4

Conversion to Low Enriched Uranium–Sourced Production and Opportunities for Research and Development

Mr. Jeff Chamberlin (U.S. Department of Energy’s National Nuclear Security Administration) commended global producers for recognizing the international threat reduction goal of eliminating highly enriched uranium (HEU) from medical isotope production facilities and investing in conversion from HEU- to low-enriched uranium (LEU)-sourced molybdenum-99 (Mo-99) production. He added that the technical progress these producers have made with conversion in a relatively short period is enormous: In 2009, a National Academies report (NRC, 2009) concluded that conversion of large-scale Mo-99 production is technically feasible and less than 10 years later (likely by the end of 2018) global production of Mo-99 would predominantly be from non-HEU sources.

However, conversion from HEU- to LEU-sourced Mo-99 production has been a challenging process, and Mo-99 producers and target manufacturers have had to resolve several technical challenges related to LEU target fabrication and processing, target validation, and radioactive waste management. The transition to an all-LEU-sourced production has also been challenging for other members of the supply chain, including generator manufacturers and nuclear pharmacy operators. Some of these challenges were discussed at the symposium and are summarized in the following sections.

TECHNICAL CHALLENGES OF CONVERSION

The experience of conversion from HEU- to LEU-sourced Mo-99 production has been similar for global producers Curium, IRE, and NTP. Conversion took about 6-7 years (IRE is still resolving some technical challenges), and the associated challenges were described by representatives of these companies as greater than anticipated and requiring high capital investments. In addition, the operating costs for maintaining LEU-sourced production are also high. Mr. Gavin Ball (NTP) noted that these challenges came with no benefit to the patient because HEU- and LEU-sourced Tc-99m are identical in terms of diagnostic potentials.

Target Fabrication and Processing

The reduction of U-235 enrichment in HEU to LEU targets is 4.7-fold. Therefore, LEU targets with the same design and dimensions as HEU targets would produce about 5 times less Mo-99 because of the lower U-235 content. This reduction in efficiency led producers to invest in improving efficiency of LEU targets by modifying the target composition.

Mr. Roy Brown described two issues Curium faced with LEU target fabrication due to the introduction of impurities: First, the aluminum alloy cladding that was selected contained a metallic impurity that formed oxides and clogged the uranium filter used during the target processing. The company solved this issue within about 6 months by designing and validating a new uranium filter that could handle the metallic impurity load. Second, the target manufacturing process at CERCA (French acronym for Company for the Study of Atomic Fuel Creation), a subsidiary of AREVA, introduced another metallic impurity into the LEU targets, that is, contamination with radioactive tungsten (tungsten-187 [W-187]), a chemical analog of molybdenum. CERCA’s Bertrand Stepnik explained that the same amount of impurity is present in HEU targets but because of the lower U-235 content in an LEU target, the relative percentage of impurity increased by a factor of five compared to the U-235 inside the HEU target. The issue, which was also faced by the other global producers who purchase targets from CERCA, was resolved after CERCA set in place certain manufacturing controls.

Target Validation

After fabrication, the LEU targets have to be validated in all the reactors used by the Mo-99 producer. For Curium and IRE, this means validation in three reactors for each company. Mr. Brown said that unexpected shutdowns of the HFR and Maria reactors and the long-scheduled shutdown of BR-2 during Curium’s validation runs caused delays in the company’s conversion schedule. Mr. Vanderhofstadt and Mr. Brown mentioned that IRE and Curium had to compete for reactor irradiation time to validate their targets and to stay on schedule with their conversion plans. This has proven problematic for IRE’s target validation schedule and qualification of LEU targets for irradiation in the HFR reactor, a reactor both companies use for Mo-99 production.

Operational Challenges

In addition to target manufacturing and validation challenges, there are operational challenges related to LEU-sourced Mo-99 production. Because more LEU targets need to be irradiated to produce Mo-99 equivalent to that of the HEU targets, more irradiation positions within a reactor are utilized. This allows for less space in a reactor for irradiation of other targets and also requires adjusting target irradiation strategies to ensure that production of other products generated in the reactor is not affected.

Mr. Ball noted that during the transition period from HEU to LEU, NTP was producing and supplying Mo-99 from both sources, which was causing “logistical nightmares” because of the different processes and training of staff involved.

Radioactive Waste Management

LEU-sourced Mo-99 production leads to increased volumes of radioactive waste, particularly liquid waste, because of the decreased production yield. Existing global Mo-99 suppliers are developing additional capacity to manage these wastes as part of their conversion efforts and the waste management costs are high. These higher waste volumes led one producer (ANSTO) to develop a technology for radioactive waste treatment, which is described later in this chapter.

DRUG REGULATORY APPROVAL CHALLENGES

When converting target material from HEU to LEU, the Mo-99 produced needs prior approval by each national drug regulatory agency within the country the generator manufacturer markets its generators. Mr. Ira Goldman (Lantheus Medical Imaging) described the validation tests needed for U.S. Food and Drug Administration (U.S. FDA) approval, and Mr. Roy Brown (Curium) described the filing process with the regulatory agencies to receive approval to sell LEU-based Mo-99 in the United States, Europe, Canada, and Asia.

Validation Process

Lantheus Medical Imaging purchases Mo-99 from ANSTO, IRE, and NTP for production of technetium generators aimed primarily for the U.S. market. Lantheus’ supply of LEU-sourced technetium generators constitutes about 50 percent of its total supply. The company aims to convert to an all-LEU Mo-99 supply in 2018. As part of its all-LEU conversion plan, Lantheus will purchase Mo-99 supplied by ANSTO’s new ANM facility. To do that the company will need to file a “prior approval supplement” with the U.S. FDA because ANM will be irradiating targets of different design from those irradiated currently by ANSTO. Mr. Goldman anticipates that the U.S. FDA approval procedure will likely be “straightforward” because ANM will be using targets and processes similar to those used by NTP, one of the current Mo-99 suppliers to Lantheus.

The validation process for Mo-99 produced at ANM will involve Lantheus performing qualification tests in three generator sizes followed by testing of kit labeling. These validation studies could take about 2 months to complete. The U.S. FDA has a 4-month statutory review period. Therefore, commercialization of technetium generators that use Mo-99 from ANM is anticipated to take about 6 months.

A similar validation process will be followed for obtaining regulatory approval for marketing IRE’s LEU-sourced Mo-99 in 2018.

Drug Regulatory Submissions

Curium is both a Mo-99 producer and a technetium generator manufacturer. Mr. Brown noted that Curium’s drug regulatory submissions were approved by drug regulatory authorities in Europe, the United States, and Asia within 2-4 months from the time of filing. According to Mr. Brown, the rapid approval was attributed to the commitment and collaboration between drug regulatory agencies and Curium’s careful global regulatory planning, which involved coordination of the submissions to the different regulatory agencies and engagement with the regulators at different stages of the conversion project.

Curium engaged in discussions with the regulators as early as 5 years prior to the date the submissions were made in order to inform the regulators about the anticipated processes and receive feedback and provide updates as the project was progressing. Curium had regular meetings closer to submission to better understand what information the regulatory authorities were anticipating and the type of appropriate submission. Following submission, the company made “polite contact,” when appropriate, to receive an update on the review schedule.

Curium had dedicated regulatory affairs groups that were tasked with investigating the submission requirements for the different regulatory authorities, coordinating submission schedules, and responding consistently to the regulators’ questions and concerns. An example of schedule coordination was the filing with European and Asian regulators: The Asian regulators required that the company had EU approval prior to submitting for approval in Asia. Curium used the European Commission’s work-sharing provision for submissions to European health authorities. (See Sidebar 4.1 for more information on the regulatory approval process in Europe.)

NUCLEAR PHARMACY OPERATIONAL CHALLENGES

Mr. David Pellicciarini (Cardinal Health) noted that, with respect to conversion from HEU- to LEU-sourced technetium generators, nuclear pharmacies do not need to seek any regulatory approvals. For example, they are not involved in validation studies that are part of the technetium generator approval process, although they may be asked by generator manufacturers who are seeking to have their generators approved to provide some cold kits for testing. Also, the nuclear pharmacies’ radioactive material licenses are not affected by conversion from HEU- to LEU-sourced technetium generator production. Although from a regulatory perspective, conversion from HEU- to LEU-sourced Mo-99 production has no effect in the nuclear pharmacy’s operations, operators face some challenges during the transition from HEU- to LEU-sourced Mo-99 production.

During the transition, some nuclear pharmacies may be dispensing radiopharmaceutical doses using both HEU- and LEU-sourced generators. Mr. Pellicciarini described three challenges that Cardinal Health’s nuclear pharmacies in the United States are facing:

1. Operations are less efficient. LEU doses can only be dispensed from LEU-sourced technetium generators but HEU doses can be dispensed by combining technetium from an HEU- or LEU- sourced generator. Combining Tc-99m from multiple generators allows for increased operational efficiencies. Strictly dispensing LEU doses could result in HEU-sourced generators not being fully utilized during the transition period.
2. Operations are more complex. With two generators available, nuclear technicians have to pay attention to whether the customer specifically requested an LEU-sourced dose, ensure that the LEU-sourced generator was used for that dose, and confirm that the paper trail accompanying the dose dispensed and shipped is correct. The latter is particularly important for customers who are seeking the $10 per dose additional reimbursement on purchases of radiopharmaceuticals sourced from non-HEU generators.¹
3. Issues exist with contingency planning and traceability. Not all nuclear pharmacies within the Cardinal Health chain purchase both HEU- and LEU-sourced generators and therefore not all nuclear technicians are trained to operate in a nuclear pharmacy that dispenses doses from both HEU- and LEU-sourced generators. If one nuclear pharmacy temporarily closes and its customers need to be supported by a different nuclear pharmacy within the chain, staff may need to be trained in managing both HEU- and LEU-sourced purchases.

Mr. Pellicciarini noted that these operational challenges will be removed when full transition to LEU-sourced Mo-99 is complete.

OPPORTUNITIES FOR RESEARCH AND DEVELOPMENT

The challenges of conversion from HEU- to LEU-sourced Mo-99 production has provided several opportunities for research and development to improve production and processing efficiencies and manage the larger volumes of radioactive wastes. Although the symposium organizing committees did not solicit presentations from representatives of all research and development efforts related to Mo-99 production under way, three of these activities were described at the symposium.

High-Density Low-Enriched Uranium Target Development

Conventional HEU aluminum alloy targets have 1.1-1.4 g uranium per cubic centimeter (U/cm³), and LEU aluminum alloy targets have 2.6-2.7 g U/cm³. To obtain Mo-99 at “per target” levels equivalent to currently available HEU targets, the density of LEU targets needs to be 8-9 g U/cm³. The Korea Atomic Energy Research Institute (KAERI) has been developing a process for production of high-density UAl_x² targets with uranium density of 3.2 g U/cm³ with the possibility of increasing it to above 9 g U/cm³.

Dr. Ul-Jae Park (KAERI) noted that conventional UAl_x targets are produced by using pulverized UAl_x powders through five steps of melting, casting, heat treatment, component analysis, and crushing. Aspherical powder of uranium alloys can be produced by centrifugal atomization. Using this technique KAERI can increase uranium content to 4.6 g U/cm³ and a uranium content of 9.0 g U/cm³ is also achievable by using U-metal powders produced by the centrifugal atomization technology.

Compared with conventional pulverized UAl_x powders, KAERI’s powders have spherical shape, smoother surfaces, and smaller surface area. These differences may lead to minor differences in dissolution behaviors during the chemical process of the targets. KAERI anticipates that development of high-density LEU targets will be completed in 2021, and the institute could start supplying the targets to the global market after that.

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¹ This regulation was issued by the U.S. Centers for Medicare and Medicaid Services in 2012.

² UAl_x refers to a mixture of intermetallic compounds of uranium and aluminum resulting from melting and casting of a uranium-aluminum binary system.

Future Efficient Molybdenum-99 Extraction Process

The decrease in yield per target and increase in liquid radioactive waste production following LEU-sourced Mo-99 production motivated a research team at the FRM-II reactor in Germany to develop two projects to regain yield and to reduce the amount of liquid radioactive waste produced during Mo-99 purification. These projects were summarized by Dr. Rianne Stene (FRM-II).

The first project focuses on developing a cylindrical LEU target with mechanically separable cladding. Since the cladding can be mechanically (as opposed to chemically) separated from the target before processing, the liquid wastes produced during target processing would be less. Further, the monolithic uranium foils promise increased yield. According to Dr. Stene, this target design is ready for industrial fabrication.

The second project focuses on developing a dry-chemical technique for Mo-99 processing and purification. The technique takes advantage of the chemical and physical properties of fluorides to achieve the separation of molybdenum from uranium. This project is in early development stages.

Synroc Waste Treatment Technology

ANSTO has for about 40 years invested in research and development of a technology called synroc (short for synthetic rock) to provide a matrix for immobilization and final disposal of various types of intermediate-level and high-level radioactive wastes, including long-lived actinide-rich waste streams. In the synroc process, the radioactive liquid waste is mixed with additives to create a slurry that is then dried to produce a free-flowing powder. The resultant powder is first thermally treated and then dispensed into cans and sealed. The cans are hot isostatically pressed, heated, and then pressure is applied. Under these conditions the powdered mixture is formed into a solid ceramic or glass ceramic block of well-defined composition. The canister is designed to collapse and form a cylindrical shape suitable for maximum waste storage efficiency.

Dr. Bruce Begg (ANSTO) highlighted three advantages of the synroc technology:

1. Maximum waste volume reduction that minimizes disposal costs,
2. Chemical durability of the waste form that reduces environmental risk, and
3. Versatility of the range of effective waste-form compositions that allows for treatment of different waste streams.

ANSTO is currently designing and building a synroc waste treatment plant (expected to be operational from late 2019) as part of the ANM project. The liquid waste from ANM processes will be stored for decay for at least 2 years prior to treatment by the synroc process. The synroc canisters will be sent to Australia’s proposed National Radioactive Waste Management Facility (NRWMF). The location of the NRWMF is currently being finalized and the facility is expected to start operations by the mid-2020s.