Regulatory Challenges in Production of Medical Radioisotopes James T. Harvey NorthStar Medical Radioisotopes, LLC, Madison, WI 2014 OAS Annual Meeting August 27, 2014 Chicago, IL USA 11/28/2018 Copyright © 2013-2014 NorthStar Medical Radioisotopes, LLC

Copyright © 2013-2014 NorthStar Medical Radioisotopes, LLC Topics 99Mo Background Market Need/Options NorthStar 99Mo Production Efforts New Generator System New Type A Shipping System NorthStar Licensing Needs Discussion 11/28/2018 Copyright © 2013-2014 NorthStar Medical Radioisotopes, LLC

Copyright © 2013-2014 NorthStar Medical Radioisotopes, LLC Mo99 Background 99Mo is parent of 99mTc 99mTc is the most widely used medical radioisotope ~75% of all diagnostic radionuclide based test majority of these nuclear stress testing for cardiac function early development and use of 99mTc can be traced to the late 1950’s/early 1960’s World need for 99Mo is about 50,000 Ci per week (70,000 Ci – 90,000 Ci EOI) US market consumes ~50% of worldwide supply ~50,000 procedures each day in the US using 99mTc No US based 99Mo production currently Reactor based production Irradiation of HEU targets; proliferation concern; conversion to LEU targets underway 235U(n,f)MFP; ~6% 99Mo yield; remaining mostly waste Production must be continuous 24/7/365 11/28/2018 Copyright © 2013-2014 NorthStar Medical Radioisotopes, LLC

Current Market Need/Options Establish a reliable supply of 99Mo, preferably a US based supply Options: Traditional reactor based approach irradiating LEU targets Traditional reactor irradiation of stable molybdenum targets; either natural molybdenum or enriched 98Mo (NorthStar in 2015) New concepts Power reactors utilizing stable molybdenum targets Solution reactors utilizing LEU as fuel Accelerator based production utilizing stable enriched 100Mo targets (NorthStar in 2016/2017) utilizing LEU target material 11/28/2018 Copyright © 2013-2014 NorthStar Medical Radioisotopes, LLC

NorthStar Neutron Capture Production Efforts NorthStar Medical Radioisotopes using MURR reactor irradiating 98Mo(n,γ) 99Mo Original 99Mo production route before “fission moly” capable of producing a specific activity of 99Mo approaching ~5 Ci/g target material Low level Class A waste only licensed under MURR license 99Mo generated does not fit into current distribution stream requires new generating system to use product and generate 99mTc in activity concentrations typical in nuclear pharmacies 11/28/2018 Copyright © 2013-2014 NorthStar Medical Radioisotopes, LLC

NorthStar Accelerator Production Efforts NorthStar Medical Radioisotopes using electron accelerator’s irradiating 100Mo(γ,n) 99Mo studied in depth at INL in mid-1990’s (Bennett, et.al.) first production tested by NorthStar at RPI in 2008; demonstrated at mCi scale; commercial scale testing in process capable of producing a specific activity of 99Mo approaching ~10 Ci/g target material Low level Class A waste only licensed as an accelerator by an WI (Agreement State); no direct NRC licensing role 99Mo generated does not fit into current distribution stream requires new generating system to use product and generate 99mTc in activity concentrations typical in nuclear pharmacies 11/28/2018 Copyright © 2013-2014 NorthStar Medical Radioisotopes, LLC

NorthStar Accelerator Efforts Beloit LINAC Facility 11/28/2018 Copyright © 2013-2014 NorthStar Medical Radioisotopes, LLC

NorthStar Accelerator Efforts Beloit LINAC Facility 11/28/2018 Copyright © 2013-2014 NorthStar Medical Radioisotopes, LLC

NorthStar Accelerator Efforts Beloit LINAC Facility 11/28/2018 Copyright © 2013-2014 NorthStar Medical Radioisotopes, LLC

NorthStar Accelerator Efforts Beloit LINAC Facility 11/28/2018 Copyright © 2013-2014 NorthStar Medical Radioisotopes, LLC

NorthStar Accelerator Efforts Beloit LINAC Facility 11/28/2018 Copyright © 2013-2014 NorthStar Medical Radioisotopes, LLC

New Generator System - RadioGenix™ 11/28/2018 Copyright © 2013-2014 NorthStar Medical Radioisotopes, LLC

History of RadioGenix Early development initiated in mid-1990’s Automated Radionuclide Separation System (ARS) first prototypes built in 2000/2001 time frame. This work was supported by the Comer Foundation. Early prototypes used demonstrate the technology viability Early prototypes evaluated by several radiopharmaceutical industry and university groups NorthStar licensed IP and received possession of all prototypes in 2005 NorthStar further developed IP to next generation (ARSII) in 2006/2007 Input from key researchers at MSKCC and AECOM ARSII used in several pre-clinical R&D efforts in nuclear medicine Improvements identified with ARSII usage incorporated into V.1 of RadioGenix (f.k.a TechneGen) in 2011/2012 time period RadioGenix V.2 now being built incorporating enhancements learned during initial NDA preparation and customer focus groups RadioGenix is now in it’s 5th generation of continued improvements 1515 11/28/2018 Copyright © 2013-2014 NorthStar Medical Radioisotopes, LLC

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 Microbiological control User Manuals NorthStar met with the FDA on February 27, 2014 to gain clarity on the CR letter NorthStar has submitted to FDA its revised Microbiological Test Plan (MTP) for comment Met with the FDA July 2, 2014 to MTP NorthStar generating necessary data for an Amendment at this time 11/28/2018 Copyright © 2013-2014 NorthStar Medical Radioisotopes, LLC 16

Type A Source Vessel NorthStar will ship source vessels to clients loaded with up to 19 Ci 99Mo System designed to allow client to mount received source vessel directly without any manipulation of source material inside Thus a source vessel that would also meet shipping requirements for up to 20 Ci 99Mo was designed and tested Size is dictated by the volume of the source material 11/28/2018 Copyright 2014 NorthStar Medical Technologies, LLC 17

Type A Source Vessel 11/28/2018 Copyright 2014 NorthStar Medical Technologies, LLC 18

Type A Source Vessel 11/28/2018 Copyright 2014 NorthStar Medical Technologies, LLC 19

Type A Source Vessel 11/28/2018 Copyright 2014 NorthStar Medical Technologies, LLC 20

Type A Source Vessel Certification Tested to meet General Design Requirements as given in 49CFR173.410 and 49CFR173.412 Testing procedures given in 49CFR173.465 and 49CFR173.466 requirements ProPack designed the package and tested all requirements including liquid dispersal All tests excluding 49CFR173.412(j)2 SPEC tested to meet 49CFR173.412(j)2, any test that required a radioactive source Dr. Roy Parker advised NorthStar during this process 11/28/2018 Copyright 2014 NorthStar Medical Technologies, LLC 21

Type A Source Vessel Certification 11/28/2018 Copyright 2014 NorthStar Medical Technologies, LLC 22

Type A Source Vessel Certification 11/28/2018 Copyright 2014 NorthStar Medical Technologies, LLC 23

Type A Source Vessel Certification 11/28/2018 Copyright 2014 NorthStar Medical Technologies, LLC 24

Type A Source Vessel Certification 11/28/2018 Copyright 2014 NorthStar Medical Technologies, LLC 25

Type A Source Vessel Certification ProPack Summary The subject package successfully met the test criteria of the sections of the CFR 49 § 173.465 and § 173.466. SPEC Results Passes 49CFR173.412(j)(2) 11/28/2018 Copyright 2014 NorthStar Medical Technologies, LLC 26

NorthStar Licensing Needs Initial R&D License from WI-DHS needed in Engineering Development facility in Madison, WI Low level license to support product development – 50 Ci 99Mo; 999 Kg DU License (Service Provider) needed for 2nd Madison, WI facility for storage & recovery of Type A shipping vessels – also 50 Ci 99Mo limit; includes DU limit of 3,000 Kg Unload spent 99Mo source vessels to recycle source vessels into the system Class A waste generated; disposed of by licensed firms under contract to NorthStar Initial license (machines) for accelerators for Beloit facility NorthStar can possess up to 16 accelerators at the Beloit site Cannot produce “material” without corresponding materials license 11/28/2018 Copyright 2014 NorthStar Medical Technologies, LLC 27

NorthStar Licensing Needs Initial building in Beloit, WI will ultimately handle 2nd Madison facility role New/transfer license shutting down 2nd Madison facility, decommission and remove from license As Beloit facility expands; increase Beloit site license In late 2015/2016 time frame, start processing Mo99 from enriched molybdenum targets via neutron capture irradiations; initial need in the low hundreds Ci 99Mo for process development/validation Each target set = ~1,200-2,400 Ci Mo99 Up to 15,000 Ci 99Mo per week possible late 2016/early 2017 Concurrently, as accelerator facility completed, additional site licensing expansion needed First accelerators start trials in late 2016 Full scale accelerator production of 99Mo by late 2017/early 2018 Up to an additional 20,000 Ci 99Mo production level in accelerator facility possible 11/28/2018 Copyright 2014 NorthStar Medical Technologies, LLC 28

NorthStar Licensing Needs Fourth building on site for production/processing other medical radioisotopes 225Ac (est: <10 Ci per month) 188W (est: <100 Ci per qtr) 68Ge(est: <100 Ci annually) Timing is still TBD but currently 2017/2018 timeframe but market demands could accelerate especially for 225Ac May request licensing of high energy (200+ MeV) proton accelerator in future also; 2018+ 11/28/2018 Copyright 2014 NorthStar Medical Technologies, LLC 29

Additional Regulatory Impact FDA approval of RadioGenix NDA NorthStar is committed to the FDA in the NDA application to provide the following: Initial user training and certification Specific Administrator training Annual update training and re-certification of Users Service controls – who can perform NRC considering issuance of a Guidance Document for RadioGenix RadioGenix is the first new piece of technology in the 99Mo market segment in more than 20 years Unique method of generating 99mTc More importantly – a platform technology applicable to other nuclear medicine radioisotopes Incorporate NorthStar’s commitment to FDA Guidance may be specific to the isotopes of use 11/28/2018 Copyright 2014 NorthStar Medical Technologies, LLC 30

Copyright © 2013-2014 NorthStar Medical Radioisotopes, LLC Summary NorthStar with support from NNSA via Cooperative Agreements to develop a domestic source of 99Mo via two routes Neutron Capture Electron accelerators Both require the generating system – RadioGenix; require new Type A shipping system NorthStar expects domestic production of 99Mo Via neutron capture in 2nd half 2015; 3,000 6D Ci in 2016/2017 Via electron accelerators in 2017/2018 at 3,000+ 6D Ci NorthStar has a separate production efforts underway in other medical radioisotopes Numerous licensing/regulatory interactions next 5+ years 11/28/2018 Copyright © 2013-2014 NorthStar Medical Radioisotopes, LLC

Copyright © 2013-2014 NorthStar Medical Radioisotopes, LLC Discussion 11/28/2018 Copyright © 2013-2014 NorthStar Medical Radioisotopes, LLC

Regulatory Challenges in Production of Medical Radioisotopes James T. Harvey NorthStar Medical Radioisotopes, LLC, Madison, WI 2014 OAS Annual Meeting August 27, 2014 Chicago, IL USA 11/28/2018 Copyright © 2013-2014 NorthStar Medical Radioisotopes, LLC