Accelerating the Future of Medical
Isotope Production
ARIS 2014, Tokyo, Japan

Paul Schaffer | Head, Nuclear Medicine | TRIUMF+OONONNTcNNO

NOOOverview
Part 1: Direct production of Tc-99m
Part 2: Radiotherapeutic Isotopes via ISOL

Takeaway Message:• Networks of accelerators (cyclotrons) are a viable option forlarge-scale medical isotope production and distribution• Funding for basic physics research leads to tangible
societal benefit

June 2, 2014

2

TRIUMFISAC

2 x TR30, CP42, TR13

11C, 18F,
44Sc,
52Mn
55Co,
68Ga,
86Y,

ARIEL

89Zr500MeV

Owned and operated as an independent
joint venture between 19 Canadian universities

Also:82Rb
103Pd
123I
201Tletc. 3

Part 1: Direct Production of 99mTc Background•
•
•
•

•

•

Demand (99Mo/99mTc, global): 20 - 40 million doses/yr
Prevalence: 85% of all Nuc. Med. scans use 99mTc
Frequency: 76,000 scans/day (>1 scan/second)
Production (of 99Mo via 235U(n,F)):• Canada (~40%), Netherlands (~40%), France (~5%), Belgium (~5%), S.
Africa (~5%), Australia (~5%)• Recent work in S. Africa and Australia is creating new dynamics
Issues:• Reactor shutdown(s): widespread shortages, costs escalating/fluctuating• Unknown future 99Mo production capacity• Aging global reactor infrastructure,• Expensive new construction,• Full-cost-recovery mandates (eliminate gov’t subsidies),• Enriched uranium - non-proliferation efforts,• Regulatory and nuclear safety challenges
Hypothesis: Future production will be from variety of sources (neutron,proton, electron) and market driven

Alternatives for 99mTc production• Alternatives are well known
Neutron ‘solution(s)’:LEU 235U(n,F)99Mo
98Mo(n,)99Mo
Photon ‘solution(s)’:238U(,F)99Mo
100Mo(,n)99Mo
Proton ‘solution’:100Mo(p,2n)99mTc
All at various stages of feasibility/concept development
5100Mo(p,2n)99mTc at the commercial scale

To demonstrate Canada’s
existing cyclotron
infrastructure...

100Mo Target

100Mo

Cyclotron
Modifications

Recycle100Mo(p,2n)99mTc

Irradiation
Parameters

Regulatory
Purificationof 99mTcO4-…can produce
commercial quantitiesof 99mTc

Goals: 1) Formulate policy on 99Mo/99mTc isotope production2) Demonstrate Feasibility/Concept
3) Translate to Commercial Sector

Direct Production of 99mTc in 1971
Background (Beaver and Hupf, U Miami):• 99mTc via cyclotron:• natMo foils 13 x 0.935” x 0.003”, 0.0061A.hr, 22 MeV• 100Mo powder at 21.4, 20.2, and 15.2 MeV,
• integrated beam: 0.00046, 0.0296, 0.00068 A.hr,
respectively.

• Conclusions:• 100Mo (97.42%) at 22 MeV and 455 A will produce 15
Ci/hr of 99mTc and 500 mCi/hr of 99Mo
• Assuming an operating cost of $100/hr, cost of 99mTc
production = $0.015/mCi !!!
J.E. Beaver and H.B. Hupf, J. Nucl. Med. 1971, 12, 739-741

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1971-2009 Development Focus:Uncertainty in 100Mo(p,2n)• No motivation to pursue given avail. of 235U(n,F)99Mo• Progress limited to data refinement in subsequent years• Lagunas-Solar, Challan, Takács, Lebeda, Gagnon…
• Foils, pressed powders; natural and enriched Mo

K. Gagnon et al., Nuc. Med. Biol. 2011, 38, 907-916• Consider also contributions from (p,x) on 100Mo and 9xMo, etc.
A. Celler, X. Hou, F. Bénard, T. Ruth, Phys. Med. Biol. 2011, 56, 5469

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The Calculated Approach:Predicting Products/Yields
100Mo(p,x) reactions of highest probability

98Tc

99gTc

99mTc

99Mo

PETtrace

TR19

CP42

A. Celler, X. Hou, F. Bénard, T. Ruth, Phys. Med. Biol. 2011, 56, 5469

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Side Reactions: 94-97Mo(p,n)
Exit Energy

Irradiation Energy

A. Celler, X. Hou, F. Bénard, T. Ruth, Phys. Med. Biol. 2011, 56, 5469

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Side Reactions: 94-97Mo(p,2n)Exit Energy

Irradiation Energy

A. Celler, X. Hou, F. Bénard, T. Ruth, Phys. Med. Biol. 2011, 56, 5469

11Target Enrichment: 94-97Mo vs 100Mo

Isotope
92Mo94
Mo95
Mo96
Mo97Mo98Mo100Mo

Enriched
A
0.005
0.005
0.005
0.005
0.01
2.58
97.39

B
0.006
0.00510.00760.00120.0016
0.41
99.54

C
0.09
0.06
0.1
0.11
0.08
0.55
99.01

D
0.003
0.003
0.003
0.003
0.003
0.17
99.815Natural
14.85
9.25
15.92
16.68
9.55
24.13
9.63

Higher 100Mo enrichment  higher purity product12

Graphical User Interface (GUI)for Yield and Dose Projections

Developed by A. Celler, X. Hou et al. at MIRG-UBC

99mTc Production via Solid Target

Irradiation (GE PETtrace)• PETtrace target assembly• 130 µA, 16 MeV on target for 360 min• Saturation yields: 2.8 GBq/μA (75.6 mCi/μA)• Demonstrated yields of ~4.7 Ci

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TR19 Solid Target System (BCCA)• TR19 target assembly• Progress:• 240µA, 18 MeV on target (360 min)• ~9.4 Ci (370 GBq) 99mTc• Next: 300µA, 18 MeV (360-540 min)• Saturation yield: 3.8 GBq/μA (103 mCi/μA)

2010-2014: Development and Installationof High-Power Solid Targets, Associated Hardware
Transfer
Drive

Automated
PurificationReceiveandDissolve

June 2, 201416

Yield Comparison: Energy, Current
Considerations
1400.00

Produced Tc-99m (GBq)1200.00
1000.00

5.8 GBq/µA, 500 µA

800.00
PETtrace 880 (our data)
600.00TR19 (our data)

3.8 GBq/µA, 300 µA

TR24 (theory, 20 MeV)

400.002.8 GBq/µA, 130 µA

200.00
0.00
012

3

4

56

7

Irradiation Time (hrs)17Technical Summary of Results• Target manufacture process, risks addressed…so far• Yields: ~340 GBq (TR19), ~174 GBq (PETtrace)• Recovery: ~93% as Na99mTcO4• Radiopharmaceutical Production:• 3 types of kits (Sestamibi, HMPAO, MDP) radiolabeled
successfully and passed standard QC (n = 3 each)• Radiochemical Purity:• Small amounts of 93Tc, 94mTc, 94Tc, 95Tc, 96Tc impurities
were observed – full quantitation underway• Non-Tc by-products (95Nb, 99Mo) collected in waste alongwith 100Mo; negligible amounts in final product• 100Mo recycled with 85% recovery yield (range 80 – 92%)

• Clinical Trial work to begin late 2014
See Bénard et al., J. Nucl. Med. 2014, 55, 1017-1022

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Results Interpretation (so far)
• Production capacity: energy, time, current• Energy – intrinsic to machine (16-19 MeV, <22MeV)• Time – defined by other commitments (3-6 hrs)
• Current – intuitive for production boost (80-300+µA); requires cyclotron power, target capabilities• 100Mo isotopic purity is important• 95,96,97Mo content is more important• 99mTc specific activity needs regulatory consideration• Presence and affect on chemistry, dosimetry• Requires regulatory input (USP, EP)

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Canada vs. Japan – Substantial 99mTc
Production Capacity Currently in Place

CanadaJapan

Population: ~35M (2012)
Annual 99mTc needs: 971 TBq
With losses: 1900 - 3000 TBq
Cyclotrons: 22+6 (16-24 MeV)
Existing Capacity: 2483 TBq(2 x 6hr runs/d, 240d/yr)

Population: ~ 128M (2012)
Annual 99mTc needs: 3552 TBq
With losses: 7,100 - 11,100 TBq
Cyclotrons: ~60 (>16 MeV)
Existing Capacity: ~10,000 TBq
20(2 x 6hr runs/d, 240d/yr)

Part 2: Isotope production at ISAC and ARIEL
TRIUMF-ISAC facility

High mass isotope production byspallation of 238U:
480 MeVProtonsVariety ofisotopes
produced
Uranium target

ISAC

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213Fr implantation for 209At

α-emitters of interest:
211At (209At)
212-213Bi
223Ra
225Ac
ISAC yield measurements:
213Fr = 7.7x108 ions/s,
213Ra = 1.6x108 ions/s
Radium-213 is co-implanted (30%),
20% decays to 213Fr  209At
80% decays to 209Rn (t1/2=29m)
83% of 209Rn decays to 209At
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Theoretical 209At build-up during 213Fr implantation
209At via 213Fr Implantationxxx

8.2 hr implantation
5.0 hr implantationx

Purity of 209At >99%
3.2 mCi @EOB No unexpected inventory
3.0 mCi @EOB No other astatine isotopes

Apparatus for 213Fr/209At collection

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209At-SPECT with hotrod phantom

Rod diameters0.85mm0.45mm
0.50mm545 keV Peak0.80mm
0.55mm

0.75mmRadionuclide therapy
with astatine-labelled peptides
209At/211At labelling studies and small animal imaging for targeting

peptides (somatostatin-receptor ligands)

209At or 123I

TATE

209At/211At labelling development in collaboration with Dr. DS Wilbur, UW

Wilbur et al, Bioconjugate Chem. (2007), 18, 1226-1240

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Future Direction: ISAC-ISOL••211Rn/211At generator
225Ac/213Bi generator

from Ra-225 decay

225Ra

225Ac

t1/2=15.0 d

t1/2= 10.0 d

Feasibility/Chemistry in lead up to full target harvest

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Future Direction(s): ARIEL

68Zn(,p)67Cu
132Te(,p)131I
154Sm(,n)153Sm
178Hf(,p)177Lu
187Re(,n)186Re
226Ra(,n)225Ra  225Ac

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Acknowledgements – Tc-99m•

The Team:• Ken Buckley, Vicky Hanemaayer, Brian Hook, Stuart McDiarmid, , Stefan
Zeisler, Frank Prato, Chris Leon, Anne Goodbody, Joe McCann, ConnyHoehr, Tom Morley, Julius Klug, Philip Tsao, Milan Vuckovic, Jean Pierre
Appiah, Maurice Dodd, Guillaume Amouroux, Wade English, Xinchi Hou,
Jesse Tanguay, Jeff Corsault, Ross Harper, Constantinos Economou• François Bénard, Tom Ruth, Anna Celler, John Valliant, Mike Kovacs•

TRIUMF and BCCA machine shops•

Finances/Admin• Niki Chen, Nina Levi, Henry Chen, Jenny Song, Steven Foster, Neil
McLean, Jim Hanlon, Ann Fong, Kevin McDuffie, Niki Martin

Acknowledgements – ISOL
Jason Crawford
Tom Ruth
Hua YangJens LassenPeter Kunz
Peter Machule
Stefan Zeisler
Stephen Chan
Linda GrahamLynne LemessurierDavid Prevost
Grant Sheffer

Joe Mildenberger
Danka Krsmanovic
Roxana Ralea
Maxim Kinakin
Stephan Blinder
Katherine Dinelle
Vesna Sossi
D. Scott Wilbur
Don Hamlin
Mike Adam
Francois Benard
Kuo-Shyan Lin

Thank you

Lia Merminga
Bob Laxdal
Colin Mortin

Canada’s national laboratory for particle and nuclear physics
Laboratoire national canadien pour la recherche en physique nucléaire
et en physique des particules

Thank you!
Merci

Owned and operated as a joint venture by a consortium of Canadian universities via a contribution through the National Research Council CanadaPropriété 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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Columbia | Queen’s Regina | Saint Mary’s |Simon Fraser | Toronto Victoria | Winnipeg| York