Domestic Mo-99 Production

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2 Domestic Mo-99 Production A look at efforts to secure a U.S. supply September 11, 2015 Roy W. Brown Sr. Director, Strategic Alliances Mallinckrodt Pharmaceuticals

3 Background on Nuclear Medicine

4 Nuclear Medicine & Radiopharmaceuticals Radiopharmaceuticals are FDA approved drugs which are labeled with small quantities of radionuclides. The radiopharmaceutical concentrates in the area of the body to be examined where special cameras capture the nuclear particles or photons emitted by the radiopharmaceutical producing a visual image of the body system, organ or tissue Globally 30 million patients benefit from these procedures each year. Tc-99m MDP Whole Body Scan Tc-99m Sestimibi Cardiac Stress Test

5 The Importance of Mo-99/Tc-99m Today, over 100 different nuclear medicine applications exist, such as diagnosing heart disease, brain disorders, infections and treating cancer DIAGNOSING THYROID CANCER More than 80% of these IMAGING THE LUNGS FOR BLOOD CLOTS applications (procedures) use Tc-99m from Mo-99/Tc-99m generators These procedures are one of the most accurate methods of combating cardiovascular disease This technique makes early diagnosis possible, thereby saving patients and the health industry millions of dollars every year SCANNING BONES FOR INFECTION DIAGNOSING BRAIN DISORDERS ACCURATELY DIAGNOSING CORONARY ARTERY DISEASE EXPOSING THE SPREAD OF CANCER

6 The Importance of Mo-99 & Tc-99m Vital part of diagnostic and therapeutic management of patients Nuclear cardiology represents 60% Bone Imaging represents 17% Other imaging of brain, endocrine system, lungs, GI & GU tract, infection, and others. There are also a number of therapeutic nuclear medicine treatments for bone pain palliation related to Prostate Cancer, Non-Hodgkin s Lymphoma and Thyroid Cancer Breakdown of Tc-99m Nuclear Medicine Studies

7 Mo-99/Tc-99m Generators Tc-99m is a very effective radionuclide to image patients, but it s 6 hour half-life creates delivery challenges. A generator provides a supply of Tc- 99m that effectively decays with the half-life of the Mo-99 (~3 days) rather than the half life of the Tc-99m (6 hours) Generators are typically used for two weeks, but can be used longer Ultra-Technekow DTE Technetium Tc 99m Generator

8 Mo-99/Tc-99m Generator Operation The conventional Tc-99m generator utilizes a chromatographic column to selectively bind the Mo-99 to the substrate (aluminum oxide) The sodium molybdate (Mo-99) is chemically bound to the aluminum oxide in the column Saline solution is passed across the column to elute the sodium pertechnetate (Tc-99m)

9 Mo-99 Market Demand* Global Mo-99 Demand by Geography 8% 3% 25% 2% 4% 58% North America EMEA Latin America Japan China Other Asia Global Mo-99 Demand Approximately: 9,000 Ci / week *Sources: Internal data. OECD report The Supply of Medical Isotopes, June 2011, with total demand revised.

10 Production of Mo-99

11 Image used with permission. Image used with permission. Image used with permission Credit photo: ANSTO Credit Photo: NRG. Credit photo: CEA Credit photo: Atomic Energy of Canada Limited. Credit photo: NMS. The Eight Main Reactors for Irradiating Mo-99 Targets Most of these reactors are years old None are located close to the largest Mo-99/Tc- 99m market (U.S.) A domestic supply would help with the security of supply High Flux Reactor (HFR) The HFR is property of the European Commission and is operated by the Nuclear Research and Consultancy Group (NRG). South African Fundamental Atomic Research Installation (SAFARI-1) OSIRIS Reactor The OSIRIS reactor is scheduled to shut down at the end of Maria Research Reactor Poland National Research Universal (NRU) Chalk River Laboratories are situated on the banks of the Ottawa River, in the upper Ottawa valley, Ontario. LVR-15 REZ Reactor Czech Republic Nuclear Research Centre (BR2) Belgian Reactor 2 OPAL Reactor Australia

12 The Current U.S. Mo-99/Tc-99m Generator Supply Chain Reactor Maria Mo-99 Extraction Mo-99 Purification Mo-99 Processing HFR BR2 LVR-15 OSIRIS Mallinckrodt Netherlands IRE Belgium Mallinckrodt U.S. Safari NRU AECL NTP Nordion Lantheus OPAL ANSTO 12 10/28/2015

13 RADWASTE SUMMIT SEPTEMBER 11, 2015 Presented by: Carolyn Haass, Chief Operating Officer 13

14 Organization Irradiation Services University Reactors Radioisotope Production Facility Engineering Design Technology Demonstration 3 rd Reactor Criticality, Shielding, and Safety Analysis ATKINS Transportation Licensing and Environmental Permitting 14

15 Primary Assumptions Single Radioisotope Production Facility (RPF) 99 Mo produced using a fission based-method Gold Standard Nominal capacity 3,500 6-day Ci; surge capacity of 1,500 6-day Ci Use low-enriched uranium (LEU) Recover 99 Mo from LEU targets using standard chemical processes Utilize network of University Reactors Utilize same target design for all reactors Recycling processed LEU for reuse as target material Fission product releases will comply with environmental release criteria and WOSMIP guidelines Generate Class A, B, and C wastes; no GTCC waste Uranium processing and storage will meet all required Safeguards & Security Requirements Accumulation Beds (e.g., carbon, others) Radioisotope Distributor Waste Management I 2, Kr, Xe Removal or Capture Mo 99 Irradiated LEU Targets from Reactor Target Dissolution Mo Recovery & Purification LEU Recovery & Recycle Decay Storage Recycled LEU back to LEU Target Production System 15

16 NWMI Project Status and Schedule Status Construction Permit (CP) Application submitted RPF preliminary design completed; Final design initiated Regularly producing Ci (6-day) of 99 Mo from proof of concept demonstrations Technology optimization currently being performed Siting Decision Taken; Option formalized Network of irradiation suppliers complete Summary Schedule NRC CP approval anticipated early 2016 Construction of RPF 2016 into 2017 Initiation of production mid

17 Technology LEU target material is fabricated (both fresh LEU and recycled U) LEU Target material encapsulated using metal cladding LEU Target LEU Targets are packaged and shipped to university reactors for irradiation After irradiation, targets are shipped back to RPF Irradiated LEU targets disassembled Irradiated LEU targets dissolved into a solution for 17

18 Facility Description 1 st Level footprint ~52,000 ft 2 High bay roof 65 ft Target Fabrication Area Mechanical area, 2 nd Floor 46 ft Hot Cell Processing area (Dissolution, 99 Mo and 235 U recovery) Top of exhaust stack 75 ft Waste Management, Laboratory and Utility Areas Basement ~2,000 ft2 (tank hot cell, decay vault) Loading dock (back) roof 20 ft 2 nd Level ~17,000 ft 2 (Utility, Ventilation, Off-Gas Equipment) WM Out Building ~1,200 ft 2 Support & Admin (front) roof 12 ft Depth below grade for Hot Cell/HIC storage 15 ft Administration Building (outside of secured RPF area) ~10,000 ft 2 18

19 NRC Licensing Strategy Combine several license activities and submit one application that covers all applicable regulations for construction/operation of RPF under 10 CFR CFR 50 Activities 10 CFR 70 Activities Irradiated Target receipt Receipt of LEU (from DOE) Irradiated target disassembly Target dissolution 99 Mo separations, purification and packaging LEU reclamation and purification Waste management Associated laboratory and support Production of LEU microspheres Target fabrication and testing Shipping/loading of fabricated targets Llaboratory and support areas 10 CFR 30 Activities Handling of byproduct material University Reactor(s) and Cask Licensee(s) will amend their current operating license s 19

20 Radioisotope Production Facility Layout Target fabrication area Administration and support area Waste management area Irradiated target receipt area Tank hot cell Utility area Laboratory area 10 CFR 70 NWMI r01 10 CFR 50 20

21 NWMI Challenges and Advantages Challenges Heavily regulated industry with significant review processes that are critical path to production National laboratory capability to support optimization testing Uranium lease take back T&C for both lease and take back Need of R&D LEU quantities not integrated Receipt of LEU for commercial production when required Requirements for LEU take back Advantages NWMI 99 Mo indistinguishable from existing supply No change to generators No change to diagnostic modality Network of existing University irradiation suppliers Assurance of supply Surge capacity Target Design Reactor safety No dissolution of metal cladding Novel process extraction and purification chemistry Proven Efficient 235 U reclamation 21

22 Micro-porous Sorbent for 99Mo/99mTc Generator using (n, ) 99Mo L.F. Centofanti Perma-Fix Environmental Services, Inc.

23 Isotope Production 23

24 Fission vs. Neutron Activation Process 235 U(n, f) 99 Mo 98 Mo(n, ) 99 Mo Requires enriched 235 U target Produces high specific activity of 99 Mo Generates high level radioactive waste Great concern about secondary fission product Export of highly controlled material required Requires high purity molybdenum Produce low specific activity of 99 Mo Generates minimal waste No fission product Non-fissile material. No proliferation concerns. 24

25 Medical Isotope Manufacture Perma-Fix Approach Perma-Fix Environmental Services, Inc. has completed initial development of a prototype 99m Tc generator using a patent pending micro-porous composite (MPCM) resin MPCM can adsorb commercially significant amounts of low specific activity 99 Mo produced by neutron activation MPCM based 99 Mo/ 99m Tc generator has the potential to allow neutron activated 99 Mo to contribute significantly to the supply chain 25

26 MPCM at a glance MPCM was prepared using phase inversion technique The surface area of MPCM is very high - 15 m 2 /g with a pore volume of cc/g MPCM is amorphous in nature Temperatures up to 100 C do not adversely affect the adsorption capacity of MPCM MPCM resin is found to be resistant to extreme ph conditions The structure of MPCM has been demonstrated to maintain its integrity when exposed to 50,000 Krad Co-60 gamma radiation 26

27 MPCM Key Properties MPCM has the capacity to adsorb up to 700 mg of Mo per dry gram compared to alumina that holds approximately 20 mg/g The elution efficiency of a MPCM based generator exceeds 80% of the 99m Tc generated Cost effective to prepare Adsorbs 99 Mo quickly and efficiently Handling and hydraulic properties similar to alumina facilitate generator manufacture 27

28 MPCM based 99 Mo/ 99m Tc Generator MPCM high adsorption capacity allows the use of neutron activated 99 Mo within a footprint similar to current generator designs Creates US Supply Chain Internationally creates local supply chain Does not require the use of uranium targets No orphan waste generated Cost competitive at existing price structure 28

29 Successful Technology Validation First set of independent tests conducted at POLATOM, the national center for nuclear research in Warsaw, Poland Reaffirmed previous testing Second set of tests conducted at the Missouri University Research Reactor (MURR) in Columbia, Missouri, USA Demonstrated 6.0 Ci Mo-99 in a column Natural Molybdenum 1.5Ci Mo-99/g of Proprietary MPCM resin higher elution efficiency (80%+) 29

30 Katrina Pitas Vice President Business Development, SHINE Medical Technologies

31 Modern, LEU-based, domestic Mo-99 production

32 SHINE Technology Overview A modernized approach to making Mo-99 Integrated production and refining SHINE irradiation unit is a hybrid Accelerator-based D-T neutron generator acts as spark plug Neutrons multiply in subcritical uranium sulfate solution, allowing for very high yield Plant capacity around two-thirds U.S. demand ( day Ci/week) Fission Mo allows use of existing supply chain, no changes to pharmacy practices Cost effective approach Fission process ensures access to other isotopes, including I-131 and Xe-133 Neutron Generator Subcritical Assembly

33 Facility Design Major facility design and community integration effort has taken place Preliminary design completed early 2013 Approximately 55,000 sq. ft. hardened production facility 8 irradiation units ensures high reliability, flexible production schedule Independent hot cell chains further increase reliability and flexibility 33

34 Regulatory SHINE noted as model applicant and moving at the speed of light by NRC Primary regulatory authority is the Nuclear Regulatory Commission (NRC) Submitted construction permit application in 2013 Approximately 4000 pages First application of its type to be docketed since the 1960s Have moved rapidly through application process Draft Environmental Impact Statement was issued in May On track for construction permit issuance late 2015/early 2016 The Commission has approved publication of a Direct Final Rule as one step addressing the construction permit application from SHINE. Others are not as far along in the process. -- Allison M. Macfarlane, NRC Chairman, August 27, 2014

35 NRC Construction Permitting Process Milestone Date Status Receipt of Construction Permit Application (Part 1of2) Receipt of Construction Permit Application (Part 2 of 2) Docketing of Construction Permit Application (Part 1 of 2) March 2013 May 2013 July 2013 Complete Complete Complete Environmental Scoping Meeting July 2013 Complete Environmental SiteAudit August 2013 Complete Issuance of Request for Additional Information on Environmental Report August 2013 Complete Milestone Date Status Issuance of Supplemental Requests for Additional Information on Preliminary Safety Analysis Report and Environmental Report Completion of Draft Environmental Impact Statement Completion of Safety Evaluation Report with Open Items Advisory Committee on Reactor Safeguards Subcommittee Meetings Advisory Committee on Reactor Safeguards Full Committee Meeting January 2015 March 2015 May 2015 July 2015 June 2015 October 2015 Complete Pending Complete Complete Underway Pending Docketing of Construction Permit Application (Part 2 of 2) Issuance of Request for Additional Information on Preliminary Safety Analysis Report and Environmental Report December 2013 September 2014 Complete Complete Publication of Safety Evaluation Report October 2015 Pending Publication of Environmental Impact Statement Mandatory Hearing on Construction Permit Application October 2015 TBD Pending Pending

36 Strategic Progress Market conditions continue to provide a unique opportunity for SHINE Supply agreements signed with GE Healthcare and Lantheus Medical Imaging in 2014 First agreements with a U.S.-based producer First supply agreements with a non-government producer Additional supply agreements under negotiation SHINE market entry coincides with NRU shutdown in 2018 and the end of Canadian emergency production

37 In Conclusion SHINE technology and process has several clear competitive advantages Demonstrated, Patented Technology Superior Economics Compatible with Existing Market Proven accelerator technology replaces nuclear reactor Avoids the use of weaponsgrade HEU completely U.S.-based, will avoid significant decay loss Operating costs much lower than reactor Substantially reduced material costs Product fits seamlessly into the existing supply chain Utilizes existing technetium generators Market validation supply agreements executed with two of the largest Mo-99 buyers

38 Jim Harvey Sr. VP & Chief Science Officer, Northstar

39 NorthStar s Technologies for Producing Mo-99 10/28/

40 Near Term and Long Term Solutions Near Term Solution (1H2016) o Missouri University Research Reactor (MURR) Contract in place effective March 2011, extended thru 2019 in 2014 o Will have the capability to produce >50% of the US requirement o Developing ORC and redundancy with Westinghouse Electric Company Long Term Solution (2017/2018) o NorthStar s electron accelerator methodology for the production of Molybdenum-99 o Will have the capability to produce >50% of the US requirement Once up and running both solutions will be used to supply not only the US market but also ROW These two approaches utilize NorthStar s RadioGenix technology in order to guarantee success 10/28/

41 Production of Mo99 NorthStar has been active in this option since 2009 o MURR originally produced Mo99 with nat-mo up until mid-1980 s NorthStar/MURR capable of producing up to 3,000+ 6D Ci per week o One target set; one or more irradiation cans, per week (60 6D Ci 3,000+ 6D Ci Mo99; nat or enriched Mo dependent) processed o Steady weekly production, and o Dedicated shipping to client pharmacies from Columbia, MO; with return of spent Mo99 solutions to Beloit, WI for recycle if enriched Mo98 used; otherwise dispose of after DNS Production start upon FDA approval of the RadioGenix system No licensing issues; within scope of MURR s current license No technical challenges 10/28/

42 Production of Mo99 via Reactor at MURR 10/28/

43 MURR NorthStar Dispensing Line #1 10/28/

44 MURR NorthStar Dispensing Line #2 10/28/

45 NorthStar Successful Integrated Production Run Announced May 5, 2015 that we successfully completed a full scale production run of 100 6D Ci that included: o o o o o o Target preparation Target irradiation Mo99 extraction/preparation Transfer to dispensing line Fill NorthStar Type A shipping vessels Ship overnight with receipt at facility within 8 hours Mount and run RGX successfully to produce Tc99m All microbiology and sterility data favorable Successful completion and validation critical to FDA approval 10/28/

46 Production of Mo99 via Electron Accelerator NorthStar has been active in this field since Nov 2007 o o NorthStar funded effort at RPI in early 2008 to validate the 1999 INL publication Produced small quantities of Mo99 in that study and validated calculated estimates and experimental results were comparable NorthStar facility will house electron linear accelerators capable of producing >3,000 6D Ci per week o o steady, redundant production on a daily basis Have completed 4 x 24hr irradiations at ANL with targets processed and resulting Mo99 shipped to NorthStar overnight for processing with RGX o 6.5 day irradiation scheduled in Sept 2015 o No major remaining technical challenges; optimizing the full process Facility location - Beloit, WI o Located immediately adjacent to a new power substation being built with NorthStar requirements incorporated in the design including redundant power from two separate transmission line sources 10/28/

47 RadioGenix 47

48 RadioGenix FDA Timeline October 2010 NorthStar met with the FDA to outline a path to NDA submission MURR submitted DMF for production via neutron capture in September 2012 NorthStar submitted RadioGenix (TechneGen) DMF in October 2012 January 2013 NorthStar submitted its NDA NorthStar received its Complete Response letter from the FDA on November 4, 2013 outlining deficiencies primarily in two areas o Microbiological Control o User Manuals NorthStar met with the FDA on February 27, 2014 to gain clarity on the CR letter o NorthStar has submitted to FDA its revised Microbiological Test Plan (MTP) for comment o Met with the FDA July 2, 2014 to MTP; appears to answer our questions NorthStar added ozone sterilization to the system and made other enhancements as a result NorthStar now generating data to support Amendment 11 to the NDA; to be submitted 4QTR15 10/28/

49 NorthStar Beloit Facility 49

50 Occupancy May 2015

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52 Waste Profile No uranium use (no Class C, GTCC or transuranic waste) thus all waste is Class A waste providing major technical and cost advantages o Tc99g requires monitoring in our waste profile 55 gal drum at 90 days decay will be <10% of limit o Other isotopes at disposal time (nat-mo targets): Initial 90d µci/ci Mo99 µci/ci Mo99 Sb-124 ( ) 3.96E E-06 Nb-92m ( ) 7.00E E-08 Nb-95 ( ) 2.13E E-08 Zr-95 ( ) 2.67E E-08 Cs-134 ( ) 6.67E E-09 10/28/

53 Selective Gaseous Extraction: A transformational Molybdenum-99production technology Tom Burnett President, Medical Isotopes, Nordion Sept 11, 2015

54 About Nordion Nordion is a health science company that provides marketleading products used for the prevention, diagnosis and treatment of disease. We ve been delivering safe, high-quality products to global customers for more than 60 years. To best serve the diversity of our customers requirements, we are organized into two business units Sterilization Technologies and Medical Isotopes. APPROXIMATELY 375 EMPLOYEES SUPPLY OVER 500 CUSTOMERS AROUND 30 PRODUCTS ACROSS MORE THAN 40 COUNTRIES

55 Nordion: Experts in the Critical Supply Chain (Mo-99) NUCLEAR REACTORS MEDICAL ISOTOPE PROCESSORS RADIOPHARMACEUTICAL MANUFACTURERS RADIOPHARMACIES AND HOSPITALS PHYSICIANS AND PATIENTS Irradiation of HEU targets to produce crude isotopes Purification of Mo-99 and distribution to global radiopharmaceutical manufacturers Tc-99m Generator manufacturing and distribution to radiopharmacies Unit dose compounding and distribution to hospital/departments Critical physiological diagnosis enabling informed therapeutic decisions Established, reliable facilities providing high-quality isotopes to global customers Specialty skills in operations, regulatory affairs and global logistics Manufacturing Mo-99 for 40 years

56 Nordion Future Mo-99 Supply Options Since 2008 Over 50 worldwide files/projects have been evaluated Both Reactor and Accelerator-Based Supply Selection Criteria 1. Non HEU-based technology/targets 2. Credible Partners 3. Leverages existing infrastructure/capabilities to drive efficiency 4. Commercial feasibility for Nordion and partners 5. Timeline - potential for commercialization in the near term

57 Nordion Current Mo-99 Supply Nordion s current supply chain utilizes the National Research Universal (NRU) reactor operated by Canadian Nuclear Laboratories (CNL) The NRU is scheduled to cease routine production of Mo-99 in November Government of Canada announced on February 6, 2015 its support of the extension of the NRU operations until March 31, 2018 to help support global medical isotope demand in the unexpected circumstances of shortages during this time. Nordion will maintain standby capability for processing Mo-99 from the NRU from Nov 1, 2016 to Mar 31, 2018 to mitigate potential global shortages and ensure processing capacity during a period of increased supply risk.

58 Nordion Announcement Feb 20, 2015 Partnership with General Atomics and the Missouri University Research Reactor (MURR) Mo-99 supply utilizing proprietary Selective Gaseous Extraction (SGE) technology Leverages existing reactor, processing facility and licensed shipping container infrastructure and capabilities Commercial production by the end of 2017

59 General Atomics Target and reactor systems design and manufacturing Trusted resource of hightechnology systems Experts in nuclear fuel cycle, including uranium mining and processing Experts in reactor design: GA TRIGA research reactors in operations around the world for over 50 years Developer of LEU technology utilizing novel reusable target design Highly Credible Partners Missouri University Research Reactor (MURR) Premium Reactor Operator and Research Center 10-megawatt facility; the largest university research reactor Operates 52 weeks a year 25-year history of successful and innovative radiopharmaceutical R&D and collaborations with industry Strong record of regulatory compliance (US NRC, US FDA) Experts in volume radiochemical processing and international shipping Nordion s partner in production of TheraSphere for over 20 years Nordion Premier Isotope Producer and Distributor Experts in Mo-99 purification into medical grade product since 1975 Strong record of regulatory compliance (US FDA, EMEA, Health Canada) cgmp/glp - licensed facility Global leading supplier of Mo- 99 with extensive marketing, sales & distribution expertise Global licensed transport container fleet

60 Missouri University Research Reactor: Proven Reliability Robust and Modular Design Source: MURR

61 Selective Gas Extraction: Reusable LEU Targets Step 1 Reusable LEU target irradiated; forms new radioisotopes Step 2 Gas introduced to target in-situ; desired isotopes are converted to volatile compounds Step 3 Gas extracted with desired isotopes and transported to collection system Mo-99 Solid Other solid products Isotope Gas Reusable LEU target

62 Key Advantages of SGE Technology Uranium waste and liquid waste greatly reduced (less than 10% of current process) High volume production up to 4,200Ci per week 52 weeks per year availability Mo-99 production flexibility production can be tailored to market demand 100% Compatible with existing Tc-99m generators and established distribution infrastructure North America based proximity to largest market Mo-99 production by SGE process is highly efficient relative to current and other proposed methods of Mo-99 production

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64 DOMESTIC MOLLY-99 PRODUCTION Moderator: Roy Brown, Sr. Director, Strategic Alliances, Mallinckrodt Pharmaceuticals Speakers: Carolyn Haass, Technical Program Director, Northwest Medical Isotopes Lou Centrofanti, President and CEO, Perma-Fix Environmental Services Katrina Pitas, Vice President Business Development, SHINE Medical Technologies Jim Harvey, Sr. VP & Chief Science Officer, Northstar Tom Burnett, President Medical Isotopes, Nordion