Healthcare Challenges for CLASP:
Radioisotopes
Jim Ballinger, Chief Radiopharmaceutical Scientist
CLASP
20 May 2014
Outline
• The clinical need: radionuclides for nuclear medicine
• The problem: aging fleet of nuclear reactors,
compounded by nuclear non proliferation initiatives
• International response: bring more reactors online
• Possible short term solution: cyclotron production
• Longer term solutions: novel technologies
Who am I?
• PhD in PET radiochemistry (Univ. of Toronto, 1985)
• 15 y nuclear medicine in Canada (Ottawa, Toronto)
• 15 y nuclear medicine in UK (Cambridge, London)
• Relevant memberships
– UK Radiopharmacy Group (UKRG)
– British Nuclear Medicine Society (BNMS)*
– Administration of Radioactive Substances Advisory
Committee (ARSAC)*
– European Association of Nuclear Medicine (EANM)
radiopharmacy committee
*Reports to DH
1. The Clinical Need
The clinical need: diagnostic imaging
• Nuclear medicine involves the administration of
radioactive drugs (radiopharmaceuticals) to
patients for functional imaging (diagnosis) of:
– Specific targeting of disease process
– Effect of disease on normal function of an organ
• Properties of radionuclides:
– Short effective half life
– Emit gamma rays (detected outside body)
– Not emit significant amounts of particulate radiation
Types of nuclear medicine studies
UK HPA 2008
Global volume of nuclear medicine
~50 million
studies per year
Market ~5 billion
USD
Report to Canadian parliament, 2009
Trend in global demand
Advantages of 99mTc
•
99mTc
is used in ~85% of nuclear medicine studies
• Available from on site generator as sterile solution
in saline
• Half life (6 h) suited to production and clinical use
• Gamma energy (140 keV)
• No particulate emissions
• Versatile chemistry allows efficient preparation of a
range of targetted agents
99Mo
99mTc
(t½ 3 d)
(t½ 6 h)
140 keV
99Tc
(t½ 105 y)
99Mo/99mTc
generator design
Tubing Needle
Metal closure
Eluent
Glass column
Lead shielding
Eluate
Sterile filter
99Mo/99mTc
generator kinetics
Radioactivity
1.0
0.8
0.6
0.4
0.2
0.0
0
24
48
Time (hours)
72
96
As simple as…. (well, almost)
+
=
2. The Problem
The problem
99mTc
•
is the predominant radionuclide used in
nuclear medicine (~85%)
•
99mTc
•
99Mo
is obtained from 99Mo generators
(t½ 3 d) is obtained from fission of 235U in a
small number of aging research reactors
• Use of highly enriched 235U (HEU) is being phased
out
• Two reactors will be decommissioned by 2016
– The largest will not be replaced (ever)
– Replacement of the other has been delayed
Yield of 99Mo from fission of 235U
Five reactors supply the world
30%
40%
10%
10%
10%
OPAL, Australia
Global supply chain
Recent problems at reactors
Period
Reactor
Problem
Nov/Dec ’07
NRU
Leak, emergency legislation
Aug ’08 – Feb ’09
HFR
Closed due to leak
Sep ’09
IRE
Radioprotection
May ’09 – Jul ’10
NRU
Closed due to leak
Feb – Aug ’10
HFR
Repair of ’08 problem
Jun – Nov ’10
Nov ’12 – May ‘13
OSIRIS Maintenance
HFR
Repair of leak
Recent problems: impact in UK
Period
Reactor
Problem
Nov/Dec ’07
NRU
Leak, emergency legislation
Aug ’08 – Feb ’09
HFR
Closed due to leak
Sep ’09
IRE
Radioprotection
May ’09 – Jul ’10
NRU
Closed due to leak
Feb – Aug ’10
HFR
Repair of ’08 problem
Jun – Nov ’10
Nov ’12 – May ‘13
OSIRIS Maintenance
HFR
Repair of leak
04/03/2009
18/02/2009
04/02/2009
21/01/2009
07/01/2009
24/12/2008
10/12/2008
26/11/2008
12/11/2008
29/10/2008
15/10/2008
01/10/2008
17/09/2008
03/09/2008
% of expected Tc-99m activity
How bad was it in 2008-09?
120.0
100.0
80.0
60.0
40.0
20.0
0.0
25/08/2010
11/08/2010
28/07/2010
14/07/2010
30/06/2010
16/06/2010
02/06/2010
19/05/2010
05/05/2010
21/04/2010
07/04/2010
24/03/2010
10/03/2010
24/02/2010
10/02/2010
27/01/2010
13/01/2010
30/12/2009
16/12/2009
02/12/2009
18/11/2009
04/11/2009
21/10/2009
07/10/2009
23/09/2009
09/09/2009
26/08/2009
12/08/2009
29/07/2009
15/07/2009
01/07/2009
17/06/2009
03/06/2009
20/05/2009
% of expected Tc-99m activity
How bad was it in 2009-10?
120.0
100.0
80.0
60.0
40.0
20.0
0.0
Confounding problem: HEU
• HEU (>20%) is considered weapons grade
• Typical enrichment is >80%
• USA has mandated international cessation of HEU
use by the end of the decade
• Reactor fuel has been converted to LEU (<20%)
• Most targets are still HEU
• Problems with conversion to LEU
– Less efficient, lower yield, more irradiation capacity reqd
– More radioactive waste generated on processing
New suppliers
• MARIA, Poland
• LVR, Czech Republic
– Targets transported to Holland or Belgium for processing
• OPAL, Australia
– Modern technology
– LEU targets
– Slow to ramp up production
Current capacity and lifetime
*6 day Ci
Consequences in 2016
–40%
–10%
Consequences in 2016
–40%
–10%
–10%
3. International Response
International response
• OECD formed Nuclear Energy Agency High Level
Group for Medical Radioisotopes (HLG-MR)
• Co-ordination of maintenance schedules at
reactors and backup supply
• Outage reserve capacity (ORC)
• Full cost recovery for reactors
• Series of reports (www.oecd-nea.org)
• Shortages have resulted in more efficient usage
Revenue distribution
Piet Louw, NTP
Cost to UK healthcare
• We have already seen the cost of generators more
than double
• OECD modelling predicts only modest further
increases due to implementation of:
– Full economic costing at reactors
– Outage reserve capacity
• However, the impact of closure of NRU and
OSIRIS is still unknown
International prospects
• FRM Munich
• Argentina???
• Russia???
• OPAL Australia
– Has signed supply agreements with American
companies
– Building new processing plant
– Plans to triple output, but will this be enough?
Projections: production capacity
OECD, April 2014
Remaining bottleneck: processing
• Closure of NRU reduces global processing
capacity by 25%
• Full conversion to LEU further reduces capacity
• Requires transport, crossing international borders
Projections: processing capacity
OECD, April 2014
Consequences for UK
• USA is the elephant, consumes 40-50% of world’s
capacity (UK ~2%)
• USA has no domestic supply, predominantly from
Canada and Holland
• Like it or not, USA will have first dibs on available
99Mo when major producers shut down, as
happened in 2009-10
• UK would like to be self sufficient for 99Mo and
other radionuclides for medical use
• Potential to develop and export technologies
4. Possible Short Term Solution
Cyclotron production of 99mTc
• Has been known about since 1960s but previously
not considered cost effective
• Very different model from generators: centralised/
regional production on a daily basis
• Infrastructure less expensive than reactor, but
operating and transport costs greater
• However, regional production is already
established for PET tracers
100Mo
(p, 2n) 99mTc
Steps in production of 99mTc
• Enriched 100Mo target
• Irradiate in proton cyclotron, 4-6 h, optimal energy
to be established, high current needed for yield
• Extract 99mTc from target
• (Recover and recycle 100Mo)
• Purify 99mTc to pharmaceutical standards
• Prepare 99mTc products on site or ship 99mTc
pertechnetate to satellite radiopharmacies
• Do the same thing again tonight
Canadian model: 6 cyclotrons
AJB McEwan, U Alberta
Estimates of yield of 99mTc
AJB McEwan, U Alberta
Remaining questions
• Cost, source, purity of 100Mo
• Optimal proton beam energy: yield vs byproducts
• Reliability of operation of cyclotron daily at high
current
• Contribution of other isotopes to radiation dose
• Regulatory aspects
• Logistics of preparation: central or local
• Overall cost: materials, labour, transport
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5. Longer term solutions (?)
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5. Longer term solutions (?)
Speculative 99Mo approaches in USA
• SHINE: Subcritical Hybrid Intense Neutron Emitter
– Pool of LEU nitrate/sulphate in subcritical assembly
driven by deuterium-tritium beam line
– Deuterium gas ionised, current directs toward tritium
target where D-T reaction produces high energy
neutrons, causing subcritical fission
• North Star: photon induced transmutation
–
100Mo
(γ,n) 99Mo
– Initial approach will use Missouri reactor
– Plan to ship liquid 99Mo which user will place on
generator
Other 99Mo approaches in Canada
• CLSI: Canadian Light Source Inc
–
100Mo
(γ, n) 99Mo using synchnotron
• PIPE: Prairie Isotope Production Enterprise
–
100Mo
(γ, n) 99Mo using linear accelerator
Most promising for UK?
• Photonuclear: 100Mo (γ, n) 99Mo
• Photofission: 238U (γ, f) 99Mo (requires nuclear licence)
• UK expertise in electron linacs and high power
targets
• 1.3 GHz superconducting technology, 10-100 mA
CI/Daresbury have significant expertise
• (Courtesy of Hywel Owen, U Manchester)
• Other radionuclides? AAAS report
Summary
• Likely to face worldwide shortage of 99Mo by end
of 2016, though extent of impact uncertain
• Direct production of 99mTc by cyclotron appears to
be the only route which could be implemented
quickly (2 y), but requires:
– Capital investment in equipment
– Logistics of preparation and distribution
– Regulatory issues (pharmaceutical, dosimetry)
• Greater longer term benefit of alternative route for
production of 99Mo
Acknowledgements
• Dr Brian Neilly, President, British Nuclear Medicine Society
• Prof Alan Perkins, University of Nottingham
• Dr Hywel Owen, University of Manchester
• Louise Fraser, Public Health England (ARSAC)
• Prof Sandy McEwan & Dr Doug Abrams, U of Alberta
[email protected]