Production of 177 Lu n.c.a. in high-flux reactors

Transcription

1 Production of 177 Lu n.c.a. in high-flux reactors R. Henkelmann, S. Marx, K. Zhernosekov, M. Harfensteller February 2013

2 Outline Targeted Radionuclide Therapy Therapeutic Radionuclides c.a. vs n.c.a. Lutetium Production of n.c.a. Lu-177 Security of supply Market overview Conclusion Preview to practical part Page 2

3 Targeted RadionuclideTherapy Principle of Targeted Radionuclide Therapy: Targeting biomolecule Labeling Therapy Page 3

4 Targeted RadionuclideTherapy Principle of Targeted Radionuclide Therapy: delivery of therapeutic doses of ionizing radiation to the malignant cells Courtesy Prof. Roger Schibli ETH Zürich Page 4

5 Targeted RadionuclideTherapy Peptide Receptor Radionuclide Therapy (PRRT): Target: Receptor Biomolecule: Peptide Linker Radionuclide 177 Lu, 90 Y, 213 Bi etc. e.g. GPCR receptors like Somatostatin receptors e.g. Peptide hormon analoga conjugates like DOTA-TATE Page 5

6 Targeted RadionuclideTherapy PRRT with Somatostatin analoga: O HO Somatostatin receptors are overexpressed in: H O N 177 Lu N N N O O OH (D)Phe - Cys - Tyr - (D)Trp Thr(ol) - Cys - Thr - Lys Neuroendocrine Tumors (Tumors of the nervoussystem) (Renal cell carcinoma) (Malignant lymphoma) (Breast cancer) Page 6

7 Therapeutic Radionuclides Radionuclides for Targeted Radionuclide Therapy: Radionuclide Halflife E mean (kev) E (y) kev Range in tissue More crossfire Y h 934 β - 12 mm Re h 763 β mm I d 182 β mm Lu d 134 β mm Tb d 154 β 75 2 mm Bi m 5870 α µm Ac d 5830 α µm Less damage of healthy tissue Page 7

8 Therapeutic Radionuclides Particle emitting radionuclides High-energy beta emitter 90 Y mean particle energy MeV Low-energy beta emitter 177 Lu mean particle energy MeV 1 mm Page 8

9 Therapeutic Radionuclides 177 Lu: rising demand 90 Y 90 Y high-energy beta emitter Number of scientific publications vs time: Therapeutic applications of 90 Y and 177 Lu - In GMP quality available since Zevalin, SIRT, PRRT Pub Med Therapeutic Studies 90 Y 177 Lu GMP 90 Y GMP 177 Lu 177 Lu Lu low-energy beta emitter 20 - In GMP quality available since Abs, PRRT Less side effects; imageable photons Year Page 9

10 Therapeutic Radionuclides Imageable Photons: Observation during treatment (SPECT): Roelf Valkema, EANM Page 10

11 Lutetium c.a. vs n.c.a Possible production routes for Lu Lu(n, ) 177 Lu 176 Yb(n, ) 177 Yb 177 Lu Hf Hf Hf Hf Lu Lu Lu 177 Lu Lu Lu 177 σ 8 σ d d - σ 8 σ d - Yb σ 68 Yb d Yb σ 3 Yb h Yb σ 68 Yb d Yb σ d - Yb h Carrier added c.a. 177 Lu No carrier added n.c.a. 177 Lu Page 11

12 Lutetium c.a. vs n.c.a Impact of the cross capture section: 176 Lu: 2100 barn 176 Yb: 2,4 barn 177 Lu: 865 barn Page 12

13 Lutetium c.a. vs n.c.a Carrier added c.a. 177 Lu Specific activity only Ci/mg (vs. theoretical 110 Ci/mg) only 25 % of hot 177 Lu atoms 75% of cold 175/176 Lu atoms Long-lived radioactive impurities: up to 0.05 % of long-lived 177m Lu! Poor quality of c.a. 177 Lu results in: limited radiolabeling performance long-lived waste management problem; environment exposure Page 13

14 Lutetium c.a. vs n.c.a No carrier added n.c.a. 177 Lu Highest specific activity > 80 Ci/mg (vs. theoretical 110 Ci/mg) and highest radionuclide purity No long-lived radioactive impurities: less than 10-5 % of 177m Lu! (below detection limit) Highest quality of n.c.a. 177 Lu offers: best radiolabeling performance no waste problem! longer shelf-life up to 2 weeks Page 14

15 Lutetium c.a. vs n.c.a Physics: Radiochemistry (EOB): Radiochemistry (EOP): Reactor physics: Nuclear medicine:? Page 15

16 Lutetium c.a. vs n.c.a Impact of the specific activity on the tumor uptake: 300 MBq of 177 Lu c.a. Dose to tumor - 35 Gy 300 MBq of 177 Lu n.c.a. Dose to tumor - 70 Gy Marion de Jong et al.; 2012 ICTR-PHE Page 16

17 Specific Activity [Ci/mg] Lutetium c.a. vs n.c.a Improved logistics with n.c.a. 177 Lu! shelf-life/ c.a. vs n.c.a. 177 Lu 100 S th = 110 Ci/mg S 1/2 = 92 Ci/mg S 1/2 = 16 Ci/mg Days Page 17

18 Market overview Producer 1 Producer 2 ITG Isotope Technologies Garching GmbH c.a c.a n.c.a Specific Activity > 740 GBq/mg at calibration date ~ 740 GBq/mg at calibration time > 3,000 GBq/mg at expiry date 177m Lu content < 0.05 % at calibration date < 0.1 % at expiry date < 10-5 % at expiry date Calibration time/ Delivery 12:00 at production day, delivery after calibration time 12:00 on Monday, Thuesday, Wednesday, Friday upon request, 24 h on 365 d/a Page 18

19 Market overview ITG: Exceptionally high specific activity, more than 3000 GBq/mg at expiry No Long-lived 177 Lu Page 19

20 Production of n.c.a. 177 Lu Yb Lu Yb 177 Lu Yb Page 20

21 Production of n.c.a. 177 Lu Ytterbium oxide Ampoule preparation Ampoule closing Irradiation Ampoule opening Targeted RadionuclideTherapy Packing and shipping Dispensing Lu / Yb -Separation Page 21

22 Production of n.c.a. 177 Lu First GMP- certified production process! - Industrialized production process - pharmaceutical grade (sterile and endotoxin-tested) - GMP- certified since 12/ Page 25

23 Security of supply Security of supply: global reactor network O HO H O N N O N N O 1, cm -2 s -1 OH 1, cm -2 s -1 3, cm -2 s -1 1, cm -2 s -1 Page 26

24 Security of supply Security of supply: planning! August Lu-177 Incoming Ampoules shipment Standardization of irradiation processes Implementation of fast and realiable logistics Intelligent scheduling Page 27

25 Security of supply Security of supply: global collaborations 177 Lu Page 28

26 Conclusion 177 Lu c.a. 177 Lu n.c.a. 177 Lu n.c.a. future Criteria Process Complexity Redundant Reactors Redundant Production Sites 3: o 7: + 8: + 3: o 1: o 3: + + Security of Supply o + + Long-lived Waste Problem Specific Activity o + + Problems are Headache of Customer Manufacturer Manufacturer Page 29

27 Conclusion Quality is: The Right Product Purity Amount Time Place Price Not even one single of promised shipment missed since April 2009 Shortest order lead time Highest specific activity: labelling even after 3 weeks possible Highest activity concentrations But: Hardest Customer Complaint: we changed the labels on the vial Page 30

28 Thank you for your attention! Page 31