Regulatory Challenges Initiating Domestic Production of Mo99

Regulatory Challenges Initiating Domestic Production of Mo99 James T. Harvey Senior Vice President & Chief Science Officer NorthStar Medical Technologies, LLC 1800 Gateway Blvd Beloit, WI 53511 NorthStar Medical Technologies, LLC has, since 2007, been working towards developing a domestic production of Mo99. We are currently pursuing two parallel paths which will lead to a domestic production capability of Mo99. The first short term path uses the Missouri University Research Reactor (MURR) to produce Mo99 via irradiation of natural molybdenum targets. This route can also be transitioned to enriched molybdenum 98 targets in the future as market needs dictate. The second long term approach is to utilize electron accelerators to irradiate enriched molybdenum 100. Both approaches require a new type of generating system, NorthStar s RadioGenix system, for producing HSA Tc99m from LSA Mo99. This talk will discuss the regulatory challenges around bringing various aspects of both production processes to market.

NorthStar Medical Technologies, LLC presentation to ANS/NCCAAPM Symposium on the Tc-99m Crisis Joint NorthStar Mo99 Production Programs 29 October 2015 4/16/2013 Copyright 2015 NorthStar Medical Radioisotopes. LLC 1

Topics NorthStar s technology for producing Mo-99 Scientific and Technical Challenges Regulatory and Licensing Challenges o FDA o DOT/IATA o Other challenges Discussion 11/3/2015 Copyright 2015 NorthStar Medical Technologies, LLC 2

Near Term and Long Term Solutions Near Term Solution neutron capture Missouri University Research Reactor It is expected that this solution will eventually be capable of producing at least 50% of the US demand Announced MOU with Westinghouse Electric Corporation (WEC) in September to investigate redundant production and Outage Reserve Capacity (ORC) Long Term Solution photon transmutation NorthStar s electron accelerator methodology for the production of Molybdenum-99 Also will be capable of producing at least 50% of the US demand Once up and running both solutions will be used to supply not only the US market but also ROW. These two approaches require NorthStar s RadioGenix technology 11/3/2015 4 Copyright 2015 NorthStar Medical Technologies, LLC

Production of Mo99 Neutron Capture NorthStar has been active in this option since 2009 o MURR originally produced Mo99 with nat-mo NorthStar/MURR capable of producing up to 3,000+ 6D Ci per week o SA of Mo99 1Ci/g 6Ci/g potentially, 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 Up to 1,000 6D Ci nat-mo targets starting in 2016 o steady weekly production, and Production upon FDA approval of the RadioGenix system No licensing issues Scientific/Technical Challenges NONE NorthStar made improvements to an already established production route to increase production capabilities 11/3/2015 Copyright 2015 NorthStar Medical Technologies, LLC 6

Production of Mo99 via Electron Accelerators Scientific/Technical Challenges Is route actually viable? o NorthStar funded effort at RPI in early 2008 to validate the 1999 INL publication o Produced small quantities of Mo99 in that study and validated calculated estimates and experimental results were comparable o Yes, it will work! Can we make a commercially viable amount at a competitive costs? o Theoretically, with a pair of electron accelerators operating at 42 MeV and 120 kw on target SA of Mo99 ~10Ci/g potentially one target set (~500 6D Ci Mo99) processed each day steady, redundant production on a daily basis weekly production of >3,000 6D Ci possible Yes, it will work (theoretically at least)! 11/3/2015 Copyright 2015 NorthStar Medical Technologies, LLC 14

Production of Mo99 via Electron Accelerators Scientific/Technical Challenges Can we cool the target with this much power density? o o o o Not with water, peroxide radicals formed by the free electrons in the water at the target face actually dissolve the target slightly Helium gas was tested in 2012, can cool target Just completed a series of 5 irradiations at ANL producing Ci quantities of Mo99 by this process Yes, we can cool the target! Are commercial electron accelerators available? o o o o Two potential suppliers, both with established >90% duty cycles NorthStar chose not to develop or use new or R&D electron accelerators must be a commercially available machine to meet required reliability E-beam sterilization Gem stone coloring Reasonable costs Yes, available at a reasonable cost! 11/3/2015 Copyright 2015 NorthStar Medical Technologies, LLC 15

Production of Mo99 via Electron Accelerators Scientific/Technical Challenges Blower Filter Mass Flow Meter Pressure Vessel Motor Target Heat Exchangers 11/3/2015 Copyright 2015 NorthStar Medical Technologies, LLC 17

RadioGenix Generating System RadioGenix allows the use of Low Specific Activity Mo99 Output is High Specific Activity Tc99m Meets all USP/EU Pharmacopeia requirements Fully automated system Platform system capable of use with other parent/daughter isotopes pertinent to nuclear medicine o Ac225/Bi213 o W188/Re188 o Ge68/Ga68 5 th Generation of the technology developed over a 20 year period NorthStar s primary regulatory challenge FDA approval of NorthStar s New Drug Application (NDA) 11/3/2015 Copyright 2015 NorthStar Medical Technologies, LLC 23

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 in March 2013 from FDA a PDUFA date of November 4, 2013 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 submitted to FDA its revised Microbiological Test Plan (MTP) for comment o Met with the FDA July 2, 2014 for MTP review NorthStar added ozone sterilization to the system and made other enhancements as a result Met with FDA 2X in 2015 to review changes and seek any additional guidance NorthStar now generating data to support Amendment 11 to the NDA; to be submitted 4QTR15 11/3/2015 Copyright 2015 NorthStar Medical Radioisotopes, LLC 27

Type A Source Vessel Source Vessel passed all required DOT/IATA testing Packaged similar to current generators on market Has similar form and weight as current generators Redesigned to all tungsten source vessel o Completed all required DOT/IATA testing last month Now have both DU and W source vessels available 11/3/2015 Copyright 2015 NorthStar Medical Technologies, LLC 34

Other Licensing/Regulatory Challenges RAM Licenses o No new licenses required for neutron capture at MURR o Wisconsin is an agreement state and will license NorthStar facilities in WI NorthStar will be licensed by two section of WI-DHS Accelerators licensed by the machines group Received machines license in 2013 Allows possession of up to 16 electron accelerators at our Beloit, WI facility Facilities handling radioactive materials licensed by the materials group NorthStar has three (3) facilities in WI currently licensed for handling radioactive materials Two (2) in Madison Beloit Gateway facility (DU only) 11/3/2015 Copyright 2015 NorthStar Medical Technologies, LLC 35

Other Licensing/Regulatory Challenges National Environmental Policy Act (NEPA) o Completed August 2012 o Signed off at DOE with a FONSI August 24, 2012 o Areas examined Water resources Air quality National Ambient Air Quality Standards Ecological resources Includes Federal and WI listed species Noise Land use Waste management Visual impacts Human and health effects potential Socioeconomics Cultural resources Infrastructure impacts Power, water, sewer needs/impacts 11/3/2015 Copyright 2015 NorthStar Medical Technologies, LLC 36

Other Licensing/Regulatory Challenges Tellico Dam on the east Tennessee River o $550,000,000 in todays dollars! 11/3/2015 Copyright 2015 NorthStar Medical Technologies, LLC 38 Copyright 2015 NorthStar Medical Technologies, LLC

Other Licensing/Regulatory Challenges OSHA o Requires compliance to Federal OSHA requirements 29CFR1904 & 29CFR1910 EPA/WI-DNR o WI-DNR uses Federal EPA guidelines o Chemicals to be used in the Beloit facility Large Quantity Generator (LQG): >1,000 Kg/month 1 Small Quantity Generator (SQG): >100 but <1,000 Kg/month Conditionally Exempt Small Quantity Generator (CESQG): <100kg/month NorthStar will meet EPA Conditionally Exempt Small Quantity Generator KOH is largest used chemical @ ~25kg/month 1) Limit hazardous waste generated per month not including defined acute hazardous waste 11/3/2015 Copyright 2015 NorthStar Medical Technologies, LLC 39

Other Licensing/Regulatory Challenges Local building requirements o o o o Site Plans: City of Beloit (Planning, Engineering, Water, Fire, Building Inspection, Assessor) Architectural Plans & Materials: City of Beloit Planning Storm water Plans: Wisconsin DNR & City of Beloit Engineering Building Plans: Building & HVAC and Wisconsin Dept. of Safety & Public Services (Plumbing) 11/3/2015 Copyright 2015 NorthStar Medical Technologies, LLC 40

Summary Two production methods for Mo99 without use of uranium Scientific and Technical challenges met Numerous licensing and regulatory challenges chief of which for NorthStar is FDA approval on our NDA 11/3/2015 Copyright 2015 NorthStar Medical Technologies, LLC 44