Transcript Presentation (part II) - Yerevan Physics Institute

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?
A.I. Alikhanian National Science Laboratory
Yerevan, Armenia
Thomas J. Ruth, PhD |
Senior Research Scientist Emeritus|
TRIUMF/BC Cancer Agency
Adjunct Professor, U. Victoria
Owned 2013
and operated as a joint venture by a consortium of Canadian universities via a contribution
through the National Research Council Canada
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Propriété d’un consortium d’universités canadiennes, géré en co-entreprise à partir d’une contribution administrée par le Conseil national de recherches Canada
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Outline
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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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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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Illustrating the simplicity of the
99Mo/99mTc generator
Developed at BNL in 1958 it was never patented.
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Global Supply Chain of 99Mo
ANSTO
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Adopted from Covidien web site
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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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Fission Yield Distribution 235U(n,f)
99Mo
99Mo
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is produced 6% of the total fission yield
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Why is HEU a concern?
Mass required to create a fissile device assuming a sphere
Why is HEU a concern?
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NRU @ Chalk River
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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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Maple Project
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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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NAS Study Members
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Would you believe anything this group says?
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Study Plan: Study Focus
• Primary focus was on Mo-99/Tc-99m supply chain
• Conversion feasibility was assessed at three points in Mo99/Tc-99m supply chain
– Costs to produce Mo-99
– Costs for technetium generators
– Costs for Tc-99m doses
• Potential impediments to conversion were assessed
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Technical
Regulatory
Timing
Impacts on supply reliability
• Examined “large-scale” and “regional” producer experiences
and capabilities
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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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Production routes to 99Mo
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Conversion to LEU Targets
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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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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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Using Mo-100 with photons
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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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TechneGen™ Generating System (prototype)
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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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Accelerator and Target for Subcritical Reactor
D(T,n)4He
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SNMMI
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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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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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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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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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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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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 F18/FDG for PET)
100Mo(p,2n)99mTc
p
99mTc
100Mo
101Tc
n
n
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IAEA 99Mo/99mTc
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CRP
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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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Project Elements and Workflow
Mo-100
Recycling
Target
Manufacture
Radiopharmacy
Tc-99m
Mo-100
100Mo(p,2n)99mTc
Purification
Cyclotron
Irradiation
Production cycle for 99mTc
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Demonstrating Proof of Concept
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NSERC/CIHR
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BCCA TR19 Target Station
Local Shield Closed
Local Shield Open
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Beam shape on target
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Low energy orthogonal target
100 mA
16.5 MeV
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Demonstrated Equipment/Capabilities
• TR19 (vaulted), PETtrace (self-shielded, vaulted)
BC Cancer Agency
TR19
13-19 MeV, 200µA
Upgraded to
300 µA
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Lawson
CPDC
GE PETtrace
16 MeV, 100 µA
Upgraded to: 150 µA
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Not shown: CP42,
20-42 MeV, 200µA
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Theor. Calculations: Beam Energy
100Mo(p,x)
reactions of highest probability
98Tc
99gTc
99mTc
99Mo
PETtrace
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CP42
A. Celler, X. Hou, F. Bénard, T. Ruth, Phys. Med. Biol. 2011, 56, 5469
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Cross Sections
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Gagnon, et al., NMB 2011
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Theoretical Calculations: Energy & Time
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Radionuclides Produced
Morley, et al. NMB 39 (2012)
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Enrichment of 100Mo from different sources
Enriched
Isotopes
92Mo
94Mo
95Mo
96Mo
97Mo
98Mo
100Mo
A
0.005
0.005
0.005
0.005
0.01
2.58
97.39
B
0.0060
0.0051
0.0076
0.0012
0.0016
0.41
99.54
Natural
C
0.09
0.06
0.10
0.11
0.08
0.55
99.01
14.85
9.25
15.92
16.68
9.55
24.13
9.63
X. Hou, A. Celler, J. Grimes, F. Bénard, T. Ruth, Phys. Med. Biol. 2012, 57, 1-17
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Enrichment of 100Mo from different sources
Enriched
Isotopes
92Mo
94Mo
95Mo
96Mo
97Mo
98Mo
100Mo
A
0.005
0.005
0.005
0.005
0.01
2.58
97.39
B
0.0060
0.0051
0.0076
0.0012
0.0016
0.41
99.54
Natural
C
0.09
0.06
0.10
0.11
0.08
0.55
99.01
14.85
9.25
15.92
16.68
9.55
24.13
9.63
X. Hou, A. Celler, J. Grimes, F. Bénard, T. Ruth, Phys. Med. Biol. 2012, 57, 1-17
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Impact of other Tc Radioisotopes on Patent
Absorbed Dose
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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
T1/2
0h
2h
8h
24 h
Tc-93
Tc-94
Tc-95
Tc-96
Tc-97m Tc-99m
2.75 h
293 min 20 h
4.28 days 90.1 days 6.01 h
0.04%
0.23%
0.07%
0.13%
0.09% 99.39%
0.03%
0.22%
0.08%
0.17%
0.12% 99.37%
0.01%
0.18%
0.13%
0.32%
0.23% 99.11%
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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Enrichment of 100Mo from different sources
Enriched
Isotopes
92Mo
94Mo
95Mo
96Mo
97Mo
98Mo
100Mo
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A
0.005
0.005
0.005
0.005
0.01
2.58
97.39
B
0.0060
0.0051
0.0076
0.0012
0.0016
0.41
99.54
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Natural
C
0.09
0.06
0.10
0.11
0.08
0.55
99.01
14.85
9.25
15.92
16.68
9.55
24.13
9.63
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Separation Chemistry
Morley, et al. NMB 39 (2012)
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Target Transfer & Dissolution
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•39 (2012): 551-9.
Chemical Purification System
39 (2012): 551-9.
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Sample High Current Production Runs
Date
Target
Duration
Peak current
Yield at EOB*
Saturated Yield*
2013/3/19
2013/4/9
2013/4/12
2013/4/16
99.01% 100Mo
99.01% 100Mo
97.4% 100Mo
97.4% 100Mo
91 min
85 min
6.6 h
6.2 h
100 μA
200 μA
200 μA
240 μA
55.5 GBq
(1.5 Ci)
96.2 GBq
(2.6 Ci)
333 GBq
(9 Ci)
348 GBq
(9.4 Ci)
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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What does this mean in practice?
• Yields around 13-14 Ci (481-518 GBq) can be achieved
at 250 µA for an overnight irradiation (9h run) at 18
MeV
• Batches of 16-17 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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Radiopharmaceutical kit labeling
• Neutral, cationic and anionic radiopharmaceutic kits
have been prepared with yields as with generator Tc99m (no evidence of any issues with quantity of Tc99g 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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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 15-20 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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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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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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IAEA - CRP
• Impact of TC-99g on SA and labelling efficiency
• Missing data for production across practical energy range
10-24 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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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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100Mo(g,n)99Mo
98Mo(n,g)99Mo
ANSTO
100Mo(p,2n)99mTc
ANSTO
graphic from http://www.covidien.com/
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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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Acknowledgements
Paul Schaffer
, Nina Levi
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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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Thank you!
Merci!
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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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