The new BR2 Reactor Perspectives for Radioisotope Production

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1 The new BR2 Reactor Perspectives for Radioisotope Production Potential Consequences from Ceased Production of Medical Radioisotope at the NRU Reactor Bernard PONSARD Radioisotopes Project Manager Chairman AIPES R&I WG BR2 Reactor 6 th Symposium on Medical Radioisotopes Challenges in production, transport and applications Mechelen, 11/05/ TH SYMPOSIUM ON MEDICAL RADIOISOTOPES MECHELEN (Belgium) MAY /22

2 Perspectives for Radioisotope Production in the BR2 Reactor 1. Introduction 2. The BR2 Reactor 3. Production of radioisotopes for diagnostic 4. Production of radioisotopes for therapy 5. Conclusions BR2 Reactor 6 TH SYMPOSIUM ON MEDICAL RADIOISOTOPES MECHELEN (Belgium) MAY /22

1. Introduction The BR2 high-flux reactor operated by the Belgian Nuclear Research Centre () is not only one of the world's most powerful material testing reactors, it is also recognized as a major

3 1. Introduction The BR2 high-flux reactor operated by the Belgian Nuclear Research Centre () is not only one of the world's most powerful material testing reactors, it is also recognized as a major facility for the global production of radioisotopes. The refurbishment performed recently ( ) will ensure a safe and reliable reactor operation for another period of 10 years, at least. The current operating regime based on 6 cycles (147 operating days) per year could be upgraded up to 8 cycles (200 operating days) subject to the economics. 6 TH SYMPOSIUM ON MEDICAL RADIOISOTOPES MECHELEN (Belgium) MAY /22

4 1. Introduction 6 TH SYMPOSIUM ON MEDICAL RADIOISOTOPES MECHELEN (Belgium) MAY /22

5 1. Introduction The new Beryllium Matrix 6 TH SYMPOSIUM ON MEDICAL RADIOISOTOPES MECHELEN (Belgium) MAY /22

1. Introduction The BR2 reactor is a major player in the production of radioisotopes worldwide: High neutron fluxes (thermal up to e+15 n/cm².s and fast up to 6 e+14 n/cm².

6 1. Introduction The BR2 reactor is a major player in the production of radioisotopes worldwide: High neutron fluxes (thermal up to e+15 n/cm².s and fast up to 6 e+14 n/cm².s), large irradiation volumes, very flexible, but limited by its operating regime ( operating days per year). 100 MW 6 TH SYMPOSIUM ON MEDICAL RADIOISOTOPES MECHELEN (Belgium) MAY /22

7 2. The BR2 Reactor Reactor type High Flux Materials Testing Reactor Pressurized, light water Be matrix, compact core HEU fuel (93% 235 U) LEU conversion project in place In operation since 1963 Refurbishments: _ _ Aluminium pressure vessel Geometry : hyperboloid of revolution Easy access to the top and bottom Diameter : 1 to 2 m Height : 8.6 m Very compact core Diameter : 1.05 m Height : 0.91 m 100 MW 6 TH SYMPOSIUM ON MEDICAL RADIOISOTOPES MECHELEN (Belgium) MAY /22

8 2. The BR2 Reactor P341 L 0 P_19 Unique shape N330 K349 K_11 N_30 L300 K % K311 G H P259 H5/CEN 180 L240 P F % G240 H % F % D % C281 C % D240 H4/330 H4 H337 E330 C % B % A % B % C221 F346 C341 A % A % B % A_ % B_60 H % C_79 H2 240 C % G % D % H1/CEN 180 B % D180 F_14 C_ A % C % H_23 E_30 C_41 0.0% A_ % B % C139 H_37 F_46 D_ % C % D % H3 H3/_30 P_41 K_49 G_60 F % G120 L_60 K109 L120 P101 H4/_90 F194 F166 H3/270 H4/210 P199 K % G % L180 K % P161 H3/150 Typical configuration 6 TH SYMPOSIUM ON MEDICAL RADIOISOTOPES MECHELEN (Belgium) MAY /22

9 3. Production of radioisotopes for diagnostic : Mo-99/Tc-99m From U-235 Targets unloading To Mo-99 6 TH SYMPOSIUM ON MEDICAL RADIOISOTOPES MECHELEN (Belgium) MAY /22

10 3. Production of radioisotopes for diagnostic : Mo-99/Tc-99m The worldwide supply of Mo-99 relies on a limited number of research reactors and processing facilities. Its production is essential for nuclear medicine as Tc-99m, obtained from Mo-99/Tc-99m generators, is used in about 80% of diagnostic nuclear imaging procedures. These applications represent approximately 30 million examinations yearly worldwide. Mo-99/Tc-99m Generator Therefore, a weekly Mo-99 production of about Ci '6-day' calibrated is required to supply North America (53%), Europe (23%), Asia (20%) and the rest of the world (4%). Given the short half-lives of Mo-99 (66 hours) and its daughter Tc-99m (6 hours), a regular supply of 99 Mo/ 99m Tc generators to hospitals or central radiopharmacies is required. 6 TH SYMPOSIUM ON MEDICAL RADIOISOTOPES MECHELEN (Belgium) MAY /22

3. Production of radioisotopes for diagnostic : Mo-99/Tc-99m Are currently represented in the AIPES Reactors & Isotopes Working Group (R&I WG) which has the task to secure the global supply of Mo-99:

11 3. Production of radioisotopes for diagnostic : Mo-99/Tc-99m Are currently represented in the AIPES Reactors & Isotopes Working Group (R&I WG) which has the task to secure the global supply of Mo-99: Eleven reactors : BR2 (Belgium), HFR (The Netherlands), SAFARI (South Africa), MARIA (Poland), LVR-15 (Czech Republic), OPAL (Australia), RA-3 (Argentina), FRM-II (Germany; currently not irradiating targets for Mo-99; 2018), NRU (Canada; no routine production from November 2016), OSIRIS (France; shutdown) / JHR (France; under construction to replace OSIRIS from 2022). Six processors : IRE (Belgium), CURIUM MALLINCKRODT Medical B.V. (The Netherlands), ANSTO Health (Australia), NTP (South Africa), CNEA (Argentina) and CNL/NORDION (Canada; no routine production from November 2016). 6 TH SYMPOSIUM ON MEDICAL RADIOISOTOPES MECHELEN (Belgium) MAY /22

12 3. Production of radioisotopes for diagnostic : Mo-99/Tc-99m Mo-99/Tc-99m Generator 6 TH SYMPOSIUM ON MEDICAL RADIOISOTOPES MECHELEN (Belgium) MAY /22

13 3. Production of radioisotopes for diagnostic : Mo-99/Tc-99m BR2 Reactor Targets shipment Targets manufacture Hospital Targets irradiation Mo-99/Tc-99m Targets processing 6 TH SYMPOSIUM ON MEDICAL RADIOISOTOPES MECHELEN (Belgium) MAY /22

14 3. Production of radioisotopes for diagnostic : Mo-99/Tc-99m The BR2 reactor has the largest world's installed irradiation capacity for Mo-99 production. Reactors Countries Targets Operating weeks / year Irradiation capacities / week [6-day Ci ] Irradiation capacities / year [6-day Ci ] End of operation BR2 Belgium HEU > 2026 HFR The Netherlands HEU (NRU) (Canada) (HEU) (40) (4 680) ( ) (Nov 2016) SAFARI South Africa HEU/LEU LVR-15 Czech Republic HEU MARIA Poland HEU OPAL Australia LEU RA-3 Argentina LEU Ref: Nuclear Energy Agency, NEA/SEN/HLGMR (2017)2, April 2017, With an installed irradiation capacity of '6-day' Ci per week, the BR2 reactor is able to produce at least : 25% of the global Mo-99 demand in average 65% in peak periods 6 TH SYMPOSIUM ON MEDICAL RADIOISOTOPES MECHELEN (Belgium) MAY /22

15 3. Production of radioisotopes for diagnostic : Mo-99/Tc-99m 6 TH SYMPOSIUM ON MEDICAL RADIOISOTOPES MECHELEN (Belgium) MAY /22

16 4. Production of radioisotopes for therapy In addition to the current production of radioisotopes for therapy (I-131, Lu-177, Ir-192, Ho-166, Y-90, P-32, ) and for palliation of metastatic bone pain (Sm-153, Re-186, Re-188, Sr-89, Sn-117m, Ra-223, ), nuclear medicine is offering new perspectives. Radioisotopes as Lu-177 are already largely used for targeted radionuclide therapy ( TRNT ) but others are under evaluation as medium-energy β - emitters having diagnostic partners, high linear energy transfer ( LET ) and Auger electron emitters ( Tb-161 ). Isotopes Half-life T 1/2 Decay mode Average Energy β - Average Energy γ Lu-177 6,71 d β kev 208 kev Sc-47 3,35 d β kev 159 kev Cu-67 2,58 d β kev 186 kev Tb-161 6,90 d β -, Auger e kev 75 kev 6 TH SYMPOSIUM ON MEDICAL RADIOISOTOPES MECHELEN (Belgium) MAY /22

17 4. Production of radioisotopes for therapy The concept of personalized medicine based on 'theranostics' is increasingly seen as a promising approach in which single radioisotopes or 'matched pairs' (Sc-44/Sc-47, Cu-64/Cu-67, Tb-152/Tb-161, Tb-155/Tb-161, ) are selected to enable pretherapy imaging and dosimetry (PET or SPECT) followed by the administration of an appropriate therapeutic dose (β - or α) to minimize the effect on healthy tissues. Matched Pairs Half-life T 1/2 Decay mode Average Energy 6 TH SYMPOSIUM ON MEDICAL RADIOISOTOPES MECHELEN (Belgium) MAY /22 β - β+ or α / Average Energy γ Ga-68 / Lu-177 0,05 d / 6,71 d β + / β kev 890 kev / 208 kev Sc-44 / Sc-47 3,97 h / 3,35 d β + / β kev 632 kev / 159 kev Cu-64 / Cu-67 0,53 d / 2,58 d β + / β kev 278 kev / 186 kev Tb-152 / Tb ,5 h / 6,90 d β + / β -,Auger e kev 1,08 MeV / 75 kev Tb-155 / Tb-161 5,32 d / 6,90 d EC,γ/β -,Auger e kev 95 kev / 75 kev Tb-149 / Tb-161 4,12 h / 6,90 d α / β -,Auger e kev 3,97 MeV / 75 kev

4. Production of radioisotopes for therapy Another challenge for research reactors as BR2 is to be qualified for the production of therapeutic Y-90 and Ho-166 microspheres for the treatment of

Radioembolization refers to a therapy in which millions of radioactive microspheres are injected into the hepatic artery combining embolization selective occlusion of blood vessels by microspheres

18 4. Production of radioisotopes for therapy Another challenge for research reactors as BR2 is to be qualified for the production of therapeutic Y-90 and Ho-166 microspheres for the treatment of metastatic liver cancer. Radioembolization refers to a therapy in which millions of radioactive microspheres are injected into the hepatic artery combining embolization selective occlusion of blood vessels by microspheres with internal radiation therapy. This procedure consists in the selective instillation of radioactive microspheres using a catheter into the hepatic artery that feeds the tumor. The microspheres block the supply of blood to the cancer cells and deliver a high dose of radiation to the tumor while sparing normal tissues. 6 TH SYMPOSIUM ON MEDICAL RADIOISOTOPES MECHELEN (Belgium) MAY /22

TheraSphere : Yttrium-90 / glass QuiremSpheres : Holmium-166 / PLLA

19 4. Production of radioisotopes for therapy Radioembolization with Y-90 and Ho-166 microspheres SIR-Spheres : Yttrium-90 / resin BTG TheraSphere : Yttrium-90 / glass QuiremSpheres : Holmium-166 / PLLA 6 TH SYMPOSIUM ON MEDICAL RADIOISOTOPES MECHELEN (Belgium) MAY /22

4. Production of radioisotopes for therapy Studies have found promizing results for the treatment of metastatic liver cancer by Y-90 and Ho-166 microspheres.

particles for tumor eradication Y-90 is a pure beta emitter Ho-166 also emits gamma radiation which allows for quantitative nuclear imaging Holmium is paramagnetic and therefore

20 4. Production of radioisotopes for therapy Studies have found promizing results for the treatment of metastatic liver cancer by Y-90 and Ho-166 microspheres. Isotopes Half-life T 1/2 Decay mode Average Energy β - Average Energy γ Y-90 64,2 h β - 0,94 MeV - Ho ,8 h β - 1,84 MeV 81 kev Y-90 and Ho-166 both emit high energy beta particles for tumor eradication Y-90 is a pure beta emitter Ho-166 also emits gamma radiation which allows for quantitative nuclear imaging Holmium is paramagnetic and therefore visible on MRI BTG TheraSphere : Yttrium-90 / glass SIR-Spheres : Yttrium-90 / resin β - β - QuiremSpheres : Holmium-166 / PLLA 6 TH SYMPOSIUM ON MEDICAL RADIOISOTOPES MECHELEN (Belgium) MAY /22

21 5. Conclusions The refurbishment of the BR2 reactor will ensure a safe and reliable reactor operation for another period of 10 years, at least. The BR2 reactor recovered its position for the global production of medical (and industrial) radioisotopes. This position could be reinforced in future by increasing the operating regime from 6 to 8 cycles, subject to the economics. New perspectives have been identified for the development of new therapeutic procedures in the field of personalized medicine ( theranostics ) and radioembolization. And last but not least, special efforts are expected to be made for Targeted Alpha Therapy (TAT). Thank You For Your Attention 6 TH SYMPOSIUM ON MEDICAL RADIOISOTOPES MECHELEN (Belgium) MAY /22

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MEDICAL RADIOISOTOPE PRODUCTION IN RESEARCH REACTORS

MEDICAL RADIOISOTOPE PRODUCTION IN RESEARCH REACTORS BR2 Potential High-Flux Consequences Reactorfrom Ceased Production of Medical Radioisotope at the NRU Reactor Bernard PONSARD Radioisotopes Project