Co-ordinated Approach to the Development and Supply of Radionuclides in the EU
|Author||N. Mario, A. Kolmayer, G. Turquet, A. Vallée, P.E. Goethals|
|Classification||6.07.4.60/53 (MISCELLANEOUS - RADIO ISOTOPES - NUCLEAR MEDICINE / MEDICAL APPLICATIONS )|
|Remarks||The objective of the present study was to fill gaps in the available information on the supply chains for the main established and novel radionuclides that have, or are expected to have, significant uses in Europe. The work also had the goal of preparing the ground for long-term European co-operation in this area. The study had to meet the following specific objectives: a. identify the main radionuclides currently in use in the European Union, and the main radionuclides expected to be used by 2030, with a particular focus on the radionuclides used in medicine; b. identify the existing and emerging methods and technologies for production of the radionuclides covered under (a) and fully describe the main elements of their respective supply chains; c. identify the main suppliers of source materials and technologies for production of radionuclides covered under (a) and the facilities which are part of the above supply chains; d. develop scenarios and concrete options for sustainable and secure supply of radionuclides covered under (a) in the EU.|
From the publication:
Executive Summary According to the new European SAMIRA Action Plan 4, there is a need to secure the supply of medical radioisotopes in the medium to long term in order to maintain EU patients’ access to vital medical procedures. The objective of the present study was to fill gaps in the available information on the supply chains for the main established and novel radionuclides that have, or are expected to have, significant uses in Europe. The work also had the goal of preparing the ground for long-term European co-operation in this area. The study had to meet the following specific objectives: a. identify the main radionuclides currently in use in the European Union, and the main radionuclides expected to be used by 2030, with a particular focus on the radionuclides used in medicine; b. identify the existing and emerging methods and technologies for production of the radionuclides covered under (a) and fully describe the main elements of their respective supply chains; c. identify the main suppliers of source materials and technologies for production of radionuclides covered under (a) and the facilities which are part of the above supply chains; d. develop scenarios and concrete options for sustainable and secure supply of radionuclides covered under (a) in the EU. Accordingly, among the large number of radionuclides with development potential, a selection of nuclides has been carried out in consensus with the Steering Group of this study, and confirmed owing to an analysis of the ongoing clinical trials at a global level. It turns out that, during the next 2 decades: - for SPECT imaging, 99m Tc should continue to be the work-horse; - for PET imaging: despite high growth expected for 68Ga, 18F should keep its current leader position; 64Cu, 89Zr and 124I are challengers; - use of radionuclides for targeted therapy will drastically increase. For the β- emitters: sharp growth is anticipated for 177Lu, particularly under its non- carrier added (NCA) form; 131I, 90Y, 223Ra should continue to be largely used. Use of 166Ho and other RN should develop. R&D progresses for α-emitters (225Ac, 212Pb, 211At), as well as for new theranostics pairs based on Terbium and Scandium. Current and future EU needs for the most important isotopes are quantified. The isotopes-specific supply chains are analysed in detail, from source material procurement up to processing of the radiochemical ready for radiopharmaceutical labelling, to identify the main security of supply challenges that they raise. Six findings conditioning security of supply are substantiated in this study. 1) Accelerators/cyclotrons and fission/neutron-activation installations are complementary in the long term, as covering different isotopes-scopes: a) accelerators/cyclotrons are particularly necessary for accompanying the anticipated development of PET imaging isotopes and, in a more distant future, for 225Ac; b) fission/activation installations are particularly needed for the future industrial bulk of neutron-activation-produced therapeutic isotopes, including NCA 177Lu. 2) If reduction of EU reliance on foreign supply is targeted, new investments are necessary in both domains, cyclotrons/accelerators and fission/activation installations, as the capability of existing installations to fulfil EU needs will deteriorate seriously. Indeed, current cyclotrons fleet will be unable to supply emerging PET isotopes. From 2035 onward, according to the life extension possibilities of BR2, HFR, Maria and LVR15, reactor’s production capacities will decline. From 2040, only RJH and FRMII will remain online if no new large installations are built. Their capacities are unable to cover fully EU needs, not only for 99Mo, but overall for essential therapeutic β-emitters nuclides such as NCA 177Lu, 131I, etc. 3) Regarding investments in large installations, several options can be envisaged: a photonuclear-based installation like SMART or an European version of Northstar, a fission-based installation like SHINE, a research reactor or a power reactor. However, the production scopes of the different options are not equivalent. a) Whereas a research reactor is able to produce simultaneously, in a proven and industrial manner, all nuclides generated by fission and neutron activation, both medical and industrial, it is not the case for developing options: i) for SMART, Go/No Go decision is scheduled by end of 2022. SMART would be able to produce essentially 99Mo and, in the future, certain accelerator-produced isotopes such as 225Ac. An alternative photonuclear-based installation, on the model of the US-Northstar using IBA’s Rhodotron technology could be envisaged as well, but with the same production scope; ii) SHINE is currently being licensed in the US only for 99 Mo, 131 I, 133 Xe production. b) Using power reactors, particularly CANDU reactors, is an interesting way to produce isotopes and is being developed in Canada. But not all the operators are ready to take the risk of perturbing their primary power production in case of potential malfunctions of the isotopes production. In addition, only 2 CANDU reactors exist in Europe, operated by Nuclearelectrica in Romania, which currently does not plan to produce other isotopes that 60Co. 4) Other critical points from a security of supply point of view are HALEU supply and the enrichment of stable isotopes: a) HALEU is essentially supplied by the US, which anticipate possible shortages beyond 2030. The ESA Advisory Committee’s Working Group on European production of low-enriched (19.75%) uranium was re-instated in spring 2021 and mandated to continue the work based on the recommendations given in the 2019 ESA report. The group will explore the necessary conditions for establishing European production capacity for HALEU to respond to the EU needs for the research reactors fuel and medical radioisotopes production; b) concerning stable isotopes, achieving satisfactory yields will necessitate the use of costly enriched targets, which raise a dual problem: their production and their recycling. Developing cyclotrons radionuclides production will increase the need for gaseous centrifugation-enriched materials, and European capabilities will have to be expanded (Urenco, and Orano as possible new entrant). For other source materials such as enriched 176Yb for NCA 177Lu production, Russian electromagnetic installations are currently the main supplier, but with limited capacities. Securing such EMS-enriched isotopes for the EU would necessitate investments (either in a EU EMS- enrichment capacity or through the development of alternative manufacturing routes). 5) Co-ordination between large European research installations is key for supplying R&D isotopes and promoting new production routes. The PRISMAS- MAP initiative federates many European research and industrial organizations for producing R&D and rarer isotopes, on the model of the US National Isotopes Development Center; such kind of initiatives are to be supported. 6) Life extension and revamping of existing installations is to be considered whenever possible, as it is currently the case for BR2, HFR, Maria and LVR-15. Based on these findings, four typical cumulative long-term scenarios are defined. With regard to their favourable cost-benefit ratio, strong coordination between large European research installations and life extension of existing installations are assumed in the four cases. The four scenarios are analysed against a series of criteria, starting with security of supply. - Scenario A: EU supply is based on accelerators/cyclotrons and existing installations, appropriately life-extended whenever possible. In this scenario, the EU can envisage self-reliance for all imaging isotopes including the emerging PET isotopes like 68Ga, but not for the main SPECT imaging isotope 99mTc. Self-reliance can also be envisaged for developing therapeutic nuclides, namely the α-emitters, but not for the fission/neutron-activated therapeutic isotopes (NCA 177Lu, etc.), which are the most interesting in the perspective of beating certain cancers in the next two decades. Import will then be necessary, and import possibilities of these isotopes will largely depend upon the success of the North American projects (SHINE, NorthStar, CANDU, etc.). - Scenario B.1: In addition to accelerators/cyclotrons, EU supply relies on large industrial installations based on emerging production routes like SMART or SHINE. In this case, self-reliance can be envisaged for 99mTc as well, but not for all therapeutics 5 such as NCA 177Lu. Like in scenario A, EU will have to rely on imports for these isotopes. - Scenario B.2: In addition to cyclotrons/accelerators, at least one new research reactor is built in Europe. In this case, EU self-reliance can be envisaged for all necessary isotopes, in a proven manner. Such option allows to maintain the EU export position and open new export opportunities as well. - Scenario C: With the addition of own capabilities for HALEU and stable isotopes enrichment, the EU reduces its reliance on foreign supply to a minimum. The second set of criteria deals with investment effort. The number of installations of each type necessary for achieving EU self-reliance is first evaluated. Using unit costs for each installation type, orders of magnitude of investments are established. Though many uncertainties remain for emerging production routes (CAPEX, production yields, etc.), it turns out that: - For scenario A, investment could be graded and optimized according to needs, development of production routes and the opportunities to co- produce several isotopes in a single installation. However, despite unit costs being relatively low, new investments in cyclotron installations (SMC & MEC) would induce very high investments due to the number of installations needed, especially for short half-life isotope production preventing long- distance shipping. Corresponding investments could amount to hundreds 5 Pending evidence that SHINE is able to produce them in an efficient manner. M€ for a new MEC network (~10 MEC) to more than 1 billion € for a full new SMC network (200 SMC across the EU). - As cyclotrons/accelerators and large installations are complementary, total investments are additive. A scenario B.1 unit like SMART could represent a 200-300M€ additional investment, whereas a scenario B.2 new research reactor could cost more than 1 billion €. - For scenario C, securing stable isotopes enrichment in the EU, along with securing HALEU supply would necessitate an additional investment of several hundred M€. - However, the optimisation of all these new investments remains to be done, when more information will be available concerning the market needs and the performance of the emerging production installations. Given the complementary production scope of the installations, a large fission/neutron activation installation remains necessary if reduction of EU dependence to foreign supply is targeted. Finally, the larger the investment, the larger the reduction of EU reliance on foreign supply. Private initiatives can generally be relied upon for graded investments in relatively low-unit-price cyclotrons. However, such private initiatives are conditional upon the existence of a market. For large installations (centralized accelerators and fission-based ones), fully private initiatives might not be practicable, due to the known difficulty of implementing full cost recovery, the high investment costs (several hundred M€) and the relatively long durations for design, construction and licensing (pre-production). In all cases, due to the many players involved in the investment decisions and the influence of the global market, the risk of investments not being made in a timely manner is high. Coping with such situations may thus require a mix of public incentives and private initiatives 6. Besides their EU security of supply merits, each scenario also presents other advantages, namely for maintaining European innovation momentum in many promising domains. However, conditioning all four scenarios is the fact that developing nuclear medicine benefits for beating cancer requires that Europe relies on all the necessary skills, that nuclear careers become appealing again for students and that public acceptance is ensured. Lastly, this study opens up additional subjects of discussion and/or further investigations. Among others: - strengthen reliability of input data (EU RN needs, performances and costs of the diverse technologies and processes, workforce needs, waste generation, etc.); - optimize the installations-mix in Europe (cyclotrons, accelerators, large industrial installations) versus relevant criteria; - pursue investigations downstream of the supply chain, in the radiopharmaceutical domain.