South African HEU but it is in the process of converting to LEU fuel; see Piani, 2007), which is located at the NECSA site in Pelindaba, and processed at that same site to recover Mo-99 and I-131. The radioactive processing waste is stored to allow decay of short-lived isotopes and then disposed of by shallow land burial (IAEA, 1998). 11 NTP declined the committee’s invitation to participate in this study. The committee obtained the information in this section from the literature and informal contacts with NTP staff.

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 MEDICAL ISOTOPE PRODUCTION WITHOUT HIGHLY ENRICHED URANIUM investment to implement. It would only be undertaken if a favorable busi- ness case could be made for expanding production. ANSTO has not produced any Mo-99 since its reactor and processing facilities were shut down in 2007. It has obtained regulatory approval to begin test irradiations of LEU targets as the first step in restarting commer- cial Mo-99 production. These irradiations commenced in late November 2008. ANSTO hopes to begin commercial production of Mo-99 from this new process in the second quarter of 2009.15 CNEA (Argentina) CNEA produces Mo-99 primarily for its domestic market and second- arily for export to other South American countries. It began producing Mo-99 using HEU targets in 1985 (Cols et al., 2000) and developed and converted to LEU-based production in 2002. CNEA manufactures its own uranium-aluminum alloy plate LEU targets (Table 2.2) from LEU purchased from the United States. The targets are irradiated in the RA-3 reactor16 at CNEA’s Ezeiza Atomic Center near Buenos Aires. Target processing is carried out in a hot cell facility at the Ezeiza site. Process wastes are also managed at the site. At present, CNEA produces Mo-99 primarily for its own domestic market.17 However, it could expand Mo-99 production within its current facilities by increasing target throughputs. Such an expansion would put CNEA in the ranks of large-scale producers. Karpov Institute of Physical Chemistry (Russia) The Karpov Institute of Physical Chemistry, located in Obninsk, Russia, has been producing Mo-99 for domestic use since 1985. It currently pro- duces about 99 percent of the Mo-99 used in the Russian market. The insti- tute manufactures its own HEU targets and irradiates them in the WWR-TS reactor at Obninsk. The institute processes the targets in a hot cell facility at the site to recover Mo-99 and to produce Tc-99m generators. It supplies generators to over 200 hospitals and clinics in the country. 15 Ian Turner, ANSTO, written communication with study director Kevin Crowley, Decem- ber 10, 2008. 16 The reactor was originally fueled with HEU but was converted to LEU in the late 1980s. The reactor is 41 years old and will probably be able to run for another 10 years. Planning has begun for a replacement reactor. 17 Bulk Mo-99 is shipped to two private companies in Argentina that manufacture tech- netium generators for the domestic market and some other South American countries.

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 MOLYBDENUM-/TECHNETIUM-m SUPPLY POTENTIAL FUTURE SUPPLIERS OF Mo-99 At least two U.S.-based organizations are examining the feasibility of producing Mo-99 for sale in the commercial market: Babcock & Wilcox (B&W) and Missouri University Research Reactor (MURR). The status of these efforts is described below. Neither of these organizations is currently producing Mo-99 on a commercial basis, and both are seeking pharmaceutical partners (presum- ably technetium generator producers) to provide financial support and/or a long-term commitment to purchase Mo-99. At the time the committee completed work on this report (November 2008), neither organization had announced a partnership. However, the committee is aware of efforts by both of the U.S. techne- tium generator manufacturers to identify alternative sources of Mo-99 sup- ply, both domestic and foreign. There are several potential barriers to such partnerships. These include the existence of long-term supply agreements between technetium generator producers and current Mo-99 producers, the long lead times (see Chapter 9) before Mo-99 from these new operations would become available, and the risk of substantial cost or time overruns from unanticipated problems encountered during construction and start-up of these new facilities. B&W (USA) B&W (formerly BWX Technologies) has developed a conceptual design for a 200 kW homogeneous solution reactor, called the Medical Isotope Pro- duction System (MIPS), to produce Mo-99 (Reynolds, 2008). This reactor is conceptually similar in design to the Argus Reactor at the Kurchatov Insti- tute in Russia, which has already been used to demonstrate the production of Mo-99 (Ball, 1999). MIPS consists of one or more modular compact cylindrical reactor vessels that contain control rods and cooling coils and is surrounded by a neutron reflector (Figure 3.3). The reactor would operate at about 80° C and at atmospheric pressure. The reactor fuel, which also serves as the target material for Mo-99 production, is a solution containing an LEU salt, such as uranyl nitrate [UO2(NO3)2], dissolved in water and acid. The reactor would be operated in batch mode to produce Mo-99: That is, the reactor would be operated to allow Mo-99 to build up in the salt solu- tion; then the reactor would be shut down and the salt solution would be pumped through an ion exchange column that preferentially sorbs Mo-99. The isotope would be recovered by washing the column. If needed, the salt solution could also be periodically processed through a fuel cleanup appa- ratus to remove other fission products. A three-reactor system could supply about 50 percent of U.S. demand for Mo-99.

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 MEDICAL ISOTOPE PRODUCTION WITHOUT HIGHLY ENRICHED URANIUM t h e ba b c o c k & w i l c o x o m pa n y c a McDermott company Control Rod Sleeve Reflux Cooling Coil Mist Eliminator Diameter: 21.8” Uranyl Nitrate Solution 47” Cooling Coils 200-kW MIPS reactor FIGURE 3.3 Schematic illustration of the aqueous homogeneous solution reactor for B&W’s MIPS. The dimensions of the reactor are shown on the figure. SOURCE: Courtesy of Gary Neeley, B&W. 3-3 The reactor design is still conceptual and research and development (R&D) is underway to address several issues (e.g., Chemerisov et al., 2008; Gelis et al., 2008; Vandegrift et al., 2008; Ziegler et al., 2008). The Argen- tine company INVAP is performing R&D under a contract with B&W on reactor design and Mo-99 sorbent efficiency. Argonne National Laboratory is carrying out DOE-funded research to provide a better understanding of the chemistry of salt solutions in operating solution reactors and the recovery of Mo-99. Of particular concern is the potential for formation

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 MOLYBDENUM-/TECHNETIUM-m SUPPLY of precipitates in the salt solution, radiation effects on the oxidation of molybdenum, and the treatment of gases produced in the reactor, especially from the decomposition of the nitrate ion. Argonne researchers report that the results to date indicate that there is a “high potential for the successful implementation of this technology” (Vandegrift et al., 2008). B&W hopes to construct the first set of up to three commercially funded MIPS facilities at a logistically attractive location to supply Mo-99 to the U.S. market. It could also supply these systems to producers in other countries. B&W estimates that it would take 5–6 years18 to bring the reactor and support facilities into operation once a radiopharmaceutical partner is identified and full funding is obtained. The cost of this project is pro- prietary. However, this schedule assumes the successful completion of the current R&D program and the resolution of several legal and regulatory issues, including: • MIPS licensing: The cost and regulatory requirements for licensing MIPS are unclear at this point and could affect its commercial viability. MIPS does not fall cleanly into any of the current licensing categories for reactors defined in 10 CFR Part 50 (Domestic Licensing of Production and Utilization Facilities). • Waste disposal: The regulatory classification of the waste produced by MIPS will affect the cost and availability of disposal. Although MIPS waste is projected by B&W to meet radiological limits for low-level waste (LLW), it is not clear whether the reactor solution waste would fall under the regulatory definition for high-level waste (HLW). There is no com- mercial disposal pathway for waste that is classified as HLW in the United States. If Mo-99 is produced in the United States, the production wastes may be stored until there is a permanent disposal path. Waste that is clas- sified as LLW can be disposed of in shallow land burial facilities as long as it is not greater-than-class-C (GTCC) waste. There currently is no disposal pathway for GTCC. • LEU availability: LEU would be required to fuel the MIPS reactor. However, the USEC Privatization Act (Public Law 104-134) restricts the sale of enriched uranium to commercial entities. Section 3112-d of the Privatization Act allows the Secretary of Energy to sell LEU that has been down-blended from the DOE stockpile to commercial entities if three requirements are met.19 It will take some time to carry out the administra- 18 Thistime estimate has not been independently verified by the committee. 19 The DOE Secretary must determine that any such inventory sales will not have a material adverse impact on the domestic uranium industry and that DOE will receive adequate pay- ment if it sells this uranium. DOE must also obtain a determination from the President that the uranium to be sold is not necessary for national security.

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 MEDICAL ISOTOPE PRODUCTION WITHOUT HIGHLY ENRICHED URANIUM tive actions necessary to meet these requirements. The committee was in- formed by a representative of the National Nuclear Security Administration that DOE should be able to complete work on these determinations in time to allow B&W to purchase LEU for its solution reactor. Of course, Food and Drug Administration (FDA) approvals for the sale of Tc-99m from the MIPS-produced Mo-99 would also have to be obtained. MURR (USA) MURR is assessing the feasibility of developing the capability to supply up to half of the U.S. market needs for Mo-99 (Butler, 2008). Production would utilize the multipurpose research reactor (Table 3.2; Figure 3.4) located on the university’s main campus in Columbia, Missouri, and a target processing facility that would be constructed adjacent to the reactor facility. MURR is working on target and process design, conceptual facility development, and waste disposition in cooperation with Argonne National Laboratory, CERCA, and INVAP. It is also participating in the International Atomic Energy Agency’s (IAEA’s) Coordinated Research Project on indig- enous Mo-99 production (discussed in the next section) to demonstrate that LEU-produced Mo-99 will meet FDA requirements (see Sidebar 8.1). MURR has performed cold tests20 to demonstrate Mo-99 recovery effi- ciency and successfully irradiated an annular test target containing 4.59 g LEU (19.75 percent U-235) for 140 hours in a reflector position in the reac- tor and processed that target using Argonne’s modified Cintichem process. MURR plans to irradiate several more targets in early 2009 to optimize the modified Cintichem process for use at the facility. MURR appears to have most of the facilities and capabilities (except hot cells) needed to produce Mo-99 for the U.S. market. The organization is producing other medical isotopes for commercial companies. It also has experience with medical isotope regulation and good manufacturing practices. The MURR reactor also appears to have sufficient capability for target irradiation. The reactor began operations in 1966 but is designed to allow replacement of all major components without extended shutdowns. The reactor is currently fueled with HEU, but it will be converted to LEU when a suitable fuel is available (see Chapter 11). A large capital investment and up to about 5 years21 will be required to design, construct, and license a Mo-99 production facility. The primary 20 Coldtesting is done without using radioactive material. 21 Thistime estimate was provided by MURR and has not been independently verified by the committee.

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 MOLYBDENUM-/TECHNETIUM-m SUPPLY FIGURE 3.4 Top view of the MURR core. SOURCE: Courtesy of the University of Missouri. regulatory barrier to production of Mo-99 at MURR is the disposition pathway for the waste from target processing. As was the case with the B&W project discussed previously, the classification of this waste as HLW or LLW will determine the cost and availability of disposal. Other Potential Future Suppliers of Molybdenum-99 The IAEA has initiated a “Coordinated Research Project (CRP) on Developing Techniques for Small-Scale Indigenous Production of Mo-99 using LEU or Neutron Activation.”22 The 5-year project, which was started in 2005, is intended to foster capacity building at the local and regional levels, improve access to nuclear medicine, and support HEU minimization. This CRP is providing technical know-how and related assistance and train- ing to assist member states in the adoption of LEU methods for producing 22 Further information on this CRP can be found at http://www.iaea.org/OurWork/ST/NE/ NEFW/rrg_Mo99.html.

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0 MEDICAL ISOTOPE PRODUCTION WITHOUT HIGHLY ENRICHED URANIUM Mo-99. Two production methods are being investigated: The main method being studied is the LEU-modified Cintichem process that uses LEU foil targets. Also being studied is a method involving neutron activation of molybdenum trioxide targets for producing a gel form of molybdenum called “gel moly.”23 Seven institutions in six countries are “contract holders” in this CRP and are receiving funding for technology development, implementation, and training: Chile,24 Libya, and Pakistan are working on the modified Cintichem process, Kazakhstan is working on the “gel moly” process, and Egypt and Romania are working on both processes. Several other organizations are assisting with technology development and training as “agreement holders,” including CNEA, Indonesian National Atomic En- ergy Agency (BATAN, Indonesia), MURR, Korea Atomic Energy Research Institute (KAERI, Korea), Bhabha Atomic Research Centre/Board of Radia- tion and Isotope Technology (BARC-BRIT, India), Institute of Atomic Energy Radioisotope Centre (POLATOM, Poland), and Argonne National Laboratory. Goldman et al. (2007) provide reports on recent progress in this CRP. As indicated by its title, the goal of this CRP is to develop small-scale indigenous production of Mo-99. However, many of the CRP participants have reactor facilities that could support large-scale LEU-based production of Mo-99 (e.g., Chile, Egypt, Indonesia, Pakistan, Poland, and Romania; see Table 3.2) if suitable commercial partners can be found. This would require significant investment and a partnership with a suitable generator producer and distributor. Investments might be required, for example, to augment and train the staff at the reactor facility so that Mo-99 produc- tion could be carried out on a reliable schedule. Additionally, the facility itself might need to be upgraded to enable the irradiation and processing of targets and to satisfy best radiopharmaceutical manufacturing practices. A radiopharmaceutical partner could provide financial resources, technical advice, and a predictable market for the Mo-99 produced by the facility. The IAEA held a consultancy meeting in Vienna, Austria, in June 2007 to assess the use of homogeneous aqueous solution reactors for the produc- tion of Mo-99 and other short-lived fission-produced products. The goals of this meeting were to foster the exchange of information and also to produce a status report on the current technology state of art. This meeting could be the first step of a longer process through another CRP to be launched to assist member states with the development of this technology for Mo-99 production and other fission-produced isotopes. 23 A discussed in Appendix D, Mo-99 produced by neutron activation has a low specific activity compared to fission-produced Mo-99. Although it can be used in technetium genera- tors, its low specific activity reduces the quantity and duration of Tc-99m yields. 24 See Schrader et al. (2007) for a discussion of recent progress in Chile.

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 MOLYBDENUM-/TECHNETIUM-m SUPPLY TABLE 3.3 Technetium Generator Sales in the United States in 2005 Distribution of Sales BMSa Mallinkcrodt Total Tc-99m generators shipped 56,000 36,500 92,500 10b 16b Average generator size (Ci) Tc-99m doses utilized (millions) 11.2 11.7 22.9 Average generator price (US$) 1400 2080 aNow Lantheus. bMallinckrodt and Bristol-Myers Squibb (BMS) generators are incorrectly transposed in the Bio-Tech Systems report. SOURCE: Bio-Tech Systems (2006). Tc-99m SUPPLY IN THE UNITED STATES The most reliable estimates of Tc-99m supply in the United States that could be obtained by the committee are provided in a report by Bio-Tech Systems (2006). It quantifies Tc-99m supply in terms of technetium genera- tor sales. The Bio-Tech Systems report estimates that over 92,000 technetium generators were sold in the United States in 2005, supplying 22.9 million doses of Tc-99m radiopharmaceutials (Table 3.3). The two U.S. distribu- tors of technetium generators were Brystol-Meyers Squibb (BMS; now Lantheus25), which normally obtains Mo-99 from MDS Nordion, and Mallinckrodt.26 Both had about an equal market share of sales based on numbers of Tc-99m doses in 2005. Normally, Tyco-Mallinckrodt’s U.S. market share is about 60 percent and BMS’s share is about 40 percent. However, Tyco-Mallinckrodt had a recall of its technetium generators in the last quarter of 2005, which lasted until April 2006 (see Chapter 4). BMS picked up the slack during this outage and supplied all of Mallinckrodt’s regular customers, thereby increasing its market share. Mo-99/Tc-99m SUPPLY CHAINS Mo-99 producers have established global supply chains to ship this isotope to each other and to Tc-99m generator manufacturers using a combination of commercial and charter aircraft and ground transport services. Tc-99m generator manufacturers have also established national and regional supply chains to move generators from their production facili- 25 BMS sold its medical imaging business to Avista Capital Partners in January 2008. The new company name (Lantheus) was announced in March 2008. 26 Another generator manufacturer, Amersham, a British company, dropped out of the technetium generator business in the United States in 1999. Amersham is now part of GE Healthcare, which continues to operate radiopharmacies in the United States.

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 MEDICAL ISOTOPE PRODUCTION WITHOUT HIGHLY ENRICHED URANIUM TABLE 3.4 Typical Process Times for Mo-99 and Tc-99m Supply Chains Process steps Typical process times (hr) U-235 target irradiation and cooling 130–168 (5–7 days) Shipping and processing of target to extract Mo-99 6–28 Mo-99 packaged and shipped 6–12 Tc-99m generator prepared and packaged 12 Tc-99m generator shipped 1–24 Tc-99m generator used by hospital or radiopharmacy 168–336 (7–14 days) ties to hospitals and radiopharmacies using both air and ground services. Perhaps the most striking characteristic of these supply chains is their time efficiency: Because of the short half-lives for Mo-99 and Tc-99m, the revenues that can be obtained from their sale depend on how quickly they can be distributed to users. Table 3.4 shows the typical times required to move Mo-99 and Tc-99m through their supply chains, which in some cases span continents. The elapsed time between the time the irradiated targets are delivered to the processing facility and delivery of a Tc-99m dose to a patient can be as little as 25–76 hours. Actual times depend on the shipping distances and availability and frequency of transportation. Figure 3.5 provides a schematic representation of the supply chains for U.S. producers of Mo-99 and Tc-99m generators. As noted previously, there are two suppliers of Mo-99 to the United States: MDS Nordion and Mallinckrodt. There are also two technetium generator manufacturers in the United States: Mallinckrodt and Lantheus, located in Maryland Heights, Missouri, and Billerica, Massachusetts, respectively. MDS-Nordion ships most of its Mo-99 from Canada to the United States by air charter to technetium generator manufacturers. It supplies its key customer Lantheus and also supplies some Mo-99 to Mallinckrodt. Lantheus supplies technetium generators to markets throughout North America. Mallinckrodt ships Mo-99 from its production facility in the Netherlands to its Maryland Heights, Missouri, facility by aircraft. Mallinckrodt has an in-house facility at Maryland Heights for preparing and shipping technetium generators. Technetium generators are shipped to radiopharmacies and hospitals across the United States, Canada, and Latin America. The generators are available in a number of different curie load- ings, generally ranging from less than half a curie to about 20 curies.27 27 Under Department of Transportation regulations, technetium generators can be shipped by Federal Express if they contain fewer than 20 curies.

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 MOLYBDENUM-/TECHNETIUM-m SUPPLY FIGURE 3.5 Supply of Mo-99, T c-99m generators, and T c-99m to North American markets. Dashed arrows indicate secondary flows of Mo-99 between these producers. The figure does not show other secondary flows of Mo-99 into the North American market. SUMMARY This chapter provides a description of the Mo-99 and Tc-99m for medical diagnostic imaging. Several important points of information pro- vided in this chapter are summarized below: • The 2006 global supply of Mo-99 was about 12,000 6-day curies per week. The 2006 supply to the U.S. market was between 5000 and

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 MEDICAL ISOTOPE PRODUCTION WITHOUT HIGHLY ENRICHED URANIUM 7000 6-day curies. U.S. supply and demand probably has not changed appreciably since 2006. • About 95 to 98 percent of the Mo-99 produced globally, and all of the Mo-99 used in the United States, is made using HEU targets. • Mo-99 is being produced with LEU targets by CNEA (Argentina) and is anticipated to be produced by ANSTO (Australia) using CNEA tech- nology. This production is primarily intended for indigenous or regional use at present, but both of these organizations have expressed a desire to become global suppliers if economic conditions are favorable. • The IAEA is supporting a coordinated research project to assist several other countries with the development of indigenous Mo-99 produc- tion using LEU, but this production is intended for domestic use only. • Mo-99 has not been produced in the United States since 1988. Presently, Mo-99 is supplied to the U.S. market primarily by two commer- cial companies: MDS Nordion (Canada) and Mallinckrodt (Netherlands). These companies utilize government-constructed and -owned reactors to irradiate HEU targets. The reactors are between about 40 to 50 years old. • T c-99m generators are supplied to the U.S. market by two com- panies: Mallinckrodt (located in Missouri) and Lantheus (located in Massachusetts). Mallinckrodt generators mainly use Mo-99 produced at Petten in the Netherlands; Lantheus mainly obtains its Mo-99 from the NRU reactor at Chalk River, Ontario, via MDS Nordion. • There are two U.S.-based organizations that are seeking support to develop domestic production of Mo-99 using LEU: B&W (located in Virginia) and MURR. However, neither organization had obtained the necessary financial support by the time this report was completed.