Molybdenum-99 for Medical Imaging (2016) / Chapter Skim
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4 Progress Toward Establishing Domestic Production of Molybdenum-99 and Associated Medical Isotopes
4 Progress Toward Establishing Domestic Production of Molybdenum-99 and Associated Medical Isotopes
Pages 87-134
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From page 87... ...
Since 2009, the Department of Energy's National Nuclear Security Administration (DOE-NNSA) has signed cooperative agreements with five private-sector companies to assist their efforts to develop domestic (i.e., U.S.-based)
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From page 88... ...
• NorthStar Medical Radioisotopes • SHINE Medical Technologies These cooperative agreements provide for 50-50 cost sharing between NNSA and these companies; NNSA provides up to $25M in cost sharing per project for work that contributes directly to the establishment of a domestic Mo-99 production capability. The first NNSA cooperative agreements were awarded to B&W and GEH in 2009 through a noncompetitive process.
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From page 89... ...
99Mo reaction o Radionuclide inventory o Production modeling ANL NorthStar Chemical processing • Chemical processing of irradiated targets • Front-end purification of irradiated Mo • Recycle process to recover enriched Mo • Large-scale dissolution process demonstration • Support to development and the FDA review of RadioGenix Mo-99 dispensing unit continued 89
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From page 90... ...
ORNL NorthStar Medical Accelerator target and • Understand the requirements for and fabrication of Mo target disks Radioisotopes production process • Develop a powder metallurgy process for fabricating accelerator target disks with a density of ≥90% • Identify parameters that affect dissolution rate of the target disks • Assist in developing recycle process for isotopically enriched Mo.
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From page 91... ...
SRNL SHINE Tritium systems • Design and fabrication of prototype cold-test TCAP unit • Design of TPS for transfer to architectural and engineering firm • TPS automation studies Y-12 High-density LEU Testing of various target designs: target technology • LEU-Foil Target Fabrication o Nickel capsule with uranium foil and annular target and uranium foil Y-12 SHINE Technical consultation Y-12 Uranium Lease and Support to the implementation of the supply portion of the Uranium Take-Back Program Lease and Take-Back Program SOURCE: Presentations to committee at Meeting #2 (see Appendix C)
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From page 92... ...
. The 3,000 6-day Ci per week production demonstration goal proved to be overly optimistic: None of the cooperative agreement partners met this goal by the end of 2013; in fact, this goal still had not been met when the present report was being finalized for publication. NNSA currently evaluates proposals for additional funding from current cooperative agreement partners using 2016 as the evaluation criterion for schedule.
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From page 93... ...
FIGURE 4.1 Domestic Mo-99 production projects supported by NNSA cooperative agreements.
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From page 94... ...
To date, NNSA has given NorthStar roughly $6M for its photon-induced transmutation project and $25M for its neutron capture project. The Mo-99 produced by these two processes has a low specific activity (1-10 curies (Ci)
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From page 95... ...
Beam Dump Lens Accelerator Concrete Lens Thick Wall Door Door Accelerator Lens Lens Beam Target Dump FIGURE 4.2 Schematic layout of an accelerator vault for NorthStar's photon-induced transmutation production project. The vault accommodates two linear accelerators and two target irradiation stations.
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From page 96... ...
The feasibility of Mo-100 production using accelerators has been demonstrated at low power, but tests of high-power systems have not yet been completed. 4.1.1.2 Neutron Capture Production NorthStar will use the University of Missouri Research Reactor Center7 (MURR)
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From page 97... ...
approval of a final amendment to NorthStar's New Drug Application (NDA) (see Appendix 4A)
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From page 98... ...
SOURCE: Courtesy of University of Missouri Research Reactor Center.
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From page 99... ...
tall, including the monitor. SOURCE: Jim Harvey, NorthStar Medical Radioisotopes.
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From page 100... ...
The LEU solution is passed through 12 The original cooperative agreement holder for this project was Morgridge Institute for Research. SHINE is now the primary cooperative agreement holder.
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SOURCE: Courtesy of SHINE Medical Technologies, Inc.
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From page 102... ...
in which they demonstrated the overall integrated process, which includes target solution preparation from uranium metal, target solution irradiation, extraction, and purification. The main difference between these experiments and the planned SHINE facility is that an electron accelerator was used in the experiments to generate neutrons.
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From page 103... ...
Additionally, hydrogen recombination using catalytic recombiners is a common process used at nuclear power facilities throughout the United States. After irradiation and cool-down, the LEU target solution is transferred to a processing hot cell and loaded onto a proprietary titanium oxide chromatography column for separation of molybdenum from uranium and most other fission products.
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From page 104... ...
4.1.3 Babcock & Wilcox B&W, now known as BWX Technologies, was awarded a cooperative agreement by NNSA on September 30, 2009, to develop a 200-kW homogeneous solution reactor, referred to as the Medical Isotope Production System (MIPS) , to produce Mo-99 (Reynolds, 2008)
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From page 105... ...
This schedule assumed the successful completion of the R&D programs and the resolution of several legal and regulatory issues, including MIPS licensing, waste disposal, and LEU availability. 4.1.4 General Electric-Hitachi GEH was awarded a cooperative agreement by NNSA on September 30, 2009, to pursue the use of power reactors as the source of neutrons to produce Mo-99 via neutron capture (98Mo(n,γ)
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From page 106... ...
GEH also signed memoranda of understanding with NuView Life Sciences (see Section 4.2.6 in this chapter) and NorthStar Medical Radioisotopes to process irradiated targets and sell the recovered Mo-99 (GEH, 2011)
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From page 107... ...
Work is under way to obtain regulatory approvals for this modified process. MURR is proposing a license amendment to its regulator (NRC)
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From page 108... ...
Nordion expects to install these targets and begin producing Mo-99 in the first half of 2018. 4.2 OTHER PROJECTS FOR DOMESTIC PRODUCTION OF Mo-99 Several private companies are working toward establishing domestic production of Mo-99 or related processes without NNSA funding.
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From page 109... ...
and export markets by irradiating LEU targets in two 10 megawatt (MW) LEU-fueled research reactors (Coquí RadioPharmarmaceuticals, 2015a)
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U fission High Medical Isotopes dissoluƟon (reactor) LEU recycle FIGURE 4.9 Five private-sector domestic Mo-99 production projects.
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From page 111... ...
needs for Mo-99 by operating the reactor at 670 kW and removing the fuel elements for chemical processing every 7 days. The company also claims that it could supply current world needs for Mo-99 by operating the reactor at 1.5 MW.27 The company has notified the NRC that it intends to file a license application to construct a reactor and processing facility near Hobbs, New Mexico.
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From page 112... ...
The targets would be processed to recover Mo-99 in a radioisotope production facility to be constructed by the company in Columbia, Missouri.31 The production facility would also be used to recover uranium from the dissolved LEU solution and recycle it back into new LEU target material. The LEU material production process would utilize a proprietary technology developed by Oregon State University.
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From page 113... ...
(Belgium) began supplying Xe-133 to the United States under an arrangement with Lantheus Medical Imaging (see Chapter 3)
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From page 114... ...
4.4 PROGRESS TOWARD ESTABLISHING DOMESTIC PRODUCTION OF Mo-99 This section provides the results of the committee's readiness assessment for each of the Mo-99 production projects described in Sections 4.1 and 4.2 of this chapter. This assessment provides the committee's collective technical judgment about the progress being made by each of these projects to demonstrate the establishment of a domestic capability to produce Mo-99.
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From page 115... ...
D: Not readily available Adequate commercially available quantities of the target materials needed to produce Mo-99/Tc-99m are not currently available from any government or commercial suppliers. Is the product (Mo-99, Tc-99m)
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From page 116... ...
Have regulatory approvals for facilities been obtained? • Irradiation • Processing A: Approval for operation The facilities to produce Mo-99/Tc-99m exist or have been constructed and the project has received approvals from regulatory authorities to operate them.
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From page 117... ...
Potential domestic suppliers also have to be able to successfully construct and operate Mo-99 production facilities and establish commercial relationships with customers. Their success in this regard will depend on a number of factors, including the availability of funding, previous experience in the medical isotope business, market timing, as well as the other economic considerations described in Section 4.5 of this chapter.
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From page 118... ...
(γ, n) SHINE GA B&W GE-Hitachi Criterion Description Has production A C Ba C B A A: Yes, at commercial scale technology been B: Yes, at pilot scale demonstrated?
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From page 119... ...
D: Project suspended a Individual components for SHINE's production technology have been demonstrated at commercial scales, but the performance of the integrated system has not. b NorthStar has received a "machines" license from state regulatory authorities to possess and install up to 16 accelerators at its Beloit facility.
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From page 120... ...
LEU LEU LFTa N/Ab LEU Mo-98 LEU C: Available from a single commercial supplier D: Not readily available Is the product (Mo-99, A A A A A B A A: Product compatible Tc-99m) compatible in B: Product partially the existing supply chain?
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From page 121... ...
It is focused on development of a resin for use in technetium generators.
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From page 122... ...
4.4.2 SHINE Medical Technologies SHINE's accelerator-driven subcritical LEU assembly Mo-99 production project received lower readiness scores because the technology has not been demonstrated at commercial scales as an integrated system, production facilities are not yet available, and some, but not all, regulatory approvals have been obtained. This project is not likely to bring Mo-99 to market until 2019, long after NRU shutdown.
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From page 123... ...
The ULTB Program is coordinated between different organizations within DOE: the NNSA Production Office provides the management and leasing of LEU and the Office of Environmental Management manages the disposition of spent nuclear fuel and radioactive waste that does not have an existing disposal path. NNSA established an intra-agency working group which coordinated the com pletion of various activities to establish the ULTB Program by January 2016, as required by the American Medical Isotopes Production Act (see Chapter 1 and Appendix A)
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From page 124... ...
propose to produce Mo-99 by fission of LEU targets36 in reactors, a process that has been well demonstrated at commercial scale and is currently being used to produce Mo-99 in Australia and South Africa. LEU is available for sale or lease from DOE (see Sidebar 4.1)
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From page 125... ...
• Supply lines from potential domestic Mo-99 suppliers to domestic users are shorter than for existing global suppliers. This lowers domestic suppliers' costs because more Mo-99 can be delivered to users for the same unit of production.
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From page 126... ...
Current Mo-99 prices are low for several reasons: • Historic government subsidies for Mo-99 production: most of the reactors and many of the facilities being used to produce Mo-99 were constructed with government funding and/or receive ongoing government support for operations. • Mo-99 production capacity and marginal costs: Global suppliers currently have excess Mo-99 production capacity (see Chapter 3)
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From page 127... ...
Some actions are already being taken as described in Chapter 5. 4.6 FINDINGS AND RECOMMENDATIONS FINDING 3A: The American Medical Isotopes Production Act of 2012 and financial support from the Department of Energy's National Nuclear Security Administration have stimulated private-sector efforts to establish U.S.
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From page 128... ...
Subsequent domestic supplier entrants will have to compete against these first entrants as well as thenexisting global suppliers, three of whom are expanding their production capacities. The expanding supply of Mo-99 to the market will put a further downward pressure on prices absent increased demand.
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From page 129... ...
Other potential domestic suppliers may recover I-131 and Xe-133 as part of their Mo-99 production processes.
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From page 130... ...
Although a DMF is not a regulatory requirement, it can facilitate the regulatory approval process for an Investigational New Drug (IND) Application, a New Drug Application (NDA)
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From page 131... ...
A DMF may be amended when this information changes: for example, when converting target material from HEU to LEU. The DMF can be reviewed by FDA to support new drug applications.41 41 See http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ DrugMasterFilesDMFs/UCM2007046.
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From page 132... ...
The NDA includes data gathered during animal studies and human clinical trials of an IND application (see Section 4A.3 for a description) .42 There are three FDA drug approval pathways described in different sections of the Federal Food, Drug, and Cosmetic Act of 1984: 1.
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From page 133... ...
The inactive ingredients for generic drug products are allowed to differ from those of the RLD only in preservative, buffer, and/or antioxidant. Additional differences are generally not permitted.44 As of August 12, 2015, no ANDA has been submitted to the FDA for Tc-99m generator (for the production of sodium pertechnetate Tc-99m injection)
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• The fees exceed the anticipated costs of FDA's review of the new drug applications. For a small business,46 FDA will waive the application fee for its first human drug application.
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