1. World Medical Isotope Crisis:
Canada’s National Laboratory for Particle and Nuclear Physics
Laboratoire national canadien pour la recherche en physique nucléaire
et en physique des particules
World Medical Isotope Crisis:
How did this happen and where are we now?
Thomas J. Ruth, PhD |
Senior Research Scientist Emeritus|
TRIUMF/BC Cancer Agency
Adjunct Professor, U. Victoria
A.I. Alikhanian National Science Laboratory
Yerevan, Armenia
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Owned and operated as a joint venture by a consortium of Canadian universities via a contribution through the National Research Council Canada
Propriété d’un consortium d’universités canadiennes, géré en co-entreprise à partir d’une contribution administrée par le Conseil national de recherches Canada

2. Outline Brief Background, why are 99Mo/99mTc important
Routes to 99Mo/99mTc
Challenges associated with each route
Status of various projects for alternative production
Future outcomes
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3. Background
Tc-99m is most widely used radionuclide for nuclear medicine procedures in the world and accounts for 80% of all procedures
Major efforts expended in connecting to biological molecules to assess
Cardiac function
Blood flow
Bone metastases
Half life & chemical properties of Mo-99 and Tc-99m are exploited to separate them in what is called a generator
Mo-99/Tc-99m generator invented at Brookhaven National Laboratory
Mo-99 half life is 66 hours, Tc-99m has a half life of 6 hours
Process of separating Mo-99 and Tc-99m called “milking”
Generators sent around the world
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5. Illustrating the simplicity of the 99Mo/99mTc generator
Developed at BNL in 1958 it was never patented. 5
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6. Global Supply Chain of 99Mo
ANSTO
ANSTO
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Adopted from Covidien web site

7. Issues US production was halted in 1989
Foreign subsidies were claimed to be the cause for lower costs abroad
Deemed “not worth it” to continue in US
Low market price, risk of reactor business, and high cost of production facilities
Half of US demand met by Canada (until 2011)
HEU has significant security issues; future will likely require use of something else
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8. Fission Yield Distribution 235U(n,f)
99Mo
99Mo is produced 6% of the total fission yield
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9. Why is HEU a concern?
Mass required to create a fissile device assuming a sphere
Why is HEU a concern?
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10. Chalk River
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11. MAPLE Project
MDS Nordion commissioned the AECL in 1996 to build two 10 MW reactors dedicated to radioisotope production that would each have the capacity to supply the world with Mo-99.
In 2002, MDSN sued AECL to take back the project due to delays. As part of this settlement AECL is obligated to supply MDSN with radioisotopes for 40 years.
In May 2008 AECL cancelled the project.
MDSN is now suing AECL for breaking the above contract. (AECL says they cannot do this until they don’t deliver!)
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12. Maple Project
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13. Mandated by U.S. Congress in Energy Policy Act of 2005
National Academy Sciences Study Origin: Production of Medical Isotopes w/o HEU
Mandated by U.S. Congress in Energy Policy Act of 2005
Reflects an effort by U.S. Congress to strike a balance between two important national interests:
Availability of reasonably priced medical isotopes in the United States
Proliferation prevention
Study sponsored by U.S. Department of Energy, National Nuclear Security Administration
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14. Would you believe anything this group says?
NAS Study Members
Would you believe anything this group says?
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15. Study Plan: Study Focus
Primary focus was on Mo-99/Tc-99m supply chain
Conversion feasibility was assessed at three points in Mo-99/Tc-99m supply chain
Costs to produce Mo-99
Costs for technetium generators
Costs for Tc-99m doses
Potential impediments to conversion were assessed
Technical
Regulatory
Timing
Impacts on supply reliability
Examined “large-scale” and “regional” producer experiences and capabilities
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16. Reliability of Mo-99 Supply
Mo-99 supply to the U.S. is fragile
Supply reliability is likely to become a serious problem for the U.S. in the early part of the next decade (now) without new or refurbished reactors
It will take time (5-10 years +) for substantial supplies of Mo-99 to become available to the U.S. from other foreign and domestic producers
AECL’s May 2008 decision to discontinue work on the Maple Reactors is a blow to worldwide supply reliability
NRU (AECL) to cease isotope production in 2016
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18. Production routes to 99Mo
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19. Conversion to LEU Targets
OPAL (Australia) Built to use LEU (2007)
OSIRIS(France) Scheduled to close in 2015
Safari (South Africa) from 50% HEU to LEU (2010)
BR2 (Belgium) >90% HEU to LEU (2013)
PALLAS (The Netherlands) to be built to use LEU (2022?)
NRU (Canada) to cease producing Medical isotopes (2016)
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20. What is the US trying? NNSA Sponsoring alternatives to HEU:
Babcock & Wilcox – Solution reactor; discontinued
GE Hitatchi – Power reactors; discontinued
SHINE Medical Technologies (UWisc)
- (D,T) Neutron generator
NorthStar- Photon approach.
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21. Using Mo-100 with photons
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22. NNSA Sponsored Effort by NorthStar
NorthStar Medical Radioisotopes irradiating 100Mo(γ,n)99Mo using an electron LINAC
studied in depth at INL in mid-1990’s
first production tested by NorthStar at RPI in 2008; demonstrated at mCi scale; commercial scale testing in process
produces a specific activity of Mo-99 of ~10 Ci/g target material
Low level Class A waste only
licensed as an accelerator by an Agreement State; no NRC licensing role
Mo-99 generated does not fit into current distribution stream
requires new generating system to use product and generate Tc-99m in activity concentrations typical in nuclear pharmacies
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23. TechneGen™ Generating System (prototype)
NorthStar Medical Radioisotopes, LLC
4/20/2017
TechneGen™ Generating System (prototype)
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Copyright 2012 & Confidential Property of NorthStar Medical Radioisotopes. LLC

24. TRL: (g,n), transformation of Mo-100
Accelerator – Concept well established, requires
development for high power
Targetry - enriched target, development work needed
Processing –Prototype exists, in clinical trials for
for other radioisotopes
Production of Tc-99m Generators – see above
Waste Management – minimal waste although
tracking of Tc-99g and non- moly isotopes required
Regulatory Approval – extensive testing required
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25. Accelerator and Target for Subcritical Reactor
D(T,n)4He
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SNMMI 25

26. TRL: Accelerator Driven Subcritical Reactor
Accelerator – conceptual stage
Targetry - – extensive testing required
Processing - – similar to existing process
Production of Tc-99m Generators – minimal changes
Waste Management – similar to existing fission
process, larger volumes?
Regulatory Approval – similar to existing fission
process
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27. Non-reactor Isotope Supply Program (NISP)
9 months into the NSERC/CIHR, Natural Resources Canada
(NRCan, announced the NISP competition (July 2010).
Secretly announced awardees in November
Officially announced awardees in January 2011
Released money the end of January 2011.
Results to be provided to Government 31 March 2012!!!
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28. Canadian Networks for producing 99mTc via proton irradiation of 100Mo
2 Networks have been funded to develop the direct production of 99mTc via the 100Mo(p,2n) reaction
Vancouver (TRIUMF CP-42 & BCCA-TR19) London (Lawson Health Sciences & CPDC (Hamilton, both PETTrace),
ACSI, Edmonton (Cross Cancer Institute –TR24), & Sherbrooke (TR24)
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29. Cyclotron-based Production of Tc-99m Radioisotopes
A Collaborative Program for the Production of Tc-99m using Canada’s Existing Medical Cyclotron Infrastructure
With support from: GE, Nordion, AAPS, others
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30. Canadian ITAP Prairie Isotope Production Enterprise (PIPE)
ITAP Funding Announced Feb 2013 – 3 year program to:
1. Secure regulatory approval of accelerator-based products from Health Canada and
2. Address operational issues identified in Phase 1 work.
3. Establish a commercial supply chain.
CLSI to become a PIPE supplier to demonstrate that they could fulfill the key supply chain role for PIPE – Mo-99 producer.
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31. Using Mo-100 with protons…
So far, we’ve looked at other ways to make Mo-99
What about making Tc-99m “directly” ?
Many moons ago, process below was validated and set aside
NOTE: Shipping & transport of 6-hr half-life Tc-99m instead of 66-hr half-life Mo-99 (akin to present-day business using F-18/FDG for PET)
100Mo
101Tc
99mTc n
100Mo(p,2n)99mTc p n
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IAEA 99Mo/99mTc CRP

32. Technical Goals: Cyclotron-based Production
Establish optimal irradiation conditions
Beam (energy, current)
Target characteristics (purity, plate, housing, transfer, recycle)
Time (irradiation, cooling)
Goals
Establish production quantity
Identify impurities
Specific activity (99m/99g ratios, other long-lived Tc)
Implications in radiopharmaceutical chemistry, patient dose
Radionuclidic purity / other non-Tc isotopes present
Implications in production waste, recycling, patient dose
Identify/Understand regulatory space
Production specifications, transport, shelf-life, etc.
To meet healthcare system demands, maximize safety
Economics
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33. Project Elements and Workflow
Mo-100 Recycling
Target Manufacture
Cyclotron
Irradiation
Purification
Radiopharmacy
Tc-99m
Mo-100
100Mo(p,2n)99mTc
Production cycle for 99mTc
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34. Demonstrating Proof of Concept
Funded by NSERC/CIHR
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35. 15 October 2013
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36. BCCA TR19 Target Station Local Shield Closed Local Shield Open
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37. Beam shape on target
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38. 15 October 2013
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39. Low energy orthogonal target
100 mA
16.5 MeV
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40. Demonstrated Equipment/Capabilities
TR19 (vaulted), PETtrace (self-shielded, vaulted)
BC Cancer Agency
TR19
13-19 MeV, 200µA
Upgraded to
300 µA
Lawson
CPDC
GE PETtrace
16 MeV, 100 µA
Upgraded to: 150 µA
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Not shown: CP42, MeV, 200µA 40

41. Theor. Calculations: Beam Energy
100Mo(p,x) reactions of highest probability
98Tc
99gTc
99mTc
99Mo
PETtrace
TR19
CP42
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A. Celler, X. Hou, F. Bénard, T. Ruth, Phys. Med. Biol. 2011, 56, 5469
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42. Cross Sections
Gagnon, et al., NMB 2011
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43. Theoretical Calculations: Energy & Time
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44. Radionuclides Produced
Morley, et al. NMB 39 (2012)
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45. Enrichment of 100Mo from different sources
Isotopes
Enriched
Natural A B C
92Mo
0.005
0.0060
0.09
14.85
94Mo
0.0051
0.06
9.25
95Mo
0.0076
0.10
15.92
96Mo
0.0012
0.11
16.68
97Mo
0.01
0.0016
0.08
9.55
98Mo
2.58
0.41
0.55
24.13
100Mo
97.39
99.54
99.01
9.63
X. Hou, A. Celler, J. Grimes, F. Bénard, T. Ruth, Phys. Med. Biol. 2012, 57, 1-17
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46. Enrichment of 100Mo from different sources
Isotopes
Enriched
Natural A B C
92Mo
0.005
0.0060
0.09
14.85
94Mo
0.0051
0.06
9.25
95Mo
0.0076
0.10
15.92
96Mo
0.0012
0.11
16.68
97Mo
0.01
0.0016
0.08
9.55
98Mo
2.58
0.41
0.55
24.13
100Mo
97.39
99.54
99.01
9.63
X. Hou, A. Celler, J. Grimes, F. Bénard, T. Ruth, Phys. Med. Biol. 2012, 57, 1-17
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47. Impact of other Tc Radioisotopes on Patent Absorbed Dose
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48. MIBI Effective Dose
The most significant contributions to the effective
dose following injection of Tc labelled MIBI from
Tc isotopes produced using 97% enriched 100Mo
Tc-93
Tc-94
Tc-95
Tc-96
Tc-97m
Tc-99m
T1/2
2.75 h
293 min
20 h
4.28 days
90.1 days
6.01 h
0 h
0.04%
0.23%
0.07%
0.13%
0.09%
99.39%
2 h
0.03%
0.22%
0.08%
0.17%
0.12%
99.37%
8 h
0.01%
0.18%
0.32%
99.11%
24 h
0.00%
0.11%
0.45%
1.67%
1.36%
96.40%
X. Hou, A. Celler, J. Grimes, F. Bénard, T. Ruth, Phys. Med. Biol. 2012, 57, 1-17
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49. Enrichment of 100Mo from different sources
Isotopes
Enriched
Natural A B C
92Mo
0.005
0.0060
0.09
14.85
94Mo
0.0051
0.06
9.25
95Mo
0.0076
0.10
15.92
96Mo
0.0012
0.11
16.68
97Mo
0.01
0.0016
0.08
9.55
98Mo
2.58
0.41
0.55
24.13
100Mo
97.39
99.54
99.01
9.63
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50. Separation Chemistry
Morley, et al. NMB 39 (2012)
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51. Target Transfer & Dissolution
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52. Chemical Purification System
39 (2012):
Chemical Purification System
39 (2012):
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53. Sample High Current Production Runs
Date
2013/3/19
2013/4/9
2013/4/12
2013/4/16
Target
99.01% 100Mo
97.4% 100Mo
Duration
91 min
85 min
6.6 h
6.2 h
Peak current
100 μA
200 μA
240 μA
Yield at EOB*
55.5 GBq
(1.5 Ci)
96.2 GBq
(2.6 Ci)
333 GBq
(9 Ci)
348 GBq
(9.4 Ci)
Saturated Yield*
4.05 GBq/μA
4.0 GBq/μA
3.3 GBq/μA
3.03 GBq/μA
Dose calibrator reading, overestimated with
99.01% Mo-100 due to Tc94m
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55. What does this mean in practice?
Yields around Ci ( GBq) can be achieved at 250 µA for an overnight irradiation (9h run) at 18 MeV
Batches of Ci will likely be achieved at 300 µA
Higher yields possible with higher energy but careful consideration of maximal threshold needed (20, 21, 22 MeV?) as it impacts:
Maximum irradiation time
Shelf life
Beam current and target design are important
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56. Radiopharmaceutical kit labeling
Neutral, cationic and anionic radiopharmaceutic kits have been prepared with yields as with generator Tc-99m (no evidence of any issues with quantity of Tc-99g or other Tc-isotopes)
Note, we have not prepared kits at the end of shelf life but do not anticipate any issues.
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57. Yield expectations
Assumptions required to predict the capacity needed:
Lost due to chemical processing (isolation + decay time)
Lost due to decay during transport and time of day usage
Usage is typically in the mCi doses
16.5 MeV, up to 130 mA for 3-6 hours - 50 and 160 GBq (1.4 and 4.5 Ci)
18 MeV, 300 mA for 3-6 hours – 255 and 480 GBq (7 and 13 Ci)
Note: We have demonstrated dual beam operation on TR19 with 200 mA on 100Mo and 60 mA on 18O
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58. TRL: Direct Production 100Mo(p,2n)99mTc
Accelerator – Use of existing cyclotrons
Targetry – High beam current demonstrated
Processing – working at intermediate scale
Production of Tc-99m Generators – not required
Waste Management – minimal, track Tc-99g
Regulatory Approval - – extensive testing required
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59. Commissioned a Coordinated Research Project (CRP)
IAEA
IAEA has assisted with the installation of numerous cyclotrons around the world
Direct production of Tc-99m is seen as an added value for these cyclotrons
Commissioned a Coordinated Research Project (CRP)
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60. IAEA - CRP Impact of TC-99g on SA and labelling efficiency
Missing data for production across practical energy range MeV
Enriched target production
Recovery and recycling of the enriched target material
Impact of recycling on the quality of Tc-99m produced.
QC metrics for assuring quality Tc-99m for clinical use
Participants: Armenia, Brazil, Canada, Hungary, India, Italy, Japan, Kingdom of Saudi Arabia, Poland, Syria, USA
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61. Specific Activity – Mo 99 Fission based Mo-99 (HEU/LEU):
> 5,000Ci/g, thus a 5 Ci generator will have 1 mg Mo
(g,n) and (n,g) Mo-99:
1-10 Ci/g dependent on flux, irradiation time, thus the generator is dealing with grams(s) of Mo
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62. graphic from http://www.covidien.com/
100Mo(g,n)99Mo
98Mo(n,g)99Mo
ANSTO
100Mo(p,2n)99mTc
ANSTO
graphic from
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63. Conclusion
9.4 Ci produced in 6 hours and we have not yet reached maximum current on TR19 cyclotron
Kits radiolabeled successfully and passed standard TLC QC (n = 3 each for anionic, neutral, cationic)
Radiation dose to patients from cyclotron Tc99m not significantly different if target composition and irradiation energy/conditions are controlled
Target dissolution and Tc99m purification methods optimized for large area targets
Clear path for regulatory approval in Canada
Practical regional production of Tc99m is now possible for large urban areas
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64. Acknowledgements
Paul Schaffer
, Nina Levi 64
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65. Acknowledgements Gratefully acknowledge discussions and use of slides:
Jim Harvey, NorthStar
Tim Meyer, TRIUMF
Anna Celler, UBC
Francois Benard, BCCA
Paul Schaffer, TRIUMF
Ed Bradley, IAEA
Kevin Crowley, NAS
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66. Thank you! Merci! 15 October 2013 ANSL
TRIUMF: Alberta | British Columbia |
Calgary | Carleton | Guelph | Manitoba | McMaster | McGill | Montréal | Northern British Columbia | Queen’s | Regina | Saint Mary’s |
Simon Fraser | Toronto | Victoria | Winnipeg | York
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