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CANM 2017 ANNUAL SCIENTIFIC MEETING – TORONTO (CANADA) – APRIL 2017 1/36

PONSARD B. Copyright © 2017

SCK•CEN

WORLD Mo-99 SUPPLYBernard PONSARD

Chairman AIPESReactors & Isotopes Working Group

Radioisotopes Project ManagerBR2 Reactor - [email protected]

Bernard PONSARDChairman AIPES

Reactors & Isotopes Working GroupRadioisotopes Project Manager

BR2 Reactor - [email protected]

CANADIAN ASSOCIATION OF NUCLEAR MEDICINE CANM 2017 Annual Scientific Meeting

TORONTO (CANADA), 21/04/2017

CANADIAN ASSOCIATION OF NUCLEAR MEDICINE CANM 2017 Annual Scientific Meeting

TORONTO (CANADA), 21/04/2017

BR2High-Flux Reactor

BR2High-Flux Reactor



SCK•CEN

I do not have a financial interest, arrangement or affiliation including receipt of honoraria or expenses

with a commercial organization that may have a direct interest in the subject matter of my presentation.

CANM ANNUAL SCIENTIFIC MEETINGAPRIL 20-23, 2017

TORONTO, ONTARIO



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1. Introduction : The Mo-99 Supply Chain

2. Current Status of the Mo-99 Supply

3. Actions taken for a Secure Supply of Mo-99

4. Future of Mo-99 Supply

5. Conclusions

BR2 Reactor

The World Mo-99 Supply : Issues and Perspectives



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The worldwide supply of Mo-99 relies currently on a limitednumber of research reactors and processing facilities.

Its production is essential for nuclear medicine as Tc-99m,currently obtained from Mo-99/Tc-99m generators, is used inabout 80% of diagnostic nuclear imaging procedures.

These applications represent approximately 30 millionexaminations worldwide per year.

Therefore, a weekly Mo-99 production of about 9.000 Ci '6-day'calibrated is required to supply North America (53%), Europe(23%), Asia (20%) and the rest of the world (4%).

Given the short half-lives of Mo-99 (66 hours) and its daughterTc-99m (6 hours), a regular supply of Mo-99/Tc-99m generatorsto hospitals or central radiopharmacies is required.


Mo-99/Tc-99m Generator



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The Current Mo-99 Supply Chain consists of : Uranium (HEU/LEU) target manufacturers nuclear research reactors for target irradiation processing facilities to dissolve the irradiated targets and extract Mo-99 Mo-99/Tc-99m generators manufacturers radiopharmacies to elute Tc-99m from the generators and prepare

radiopharmaceutical doses to be injected to the patients for diagnosis transport companies to ship the produced activities to the different

participants involved in the supply chain

Carriers More carriers

Processing Facilities

Users

HospitalsNuclear Reactors

From the producers to the users … No time to lose …




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Targets manufacture

Targets irradiation

Targets shipment

Mo-99/Tc-99m

BR2 Reactor


Targets processing

Hospital



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Targets irradiation

OPERATIONSINVOLVED

TIME SCALE

EVOLUTION OF THE 99MO ACTIVITY

IRRADIATION IN THE REACTOR

UNLOADING FROM THE REACTOR …

LOADING CONTAINERS

SHIPMENT CONTAINERS

PROCESSING IRRADIATED TARGETS

SHIPMENT BULK Mo-99

MANUFACTURE and DELIVERY GENERATORS

USE IN HOSPITALS

150 HOURS

12 HOURS

4 HOURS

4 HOURS

12 HOURS

12 HOURS

12 HOURS

120 HOURS

1000 Ci Mo-99 ‘EOI’/ target

810 Ci / target

640 Ci bulk Mo-99

500 Ci Mo-99

120 Ci Mo-99 ‘6-DAY’g

Production of Mo-99/Tc-99m in the BR2 Reactor




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Targets irradiation

Mo-99 Global Demand

About 9.000 Ci Mo-99 ‘6-day’ calibrated per week !!!

Or about 468.000 Ci Mo-99 ‘6-days’ calibrated per year !!!

The “6-day Ci”is a unit of

measure thattakes the Mo-99 decay rate into

account, the losses during shipments and

processing, and represents an

average amount of Mo-99 that

would be available for use

6 days after processing

g


9.000 Ci Mo-99 ‘6-days’

55.000 Ci Mo-99 @ EOI45.000 Ci Mo-99

available for shipping



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From U-235

To Mo-99

Targets unloading




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From U-235

To Mo-99




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Historically, there were only five nuclear reactors involved in theproduction of Mo-99 on an industrial scale, i.e. NRU (Canada),HFR (The Netherlands), BR2 (Belgium), OSIRIS (France) andSAFARI (South Africa).

They irradiated Highly Enriched Uranium (HEU) targets for theproduction of about 95% of the available Mo-99 by fourprocessing facilities: AECL/MDS NORDION (Canada), NTP (SouthAfrica), IRE (Belgium) and MALLINCKRODT (The Netherlands).

However, these ageing reactors - most of them are currently over50 years old - are subject to unscheduled shutdowns and longermaintenance periods making the Mo-99 supply chain vulnerable.

Several severe disruptions have been experienced since 2008due to the occurrence of problems at different stages of the supplychain: reactor outages, release of activity from processing facilities,recall of Mo-99/Tc-99m generators by the manufacturers, …

2. Current Status of Mo-99 Supply



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The Association of Imaging Producers & Equipment Suppliers(AIPES) members consist of many of the major globalpharmaceutical and imaging equipment companies in the field ofnuclear medicine.

The AIPES Reactors and Isotopes Working Group (R&I WG)includes the major research reactors involved in the irradiation ofuranium targets for the production of Mo-99, the major Mo-99industrial processors and the major Mo-99/Tc-99m generatormanufacturers.

The AIPES R&I WG reports to the AIPES Executive Committeeand communicates regularly on the status of internationalproduction of Mo-99 and other medical radioisotopes to majorinternational stakeholders such as: the European Observatory for Medical Radioisotopes the OECD/NEA High Level Group on Medical Radioisotopes (HLG-MR).




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Are currently represented in the AIPES Reactors &Isotopes Working Group (R&I WG) which has the task tosecure the global supply of Mo-99:

Eleven reactors : BR2 (Belgium), HFR (The Netherlands),SAFARI (South Africa), MARIA (Poland), LVR-15 (CzechRepublic), OPAL (Australia), RA-3 (Argentina), FRM-II(Germany; currently not irradiating targets for Mo-99; 2019),NRU (Canada; no routine production from November 2016),OSIRIS (France; shutdown) / JHR (France; under constructionto replace OSIRIS from 2022).

Six processors : IRE (Belgium), CURIUM MALLINCKRODTMedical B.V. (The Netherlands), ANSTO Health (Australia),NTP (South Africa), CNEA (Argentina) and CNL/NORDION(Canada; no routine production from November 2016).




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HFR Reactor

OSIRIS Reactor

BR2 Reactor FRM-II Reactor MARIA Reactor

LVR-15 Reactor

SAFARI Reactor

NRU Reactor

OPAL Reactor

RA-3 Reactor 2. Current Status of

Mo-99 Supply

JHR Reactor



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The estimated Mo-99 Irradiation Capacities of the researchreactors currently involved in the Mo-99 production:

Reactors Countries Targets Operating weeks / year

Irradiation capacities / week

[6-day Ci ]

Irradiation capacities / year

[6-day Ci ]

End of operation

BR2 Belgium HEU 21 7 800 163 800 > 2026

HFR The Netherlands HEU 39 6 200 241 800 2024

(NRU) (Canada) (HEU) (40) (4 680) (187 200) (Nov 2016)

SAFARI South Africa HEU/LEU 44 3 000 130 700 2030

LVR-15 Czech Republic HEU 30 3 000 90 000 2028

MARIA Poland HEU 36 2 700 95 000 2030

OPAL Australia LEU 43 2 150 92 450 2055

RA-3 Argentina LEU 46 400 18 400 2027

Ref: Nuclear Energy Agency, NEA/SEN/HLGMR (2016)2, June 2016, www.oecd-nea.orgUpdated HLG-MR Meeting – February 2017

The NRU reactor and the CNL/NORDION processing facility in Canadaceased routine production of Mo-99 at the end of October 2016.




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The estimated Mo-99 Production Capacities of theprocessing facilities currently involved in the Mo-99 production:

Processors Countries TargetsProduction

weeks / year

Production capacities /

week [6-day Ci ]

Production capacities / year

[6-day Ci ]

LEU conversion

MALLINCKRODT The Netherlands HEU 52 5 000 260 000 2017

(CNL/NORDION) (Canada) (HEU) (40) (4 680) (187 200) (No)

IRE Belgium HEU 52 3 500 182 000 2016

NTP South Africa HEU/LEU 44 3 000 130 700 2016

ANSTO Health Australia LEU 43 2 150 92 450 LEU

CNEA Argentina LEU 46 400 18 400 2027

The NRU reactor and the CNL/NORDION processing facilityin Canada ceased routine production of Mo-99 at the end ofOctober 2016.


Ref: Nuclear Energy Agency, NEA/SEN/HLGMR (2016)2, June 2016, www.oecd-nea.orgUpdated HLG-MR Meeting – February 2017



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Several organizations have been working together since2008 to define measures that should be taken to securethe supply of Mo-99 in the short, medium and long term :

the OECD Nuclear Energy Agency (NEA), the International Atomic Energy Agency (IAEA), the Association of Imaging Producers and Equipment

Suppliers (AIPES) the European Commission (EC) the US Department of Energy (US DOE), …

The 'High Level Group' on the Security of Supply ofMedical Radioisotopes (HLG-MR) has been created in April2009 to examine the underlying reasons for the shortagesand to develop a policy approach to ensure their long-termsecurity of supply.




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The HLG - MR established six principles for a long-term secure Mo-99/Tc-99msupply: Principle 1: All Tc-99m supply chain participants should implement full-cost

recovery, including costs related to capital replacement. Principle 2: Reserve capacity should be sourced and paid for by the supply

chain. A common approach should be used to determine the amount of reservecapacity required.

Principle 3: Recognizing the role of the market, governments should establishthe proper environment for infrastructure investment, to implement full-costrecovery methodology, …

Principle 4: Given their political commitments to non-proliferation and nuclearsecurity, governments should provide support, as appropriate, to reactors andprocessors to facilitate the conversion of their facilities to LEU …

Principle 5: International collaboration should be continued through a policyand information sharing forum, recognizing the importance of a globallyconsistent approach to addressing security of supply of Mo-99/Tc-99m …

Principle 6: There is a need for periodic review of the supply chain to verifywhether Mo-99/Tc-99m producers are implementing full-cost recovery, whetherplayers are implementing the other HLG-MR approaches and that operatingschedules coordination has no negative effects on market operations.

NEA, "The Supply of Medical Radioisotopes: The Path to Reliability",

OECD 2011, NEA No. 6985, ISBN-978-92-64-99164-4, Paris, France.




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Some critical periods wereexpected in 2016-2018 due to: definitive shutdown of the

OSIRIS reactor in December2015 and cease of routineproduction of Mo-99 at the endof October 2016 in Canada

constraints on processingfacilities

impact of the conversion fromHEU to low enriched uranium(LEU) targets

0

200 000

400 000

600 000

800 000

1 000 000

1 200 000

1 400 000

1 600 000

1 800 000

2010

2013

2016

2019

2022

2025

2028

Ann

ual s

ix-d

ay c

urie

s EO

P

Current Supply vs. DemandDemand at 5%annual growth

Demand fromNEA study

Maximumpossiblesupplycapacity fromcurrent reactorfleet

20162018

While the current situation looks very secure, the supply chainremains fragile and further Mo-99 supply shortages could beexpected in future.



The Mo-99 demand is expected to grow as follows in the next future: 0,5%per year in mature markets; 5% per year in emerging markets.




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0

100000

200000

300000

400000

500000

600000

700000

Jul-Dec Jan-Jun Jul-Dec Jan-Jun Jul-Dec Jan-Jun Jul-Dec Jan-Jun Jul-Dec Jan-Jun Jul-Dec Jan-Jun Jul-Dec

2015 2016 2017 2018 2019 2020 2021

6-da

y cu

ries

Mo-

99 p

er 6

mon

th p

erio

d

NEA Demand growth (with no ORC) NEA Demand growth (+ 35% ORC)

The current Mo-99 demand is 9 000 Ci 6-d calibrated per week. An additional 35% ORC (Outage Reserve Capacity) should be applied to

secure the supply.

20152021






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The European Observatory on the Supply of Medical Radioisotopeshas been created in 2012 to secure the availability of Mo-99 andother therapeutic radioisotopes in Europe.

Several actions have been taken by the AIPES 'Reactors andIsotopes' Working Group in the past years to improve the Mo-99production monitoring and provide suitable communication tostakeholders.

The ERT (Emergency Response Team) has been created in 2012within the AIPES 'Reactors and Isotopes' Working Group to followproduction and supply issues – week by week – through conferencecalls if requested. This continuous follow-up allows to identifypotential Mo-99 shortages and to define action plans with researchreactors, processors and generator manufacturers, including supportfor ‘fresh’ and ‘irradiated’ targets shipments.

As a result, there were no significant supply shortages in theperiod 2014 - 2016 despite several reactor and processing facilityevents.




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To ensure security of supply, the AIPES R&I WG tries : to achieve the best possible coordination of the reactor operating

periods to provide an optimal global coverage during planned reactor

shutdown periods for refueling and maintenance to solve problems through its Emergency Response Team (ERT)

In the case of any unexpected event affecting the Mo-99international supply, the R&I WG activates its EmergencyResponse Team (ERT) to exchange information and tocoordinate compensating measures between theresearch reactors, processors and other stakeholders withthe objective of maintaining secure global supply of Mo-99.




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Actions at Research Reactor level Enhancement of reliability Implementation of the principles recommended by the OECD/NEA

HLG-MR such as “Full Cost Recovery” and “Outage ReserveCapacity”

Refurbishment of existing facilities as the BR2 research reactor(Belgium), allowing another 10 years – at least – operation

Flexibility of the operating periods (especially MARIA and LVR-15) Better coordination of the operating periods

Actions at Processor level Increased capacity in the plants located in The Netherlands,

Belgium and Australia Excellent cooperation between the major processors

Actions at Generator Manufacturer level Diversification in Mo-99 sourcing




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The "VERSAILLES Mo-99 MODEL" has been developed andvalidated by AIPES in 2014 based on data provided in theOECD/NEA (2013/2014) reports and feedback delivered by theAIPES representatives (processors and generators manufacturers)for the years 2013 and 2014.

This model follows the global Mo-99 maximum weekly reactorproduction capacity – week by week – and is now considered asbeing a suitable tool to assist reactor scheduling and to identifypotential periods at risk that require further investigation at theprocessor and generator manufacturer levels of the Mo-99 supplychain.

The AIPES R&I WG continues to focus attention and effort regardingthe situation of the research reactors which produce Mo-99 for theperiod 2017 and beyond, especially given the definitive shutdown ofthe OSIRIS reactor at the end of 2015, the restart of the BR2 reactorafter its scheduled extended shutdown (March 2015 - July 2016) toreplace its beryllium matrix and the fact that the NRU reactor ceasedroutine Mo-99 production from November 2016.




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Results of the AIPES "VERSAILLES Mo-99 MODEL" appliedto the year 2017 :




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It should be noticed that a reactor production capacity belowthe 9.000 '6-d' Ci red line during a particular week does notmeans that the reduced Mo-99 production capacity wouldresult into a severe Mo-99 shortage which would not bemanageable by the supply chain and impact patienttreatments seriously.

However, the model is able to identify periods at risk whichneed to be further investigated at processor and generatormanufacturer level. Suitable action plans can then be definedto mitigate the impact in the supply chain in case of necessity.

It appears from the previous slides that a number of actionshave been undertaken to ensure that - barring unforeseendevelopments - there will be secure and sufficient supplythrough 2017 and that no Mo-99 shortage is anticipated.




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The definitive shutdown of the OSIRIS (France) reactor end of2015 and the decision taken by the Government of Canada tocease routine Mo-99 production at the NRU (Canada) reactorfrom end of October 2016 resulted in a reduction of about 30%of the global Mo-99 production capacity at the end of 2016.

Nevertheless, the Government of Canada has decided tosupport an extension of the NRU operations until March 31,2018 after which the reactor will be shut down definitively. NRUwill remain fully operational to perform material testing programsand production of radioisotopes other than Mo-99 such asCo-60 but not Xe-133 which is a fission product resulting fromthe dissolution of targets irradiated for Mo-99 production.

However, it is Canada’s intention to keep the NRU reactoravailable between November 1, 2016 and March 31, 2018 as aback-up production capacity for Mo-99 in case of significantshortage on the market.

4. Future of Mo-99/Tc-99m Supply



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Reactor Production Routes Fission of solid LEU targets : 235U(n,fission)99Mo Fission of LEU in solution : 235U(n,fission)99Mo Neutron capture : 98Mo(n,γ)99Mo

Accelerator Production Routes Photofission reaction : 238U(γ,fission)99Mo Photonuclear reaction : 100Mo(γ,n)99Mo Photoneutrons generated from e- beam for fission LEU in solution D-T neutron generators to fission LEU in solution: 235U(n,fission)99Mo Spallation neutron source production (ADS) : 235U(n,fission)99Mo Direct 99mTc production by cyclotron : 100Mo(p,2n)99mTc

Alternative methods for producing Mo-99 and Tc-99m without the use of HEU …




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As reported by the OECD, new irradiation projects are underdevelopment for the production of Mo-99/Tc-99m, under which:

Irradiators Countries TargetsOperating weeks /

year


[6-day Ci ]


[6-day Ci ]

Full production

RIAR Russia HEU 50 1 000 50 000 2015KARPOV Russia HEU 48 350 16 800 2015

MURR NorthStar USA Mo-98 natural 52 750 39 000 2017

MURR NorthStar USA Mo-98 enriched 52 2 250 117 000 2018

NORTHSTAR USA Mo-100 LINAC 52 3 000 156 000 2018

FRM-II Germany LEU 32 2 100 67 200 2019MURR/GA USA LEU 52 4200 218 000 2019

SHINE USA LEU solution 50 4 000 200 000 2020KJRR Korea LEU 43 400 17 200 2020RA-10 Argentina LEU 48 2 500 120 000 2020CARR China LEU 34 1 000 34 000 2021RMB Brazil LEU 41 1 000 41 400 2021JHR France LEU 32 4 800 153 000 2021

Ref: Nuclear Energy Agency, NEA/SEN/HLGMR (2016)2, June 2016, www.oecd-nea.org




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As reported by the OECD, new processor projects are underdevelopment for the production of Mo-99/Tc-99m, under which:

Irradiators Countries Targets Operating weeks / year


[6-day Ci ]


[6-day Ci ]

Full production

RIAR Russia HEU 50 1 000 50 000 2015

KARPOV Russia HEU 48 350 16 800 2015

MURR NorthStar USA Mo-98 natural 52 750 39 000 2017

ANSTO Australia LEU 43 3 500 150 500 2017

MURR NorthStar USA Mo-98 enriched 52 2 250 117 000 2018

NORTHSTAR USA Mo-100 LINAC 52 3 000 156 000 2018

NORDION Canada LEU 52 4 200 218 400 2019

SHINE USA LEU solution 50 4 000 200 000 2020

KJRR Korea LEU 43 400 17 200 2020

MARIA Poland LEU 40 1 000 40 000 2020

CNEA Argentina LEU 48 2 500 120 000 2020

CARR China LEU 34 1 000 34 000 2021

RMB Brazil LEU 41 1 000 41 400 2021Ref: Nuclear Energy Agency, NEA/SEN/HLGMR (2016)2, June 2016, www.oecd-nea.org




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The recurrent supply shortages highlighted the vulnerability ofcentering production on a limited number of ageing reactorsand encouraged the industry to develop new projects andnew production routes to increase and diversify productioncapacities.

Several new projects are expected to be commissioned in theperiod 2017 – 2021 and will help to increase and diversifyproduction capacities of Mo-99 and Tc-99m in future.

The Mo-99 production by irradiation of LEU uranium targetsin research reactors is however expected to remain the mainproduction route in future.

5. Conclusions

Thank You For Your Attention …



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