Research Reactor Group

1. Introduction

Technetium 99m, the daughter product of Molybdenum 99 (Mo-99), is the most commonly utilized medical radioisotope in the world. Annually, it is used for approximately 20-25 million medical diagnostic procedures, alone comprising some 80 % of all nuclear medicine procedures. There are only a few major commercial producers of Mo-99, all of them irradiating HEU targets in research, test, or isotope production reactors and recovering Mo-99 in dedicated processing facilities.

In line with RERTR, and the objective of minimizing and eventually eliminating the use of HEU in civil commerce, national and international efforts are underway to shift the production of medical isotopes away from the use of HEU.

A small but growing amount of the current global Mo-99 production is derived from the irradiation of Low Enriched Uranium (LEU) targets. Argentina has been producing Mo-99 from LEU targets since 2002, and Australia plans to greatly increase its Mo-99 production from LEU now that its new OPAL research reactor is in operation. Additionally, small but also growing volumes of Mo-99 are made from the irradiation of molybdenum 98 (neutron activation technique).to produce Tc-99m., principally in Brazil, China, and India.

The IAEA became aware of the interest of a number of developing Member States that are seeking to become small scale, indigenous producers of Mo-99 to meet local nuclear medicine requirements. Such production is potentially attractive in order to further develop domestic nuclear technology capabilities, take advantage of relevant nuclear facilities and expertise, reduce dependence on foreign supply, and save hard currency expenditures. The IAEA responded to the interest of such states and initiated Coordinated Research Project (CRP) T.1.20.18 “Developing techniques for small-scale indigenous production of Mo-99 using LEU or neutron activation: in order assist countries to pursue such Mo-99 production.

2. Coordinated Research Projects (CRP)

A CRP is a collaborative research arrangement organized, executed, and funded by the IAEA to promote technology transfer through the dissemination of peaceful applications of new nuclear technologies. A CRP typically involves approximately five institutions from countries which have successfully implemented a particular nuclear or isotopic technique, and a similar number of institutions which are seeking to establish the technology. (For full description of CRPs, see http://www-crp.iaea.org/).

The IAEA notifies member states of approved CRPs so that interested countries may apply to take part.

Technology “donor” institutions (agreement holders) participate in the CRP free of charge, although their attendance at the Research Coordination Meetings (RCM) are financially supported by the IAEA. Technology “recipient” countries (contract holders) receive nominal funding from the IAEA (generally 4000 EURO per year) for an agreed set of activities, but must supplement the IAEA funding with institutional and national resources. Their expenses to participate in the RCMs are also financially supported by the IAEA.

CRPs are usually planned and structured based on a coordinated set of activities which will take place over the 3-5 years duration. Work plans and coordinated activities, including standardized procedures and protocols, are determined in the First Research Coordination Meeting (RCM). Additional RCMs take place at approximately 15-18 month intervals, to monitor progress in the work plans and coordinated activities and to prepare a written report (normally an IAEA TECDOC) on the results and outcomes.

3. History

This project was initiated with an IAEA Consultants Meeting in Vienna in November 2004. This meeting was attended by participants from Argentina, Belgium, Canada, Netherlands, South Africa and the U.S., including representatives of the four major commercial producers of Mo-99. The meeting reached a consensus on the scope, methodology, and objectives of the projected CRP, including the inclusion of n,gamma neutron activation (gel generators) technology. The U.S. Department of Energy made an extrabudgetary contribution to begin the CRP to begin in 2005, whereafter it has been funded from the IAEA regular budget. (Note: DOE made an additional extrabudgetary contribution in 2006 to support purchase of glassware for target processing via the LEU-modified Cintichem process and for a workshop on operational aspects of Mo99 production). The CRP proposal was approved by the IAEA Research Contracts Committee in February 2005.

A Potential Mo-99 Producers Workshop was held in May 2005 in Buenos Aires, Argentina, hosted by the National Nuclear Energy Commission (CNEA) of Argentina, CNEA provided most of the lecturers, along with lecturers from Argonne National Lab (USA) and ANSTO (Australia) on aspects related to fission moly production and from Brazil and India, concerning gel moly production. There were participants from eleven countries, who also made presentations on their national requirements for Mo-99, current means for satisfying local demand for Mo-99, and their technical capabilities and facilities for producing Mo-99. Two commercial companies involved in target fabrication for Mo-99 production attended as observers, but none of the four major commercial producers of Mo-99 participated.

Following the workshop, interested countries submitted proposals for both research agreements and research contracts. The IAEA convened a Consultants Meeting in July 2005 in Vienna to review the proposals, and the selected proposals were submitted and approved by the Research Contracts Committee in September 2005.

4. Objectives

The objectives of the CRP are to:

• Assist member states with the adoption of LEU Cintichem (foil targets) or neutron activation (gel moly) technology for producing Mo-99,
• Further demonstrate efficacy of LEU target and neutron activation production of Mo-99,
• Foster capacity building for local/regional self-sufficiency to meet Mo-99 needs,
• Advance international non-proliferation and nuclear security objectives, while promoting sustainable development and the sustainability of nuclear research institutes.

The CRP does not specifically include the objective of conversion to LEU of the large-scale, HEU-based commercial production of Mo-99. However, the IAEA has encouraged the active participation of the major commercial producers in carrying out the objectives of the CRP and the commercial producers participated as observes in the First Research Coordination Meeting and are contributing to a workshop to be held in Vienna in November 2006 (see below).

5. Purpose

The CRP aims to assist recipients to research, test, and evaluate the LEU modified Cintichem process with LEU foil targets, and neutron activation of natural molybdenum oxide targets and utilization of gel generators. o-called “Freeware Technology” for LEU fission and gel moly production of Mo-99. Contract holders will be assisted in evaluate options to access such technology, build their own technology, or purchase alternate LEU and neutron activation based technology. The experimental evaluation of Freeware Technology will be used to disseminate information of the technological options and requirements.

6. CRP Activities/Output

The technology transfer being carried out under the CRP includes the provision of technical expertise, information sharing between participants, and the provision of some laboratory equipment and related materials. Technology transfer addresses all steps: target preparation (including supply of a small number of test targets), irradiation, radiochemical processing, safety, quality control and quality assurance, and waste management.

It is expected that as a result of the work undertaken in the CRP, participants will obtain the necessary skills and technology to begin limited local production of Mo-99 from LEU targets and processing or from neutron activation. The requirements for Mo-99 gel preparation following (n, gamma) production will also be reviewed based on the experience gained through the CRP.

The final output will be an Agency publication that will review the work that occurred, results achieved, and to define standardized technological approaches.

7. Participants

Six institutions in five countries have been awarded research contracts:

• Chile: foil targets, LEU-modified Cintichem process
• Kazahkstan: gel generators
• Libya: foil targets, LEU-modified Cintichem process
• Pakistan: foil targets, LEU-modified Cintichem process
• Romania (IFIN-HH): gel generators
• Romania (Pitesti): foil targets, LEU-modified Cintichem process

Six institutions in five countries have been awarded research agreements:

• Argentina: LEU fission moly implementation
• Republic of Korea: development of LEU foil targets
• India: standardization of gel generators and feasibility of fission moly
• Indonesia: development of LEU foil targets, LEU-modified Cintichem process
• U.S. (Argonne National Laboratory, ANL): foil targets, LEU-modified Cintichem process
• U.S. (University of Missouri Research reactor): foil targets, LEU-modified Cintichem process; scope and level of work to obtain U.S. FDA approval for Mo-99 from LEU.

8. First Research Coordination Meeting (RCM)

The first RCM was held 6-9 December 2005 in Vienna. It was attended by the Chief Scientific Investigators of each contract and agreement holder, plus observers from BWXT, CERCA, the Institute for Radioisotope Elements (IRE), MDS Nordion, Nuclear Energy Corporation of South Africa (NECSA), Nuclear Research Group (NRG) Petten, and Tyco Medical/Mallinckrodt. Each contract holder provided a briefing on their national nuclear medicine requirements for Mo-99/Tc-99m, the relevant infrastructure at the institute, and their draft work plans for the CRP.

Two of the contract holders had submitted proposals to pursue neutron activation (“gel moly”) technology, the other four fission molybdenum approaches. After discussions in sub-groups, all four of the fission moly contract holders decide to pursue LEU foil targets with the LEU-modified Cintichem process. The RCM subsequently reviewed, revised and finalized the individual country work plans, established a set of coordinated activities for both fission and gel moly groups, specified the material and expert assistance requirement, and agreed on a list of action items with dates/milestones.

The fission moly coordinated activities include:

• perform calculations for irradiation of targets, including sharing and peer review of the calculations.
• prepare completed safety cases for target irradiation.
• IAEA coordinate supply of uranium foil, Ni foil, and aluminium tubes to prepare generic targets
• fabrication and welding of generic targets
• prepare and test equipment and hot cell facilities for target disassembly and processing
• develop QC plan based on QC procedures to be supplied by ANL
• evaluate options and identify plans for radioactive waste treatment and disposal.
• Irradiation and processing of actual targets.

The gel moly coordinated activities include sharing of data on gel preparation procedure, exchange of inactive samples, harmonization of evaluation methods and acceptance criteria with respect to yield and purity on active runs, exchange of data on:

• safety documents,
• QC documents,
• production sheet,
• components of gel generators,
• evaluation results, and
• gel generator operation

After the RCM, and to implement one of the meetings actions, the IAEA established a restricted access website for project participants which includes all project-related documents (including from the RCM, workshops, and documents created by the participants in response to action items and milestones) and a discussion board. This web site has become the focus of written information exchange and communication for coordination of the CRP.

9. LEU Foil Workshop, Serpong, Indonesia

Another action resulting from the RCM was the holding of a Workshop on LEU Foil Target Fabrication, Irradiation, and Chemical Processing Using the Modified Cintichem Technique at the radioisotope production facilities and reactor of the National Atomic Energy Agency of Indonesia (BATAN) in Serpong, Indonesia from 6-11 March 2006. This workshop was based upon a U.S.-Indonesia cooperative agreement for the conversion of Indonesia’s Mo-99 production to LEU foil targets. Lectures on foil preparation, target fabrication, assembly and disassembly, and irradiated target processing were provided by ANL scientists, and facility visits and technology demonstrations were conducted in BATAN’s facilities by BATAN scientists and technicians.

Also at the workshop, the action item list from the RCM was reviewed, updated, and a number of items were added. Calculations for the design of foil targets was further specified, and Romania2 was tasked to prepare a “model” of the calculations required for irradiation of targets. The IAEA specified that it would determine the legal and administrative requirements to supply foil with nuclear material (DU and/or NU, and LEU) and the Korean Atomic Energy Research Institute was requested to supply such foils for test irradiations.

10. Provision of Materials

In accordance with the action plans from the RCM and Serpong Workshop, aluminium tubes were shipped directly by ANL to three of the fission moly institutions in March 2006. Administrative and export licensing requirements delayed the shipment to the fourth institution until October 2006. These materials are being used for target fabrication and cutting

After receipt of extrabudgetary funds from U.S. DOE, IAEA proceeded with an order to procure glassware for the Cintichem process for the CRP holders. The order was finalized in early October 2006, and six sets of the glassware (consisting of five items each: single and double-ended bottles, fritted glass column, two other length columns) are to be shipped directly to institutions, with ANL receiving four sets.

IAEA undertook a review of the legal requirements in regard to IAEA serving as the focal point for supply of LEU foil under the CRP. This legal analysis concluded that the IAEA would need to conclude Project and Supply Agreements to be approved by the Board of Governors in order to supply the nuclear material (DU and/or NU, and LEU) contained in the foil. KAERI agreed to supply a small number of test LEU foils for the CRP directly to several of the contract holders with which it has existing nuclear cooperation arrangements and specifications for the foil to be supplied is being determined based on the calculations performed by the institutions. For other institutions, IAEA is arranging for the supply of test foils from CERCA.

11. Commercial Industry Involvement

Since the beginning of the formulation of the project, the IAEA has endeavoured to maintain close contact with the major radiopharmaceutical producers and to involve them in the CRP. As previously noted, all the major Mo-99 producers - the Institute for Radioisotope Elements (IRE), MDS Nordion, Nuclear Energy Corporation of South Africa (NECSA), and Tyco Medical/Mallinckrodt – participated as observers in the 1st RCM. In addition, BWXT, CERCA, and NRG Petten also participated as observers in the 1st RCM

A side meeting and other discussions related to the CRP were held during the Research Reactor Fuel Management Meeting (RRFM) in Sofia, Bulgaria 1-3 May 2006. As a result, an agreement was reached in which MDS Nordion, NRG Petten, and Tyco Medical agreed to hold a workshop at their facilities in Belgium and the Netherlands on operational aspects of Mo-99 production. NECSA also agreed to contribute to this workshop. Due to security-related issues, it was later decided to move the workshop to Vienna (see below).

12. Workshop on Operational Aspects of Mo-99 Production

The IAEA will host a Workshop on Operational Aspects of Mo-99 Production in Vienna 28 November–1 December 2006. The workshop, supported with extrabudgetary funding from the U.S. Department of Energy, will include lectures on:

• target plate manufacture
• foil target production
• target irradiation
• irradiated plate/foil processing
• logistics, storage, and transportation
• environmental and waste management
• physical security/protection

The lectures will be presented by experts from BWXTCERCA, MDS Nordion, NRG Petten, Tyco Medical, NECSA. There will also be presentations on solution reactors to produce Mo-99 and the U.S. National Academy of Sciences study on Medical Isotope Production Without HEU. A review of action items from the 1st RCM and Serpong Workshop will also be made, and there will be a discussion of activities during the second year of the CRP and for the second RCM in Romania.

13. Second Year Activities

The 1st RCM Workplan includes the following major activities and milestones for the fission moly group second year of the CRP:

• Completion of calculations for target irradiation (12/06)
• Finalize and submit safety analysis reports (12/06)
• Finalize irradiation rig and target designs.
• Finalize procedures and protocols, including quality assurance
• Cold assembly, testing, and disassembly of targets
• Preparation and testing of hot cell facilities and equipment

The gel moly group workplan includes exchange of the detailed safety document, exchange of QC document and QC sheet, exchange of production sheet and information on components of gel generator. It is planned that a small workshop event will be held for the gel moly group in the first half of 2007.

The Second Research Coordination Meeting will be held in Bucharest, Romania, tentatively scheduled for 16-20 April 2007.

The University of Missouri Research Reactor joined the CRP as a research agreement holder and will specifically undertake work related to determining the requirements for U.S. Food and Drug Administration approval of Mo-99 produced from LEU.

14. Future Activities

The work-plan calls for fission moly participants to carry out irradiation of LEU targets in December 2007 with processing of hot targets to follow in January 2008. The gel moly group is expected to carry out irradiation of molybdenum trioxide target and prepare both Mo-99 zirconium molybdate (Zr-Mo) gel powders and gel column generators in the same time frame.

At the Third RCM, to be held in the third quarter of 2008, the participants will:

• Compare, interpret, and assess results, provide follow-up, and suggest adaptive changes,
• Review whether product meets specifications and purity requirements,
• Make modifications to improve future efforts, and
• Compile material to publish Agency TECDOC on the final results

15. Conclusions

The CRP has made good progress in its first year:

Romania (Pitesti): posted its fission moly target calculations on the project website in late May 2006, and then performed a second analysis based on modification of irradiation device and completion of the TRIGA LEU conversion, finished the target design, is working on equipment design and fabrication for target assembling, and has designed hot cell for target disassembly and cutting equipment.

• Chile: made preliminary calculations for irradiation of targets, finished design of three assemblies for LEU target preparation and a target cutter, undertook work regarding hot cell ventilation, tele-manipulators, and other equipment, and developed a complete flow diagram for chemical processing.
• Libya: has performed initial calculations for target design and irradiation, is working on the safety case information, and reviewed existing hot cell infrastructure and determined that it is adequate.
• Pakistan: performed R&D for fabrication of foils, carried out calculations regarding irradiation of foil annular targets at different neutron flux, performed dissolution of depleted uranium and aluminium, the latter to replace mechanical disassembling of annular targets.
• Kazakhstan: performed experiments to determine optimal design of the gel column, made calculations to determine the lead thickness for portable gel generator shielding, and performed experiments to modernise the Zr-Mo gel preparation.
• Romania (IFIN-HH): prepared three samples of zirconium molybdate gels after irradiation of molybdenum oxide target at TRIGA, Pitesti and then analyzed.
• India has completed the commissioning of a production facility for gel generators, and following a few trial runs of 2 Ci and 10 Ci batch size of Zr-Mo gel, have commenced limited production and supply of gel generators for use in hospital radiopharmacies.
• Indonesia continues to progress toward goal of conversion to LEU targets in 2008.
• U.S. University of Missouri MURR’s joining brings substantial experience in radiopharmaceutical development, testing, and product licensing to the CRP.

A number of issues and delays have been encountered, especially concerning the supply of test foils, but these are being overcome. The work accomplished to date has established most of the preconditions for further progress in the second year of the CRP, in order to successfully achieve the CRP’s objectives.

The CRP is directly supportive of RERTR objectives, as it will help encourage the further use of LEU and neutron activation technologies by building experience and consensus on their use, within the context of an internationally-coordinated project. The results and experience gained will also help strengthen local capability for undertaking small scale Mo-99 production in participant countries, and could add to security of supply for this important medical radioisotope. In addition, it will facilitate enhanced utilization of research reactors by local production of radioisotopes, and consequently could serve to improve sustainability of such institutions.

For further information please contact:

• Pablo Adelfang, p.adelfang@iaea.org (phone +43-1-2600-22770,
• Ira N. Goldman, i.goldman@iaea.org (phone) +43-1-2600-22782,
• Natesan Ramamoorthy, n.ramamoorthy@iaea.org (phone) +43-1-2600-21700