A running centre for radioisotope production: present and future perspectives

M. Marengo A running centre for radioisotope production: present and future perspectives Medical Physics Department University Hospital S.Orsola Malpighi, Bologna mario.marengo@aosp.bo.it mario.marengo@aosp.bo.it Oultine presentation of the Bologna centre issues on QA in cyclotron production target yield ion source efficiency beam transmission enriched water usage vacuum level production of 11 C Radiopharmaceuticals solid targets for PET cyclotrons production of non standard radionuclides 1

Emilia Romagna: 4 million inhabitants Bologna: 450 k inhabitants in the city, 1 million including the surrounding area An academic Hospital (about 1600 patient bed, 5300 staff) held jointly by the National Health Service and the University of Bologna. 1 GE PETtrace cyclotron (16.5 MeV H -, 8.4 MeV D - ) 14 hot cells, 10 synthesis modules 1 sterile vial dispenser, 2 sterile syringe dispensers 3 PET-CT scanners 4 double head gamma cameras 1 small animal PET, 1 small animal CT 2

Classified production lab Quality Control lab Dose calibrator LAL GC for check of T 1/2 SPECT radiopharmaceuticals QC ph meter HPLC 11 C, 18 F 2D imager (used also as radio-cromatography scanner) 3

Radiopharmaceuticals About 10500 patient studies/year 11 C-Choline 11.6 % 11 C-Methionine 2.0 % 11 C-Acetate 0.5 % 18 F-DOPA 0.4 % 68 Ga-DOTA 3.9 % 18 F-FDG 81.5 % Other available: 18 F-FLT, 18 F-FHBG, 11 C-MEHD, 68 Ga-Citrate, 64 Cu-ATSM Staffing at the Bologna PET Centre Nuclear Medicine Department 9 NM specialists physicians an average of 8 NM residents 14 technologists 5 nurses Radiopharmacy Unit 2 PhD Radiopharmacists (permanent position) 6 Lab Technologists (permanent position) 2 MSc Radiopharmacists/Radiochemsists (non permanent) Medical Physics Department ~ 30 people, organized in three Units The Nuclear Medicine Physics Unit has: 3 PhD physicist (permanent position) 2 technologists (permanent position) 1 physicists (non permanent) an average of 2 3 PhD residents or MSc students in Medical Physics or Biomedical Engineering 4

Rationale for cyclotron QA Cyclotrons are radiological equipment to which all criteria and requirements as regards Quality Assurance apply. In particular, the needs for acceptance testing and routine quality control: to verify accomplishment of contractual agreements to characterize performance of the system to optimize use and reduce down time to safeguard the investment Relative difficulty in maintaining routine radionuclide production 8.00 How hard is (arb.un.) 7.00 6.00 5.00 4.00 3.00 2.00 1.00 0.00 < 1.5 Ci / day > 2.5 Ci / day 0 50 100 150 200 250 300 Production days/year 5

Routine work cycle at the PET centre in Bologna 5.30: start; environmental and operational tests (temp, gases, voltage ) 5.45: pre irradiation of 18F target with H2O16 6.00: activity bolus delivered to a research hot cell; test of production; rinse & drying 6.00: start testing and loading 18F-FDG module 6.10: start of first 18F- production 6.15: preparing the vials dispensing unit 6.30 7.00: checking of cyclotron parameters 7.00: preparation of the insulator for unit dose dispensing 7.00: start preparation of the QC equipment 7.30: first irradiation is almost ready; final check of all systems 7.30: start preparation of the 11C module for Choline / Methionine 7.45: end of first bombardment and delivery of activity to the 18F-FDG module 7.50: rinse the 18F-target; start 18F-FDG synthesis 7.50: preparation of the 11C target 8.00: start 11C bombardment 8.15: end of 18F-FDG synthesis; start of sterilization and vials dispensing 8.30: delivery of 11C to synthesis module; start of Choline / Methionine synthesis 8.40: first vial of 18F-FDG ready; taken sample for QC 8.55: 18F-FDG QC completed; first patient dose dispensed 8.55: end of 11C Choline / Methione synthesis; sterilization 9.00: 11C Choline / Methione sample for QC 9.15: 11C Choline / Methionine QC completed; first patient dose dispensed Routine QA tests test of target yield with H 16 2 O real time check of irradiation parameters ion source efficiency beam transmission mass of enriched water used delivery time of radioactive bolus vacuum levels 6

Check of the yield in 18 F - production Activity (mci) 10000 run on H 2 18 O al 96 % irradiation time 60 min beam current 35-38 µa delivery and measure in activity calibrator correction for 13 N produced 1000 A produced = S I target tirradiation ln(2) T1 / 2 ( 1 e ) 100 0 30 60 90 120 150 180 210 The Saturation Yield is a measure of the performance of the target Time (min) Target #1: 2495 mci in 60 min a 38 ma; S = 207 mci/µa Target #4: 2510 mci in 60 min a 38 ma; S = 209 mci/µa Constancy check of 18 F - target using H 2 16 O H 2 18 O is costly and cannot be used for routine tests during routine production activity cannot be measured accurately a short pre irradiation (10 min, 10 µa) on H 2 16 O is used as a routine check 13 N produced is delivered to an activity calibrator and measured for 3 minutes activity is delivered to a different hot cell from the synthesis module one no interference with production (apart a short delay ) this can be seen as constancy tests of target performance Ratio (Yield with H 2 18 O) / (Yield with H 2 16 O) 5.5-6.0 Acceptable values of yield with H 2 16 O > 32 mci/µa Typical values obtained of yield with H 2 16 O = 36.5 + 0.3 mci/µa 7

Constancy check of 18 F - target using H 2 16 O Resa a saturazione con H 2 16 O (Target #1) 42.0 Resa a saturazione (mci/microa) 40.0 38.0 36.0 34.0 32.0 30.0 24/05/2002 13/07/2002 01/09/2002 21/10/2002 10/12/2002 29/01/2003 20/03/2003 09/05/2003 28/06/2003 17/08/2003 Data Check of stability of parametrs during irradiation 8

Check of the efficiency of the Ion Source the Ion Source produces the beam thanks to a discharge in a flow of neutral H 2 gas during routine operation, at a given value of current on the target should correspond a stable value of arc current in the IS the arc current is typically (depending on the type) of tens hundreds ma, while target currents are typically tens of µa. we can define the efficency of the IS as: Target current (µa) Arc current (ma) this ratio comes automatically out in % o a variation in the reference values may be a symptom of a fault or malfunction typical values of IS efficiency depends on the type of system; a reference value should be established for each cyclotron, just after installation. Stability of the efficiency with time can then be checked as part of routine QA i.e for the PETtrace, typical values of IS efficiency are > 0.20 % o Check of beam transmission cyclotrons have a retractable probe that allows intercept and measure beam current just out of the Ion Source Transmission = 100 x Current on stripping foil (or on target) Current at the probe transmission measures how much of the beam is loss during acceleration; this percentage depends on the type of cyclotron and should be stable with time (for each type of particle) Why we lose beam? the slit in the chimney of the Ion Source is not in the correct position the mechanical set up of the central region of the cyclotron is not optimal the magnetic field is not tuned properly the vacuum level is not good and residual gas strips electrons from negative ions. 9

Check of the mass of H 2 18 O water loaded for 18 F - targets it is essential to verify that the target loading system (syringe pumps, valves, fittings) is in good order and tighten it is recommended to check periodically the weight of a bolus of water ( normal purified water can be used), by filling the target and delivering the contents in a clean vial, whose mass has been weighted it is recommended to note the initial weight of syringes or vials of enriched water in use and measure the residual mass at the time of refilling. Dividing by the number of filling operations (that should be recorded ) it is possible to estimate the average mass loaded. This should be in agreement with typical reference value. Check of stability of vacuum levels Air IN filter Penning gauge Pirani gauge Beam exit valve daily record of vacuum level measured by the different gauges help to recognize eventual faults in the vacuum system Vent valve High vacuum valve Diffusion pump Pirani gauge Vacuum chamber Backing chamber Target 1 Roughing valve Backing valve Mechanical pump Oil filter 10

Management of faults and non conformances Problem / fault Principal problems / faults are classified and coded Recording on data base Treatment Report recording and treatment of every fault / problem encountered during operation allows reporting problems / faults in an objective way reliable statistics of faults immediate support for repeated faults Routine work cycle at the PET centre in Bologna 5.30: start; environmental and operational tests (temp, gases, voltage ) 5.45: pre irradiation of 18F target with H2O16 6.00: activity bolus delivered to a research hot cell; test of production; rinse & drying 6.00: start testing and loading 18F-FDG module 6.10: start of first 18F- production 6.15: preparing the vials dispensing unit 6.30 7.00: checking of cyclotron parameters 7.00: preparation of the insulator for unit dose dispensing 7.00: start preparation of the QC equipment 7.30: first irradiation is almost ready; final check of all systems 7.30: start preparation of the 11C module for Choline / Methionine 7.45: end of first bombardment and delivery of activity to the 18F-FDG module 7.50: rinse the 18F-target; start 18F-FDG synthesis 7.50: preparation of the 11C target 8.00: start 11C bombardment 8.15: end of 18F-FDG synthesis; start of sterilization and vials dispensing 8.30: delivery of 11C to synthesis module; start of Choline / Methionine synthesis 8.40: first vial of 18F-FDG ready; taken sample for QC 8.45: end of 11C Choline / Methione synthesis; sterilization 8.50 : 11C Choline / Methione sample for QC 8.55: 18F-FDG QC completed; first patient dose dispensed 9.05: 11C Choline / Methionine QC completed; first patient dose dispensed 11

11 C- Choline vs. 18 F-FDG 11 C-choline 18 F-FDG New high pressure, high yield 11 C target for the PETtrace 11C target pressure 40.0 Pressure (bar) 35.0 30.0 25.0 20.0 15.0 10.0 5.0 0.0 0.0 20.0 40.0 60.0 80.0 100.0 Target current (ua) Curva di decadimento 100000 Attività (MBq) 10000 1000 Target volume 80 cm3 Filling pressure 180 psi (12 bar) Tragte pressure in irradiation 440 psi (~ 30 bar) Saturation yield ~ 115 mci/µa Production at 30 min, 80 µa ~ 6 Ci 100 10 1 0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 Tempo (min) 12

11 C production typical production prior to irradiation, the target is filled with the target gas and voided along the line connecting with the synthesis module: this is used in order to remove environmental CO 2 that will reduce specific activity typical irradiation 20-25 minutes @ 60-70 µa leads to the production of 160 180 GBq (approx 4500 5000 mci) of 11 C-CO 2 the cycle of voiding the target is essential for proper removal of the activity produced from the target no cleaning is necessary after the daily production Logistics of 11 C studies Waiting time for proper uptake of 18 F-FDG (not less than 45 minutes, optimal 70 80 minutes) Pat. 1 Pat. 2 Pat. n 18 F-FDG patient s studies sequence 11 C patient s studies The optimal solution is to place 11 C studies in the initial early morning time, during the uptake phase on the first 18 F-FDG administered patients Interleave 11 C and 18 F-FDG studies is a problem in order to maintain proper sequence and uptake time 13

There are more things in heaven and earth, Than are dreamt of in your philosophy Quality Assurance Long lived positron emitters Studies of slow metabolic processes Possibility of quantification of radiation dose in target radiotherapy Isotope Nuclear Reaction T ½ Decay Mode (%) E β+ max MeV I γ in kev (%) 64 Cu 64 Ni(p,n) 64 Cu 12.7 h β + (17.4) EC(43.6) β - (39) 653.1 1345.8 (0.47) 89 Zr 89 Y(p,n) 89 Zr 78.41 h β + (22.74) EC(87.26) 901.7 908.96 (100) 86 Y 86 Sr(p,n) 86 Y 14.74 h β + (31.9) EC(68.1) 2260.3 1076.6(83) 627.7(32.6) 1153.0(30.5) 55 Co 58 Ni(p,α) 55 Co 17.5 h β + (77) EC(23) 1498 931.3(75) 477(20.2) 1408.4(16.9). 76 Br 76 Se(p,n) 76 Br 16.2 h β + (54.6) EC(45.4) 3381 559.1(74) 657(15.9) 1853(14.7) 124 I 124 Te(p,n) 124 I 4.17 d β + (22.9) EC(77.1) 3159 602.7(63) 1691(10.9) 722.7(10.35) 14

Solid target solutions for IBA cyclotrons The solid target installed on the PETtrace in Bologna Target coin Developed in cooperation with TEMASinergie 15

Target load and download Target 64 Cu production - Electroplating procedure 3ml of 6.0 M nitric acid Evaporated to dryness 60 minutes at 180 C. 1 ml concentrated H 2 SO 4 4 ml H 2 O The ph to 9 with about 5 ml of NH 4 OH 25.0% V=2.4 V Distance = 5 mm Starting current =130-150 ma Plating temperature= 60 C Quantity= 250 mg Thickness = (180 ± 20) µm Time =24-36 h The final solution was then adjusted to 15 ml with deionized water. Cicoria G. et al."automatic system for 64Cu production, recovery of 64Ni and 64Cu-ATSM synthesis". Eur J Nucl Med Mol Imaging 36 suppl. 2, 2009 16

Reliable electroplating technique The target layer should adhere strongly to the target backing. This condition should be maintained up to a temperature (in irradiation conditions) near to the melting point of the target metal; the target deposit should be homogeneous, smooth, with uniform density (no occlusions or vacuum gaps), and with a well defined thickness (typically from a few tens to several hundred microns), depending on the cross section curve and on the beam energy and angle geometry; the interface between the metal deposit and the backing support should be free of gaps or traces of other materials arising from less than optimal electroplating. data courtesy of G. Cicoria Production of 89Zr Yttrium has only the 89 isotope; natural non enriched material is used. Pellets can be prepared according several methods, starting from metallic 89Y and mixing with grafite, or stating from 89Y oxide powder and pressing; in our initial experience, we have used a foil of pure 89Y firmly connected to a copper backing. 600 150 μm foil Cross Section [mb] 500 89Y(p,n)89gZr natal 89Y(p,2n)88Zr 400 89Y(p,pn)88Y 89Y 300 150µm 500µm 89Y 150µm 200 100 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Energy [MeV] 17

Preparation of the target material Helium cooling 32 mm Copper backing 14 mm Aluminum degrader 32 mm Yttrium target foil Havar foil Production of 65 Zn cross section (mb) 250.00 200.00 150.00 nat Cu : 69.2% 30.8% 63 65 Cu; Cu 100.00 50.00 0.00 0.0 5.0 10.0 15.0 20.0 25.0 30.0 Energy (MeV) What is the usefulness of 65 Zn? 18

Conclusions? according to basic physical data (particle energy, cross section, ), several interesting radionuclides for both diagnostic and therapeutic use can be produced by hospital based cyclotrons the multiplicity of these radionuclides makes difficult to think to dedicated and optimized targets for each of them a multi-purpose target for solid material irradiation is feasible and seems to be a promising tool for applied clinical research in Nuclear Medicine techniques for preparation of solid targets material represent a field in which research work is needed and could lead to significant improvements 19

Conclusions! applied research in the above presented fields is really promising for important results, with a potentially relevant clinical impact development of these researches in an operational setting needs not only time and equipment, but mainly human resources. Training of qualified, skilled scientists and professionals is now a fundamental task Quality Assurance, Quality Management, regulatory compliance are necessary tools, but they should not take all of our energies and make us forgot our final goal mario.marengo@aosp.bo.it NM Physicists M. Marengo, C. Pettinato, G. Cicoria, D. D Ambrosio Physics Technologists D. Pancaldi, S. Civollani PhD Physics students F. Zagni, G. Lucconi MSc Physics & Engineering students M. Pedacchia, S. Larocca Radiopharmacists / Radiochemists S. Boschi, F. Lodi, C. Malizia, V. Lanzetta Radiopharmacy Technologists F. Bignami, R. Bignami, A. Martignon, E. Babbore, I. De Nicola, N. Spataro NM Doctors S. Fanti, P. Castellucci, P. Zagni, G. Gavaruzzi P. Guidalotti, M. Levorato,, G. Montini, C. Nanni, V. Allegri 20

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