MIRP) March 31, 2015 I

5-Year Strategic Plan Brookhaven National Laboratory, Medical Isotope Research and Production Program (MIRP) March 31, 2015 I. Summary The mission of the BNL Isotope Program is to produce and sell (through the National Isotope Development Center - NIDC) medical and industrial radioactive isotopes generally not available elsewhere, and provide related isotope services. Our highest priority goal is the desire to be a radioisotope producer of outstanding quality and in full compliance with current Good Manufacturing Practice (cGMP) protocols. To support this effort it is necessary to maintain and improve the current infrastructure. We also strive to perform outstanding research in the development of radioisotopes for medical and industrial purposes that will further the benefits of nuclear science to society. For the future, it is essential to conduct the necessary R&D on new and improved isotope production and processing techniques in response to changing user community needs and feedback from national advisory bodies, such as NSAC. The present facilities, operations and authorized staff support a robust program of year round availability of needed radioisotopes and a program of research for the future. In this strategic plan we aspire for the BNL Isotope Program to enhance its role in the DOE complex as a significant distributor of radioisotopes for medicine and industry and the development of the next generation of radioisotopes for the nuclear science community. II. Radioisotope Program Overview This program uses the Brookhaven Linac Isotope Producer (BLIP), and the associated radiochemistry laboratory and hot cell complex in Building 801 to develop, prepare, and distribute to the nuclear medicine community and industry some radioisotopes that are difficult to produce or are not available elsewhere. The BLIP, built in 1972, was the world’s first facility to utilize high energy protons for radioisotope production by diverting the excess beam of the 200 MeV proton LINAC to special targets. After several upgrades BLIP continues to serve as an international resource for the production of selected isotopes that are generally unavailable elsewhere. The overall effort entails:

1) target design, fabrication and testing 2) irradiations 3) radiochemical processing by remote methods in the 9 hot cells of the Target Processing Laboratry (TPL) 4) Quarantining of materials and Quality Control (which includes chemical and radiochemical analysis) 5) waste disposal 6) facility maintenance 7) new isotope and application development 8) isotope packaging, and shipping 9) service irradiations (without chemistry) upon request and as appropriate with costs recovered

III. Present Facilities and Capabilities

The current and five year goals of the BNL Medical Isotopes Research and Production Program (MIRP) are: 1) To conduct research and development into production of research radioisotopes in response to changing needs of the medical community taking into account feedback from National Isotope Development Centre (NIDC) and national advisory bodies, such as the National Academy of Science and the Nuclear Science Advisory Committee (NSAC).

225 Research radioisotopes currently under investigation include Ac (alpha emitter, t1/2 = 10 67 72 days), Cu production at moderate proton energies (< 45 MeV), As (positron emitter, t1/2 = 44 44 26 hour), Ti (gamma emitter, t1/2 = 60 yr; parent to positron emitter Sc, t1/2 = 3.35 hour), 191,195m,188 Pt (gamma emitter, t1/2 = 2.83 days; auger emitter t1/2 = 4.02 days and gamma 186 emitter, t1/2 = 10.2 days, respectively) and Re (beta emitter, t1/2 = 3.72 days).

2) To produce and sell medical and other industrial radioisotopes generally not available elsewhere. The current portfolio (2015) of radioisotopes sold from BNL (through NIDC) is summarized in Table 1 below.

Table 1. Radioisotopes produced using MIRP facilities and sold through NIDC as at start 2015. Radioisotope Characteristics Demand 82 Sr gamma emitter, t1/2 = 25.34 days high 63 Ni* beta emitter, t1/2 = 101.2 years high 55 Fe* low energy X-rays, t1/2 = 2.74 years) moderate 65 Zn Gamma emitter, t1/2 = 243.9 days) moderate 83 Rb Gamma emitter, t1/2 = 86.2 days) moderate 86 Y Gamma emitter, t1/2 = 14.74 hours) low 67 Cu Gamma and beta emitter, t1/2 = 2.58 days) low 7 Be Gamma and beta emitter, t1/2 = 53.22 days) low * The 63Ni, 55Fe isotopes are produced in the HFIR at ORNL are shipped to BNL for final preparation for distribution. As of Janurary 2015 63Ni will no longer be dispensed at BNL as this isotope will be dispensed at ORNL.

The MIRP facilities can be divided into three distinct areas or capabilities: 1) Irradiation capabilities [which includes Brookhaven Linac Isotope Producer (BLIP) and supported by 2.0 FTE BLIP Operators] 2) Chemical processing capabilities [which includes Target Processing Facilities with 7 hot- cells, one chemistry, 3 radiochemistry and instrumentation laboratory, supported by 3 TPL Operators and a 4th TPL operator was hired this month] 3) Research capabilities [which include four radiochemistry laboratories and 2-4 Hot-Cells, supported by 3 FTE scientists]

By the far the most demanding requirements for the MIRP program come with the production of radioisotopes to meet cGMP requirements and or current Good Clinical Research Practices (cGRCP). Compliance with cGMP is essential for the production of 82Sr, an Active Pharmaceutical Ingreditent (API) use in the production of the commerical available 82Sr/82Rb generator. The 82Rb is used in Positron Emission Tomography (PET) cardiac imaging. Long term, compliance with cGRCP is potentially required if the large scale production of the 225Ac is implemented and it is used in human clinical trials of radiotherapeutic agents.

An overview of capabilities in each area will be summarized below. The current status, improvements implemented in FY14/FY15 and identified deficiencies and single point failures that require attention over the next 5 years (FY2015 - FY2020) are also presented. BLIP-irradiation capability The BLIP was constructed in 1972 and was the world’s first facility to utilize high energy protons for radioisotope production. BLIP utilizes excess beam capacity of the 200 MeV Linear Accelerator (Linac) that injects protons into the Booster synchrotron for injection into the AGS then RHIC. (see Figure 1). The Linac and is capable of accelerating H- ions to produce 66, 90, 118, 140, 162, 184 or 202 MeV protons at 37-48 mA current for 425 μs duration with a 6.67 Hz repetition rate. Averaged maximum intensity of 115 μA was routinely reached in FY2014. In 2015 FY, with the intial phase of the Linac Intensity Upgrade project complete, the Linac has reached currents of 142 μA.

At present, an administrative limit of 115 A has been placed on the beam current to BLIP due to target heating considerations. Once the Raster Project (described later in this document) is complete in 2016 the target beam heating problem will be resolved so the full Linac beam current can be utilized, subject to the usual limitations when proton beams are used in RHIC. When running concurrent with the RHIC polarized proton program BLIP receives about 90% of the available beam pulses.

A 30m transport line delivers the protons to a shielded target area for radioisotope production. The target area at BLIP consists of an underground 2.44 m diameter tank containing sand shielding, a 9.2 m high by 40 cm diameter shaft filled with water and a 9.2 m high by 20cm diameter inspection shaft (see Figure 2). A hot-cell, situated over the inspection shaft, is used to transfer the two target assemblies boxes, to and from the irradiation area. The target boxes are immersed in a water tank at the base of the shaft and cooling water is forced past each face of the targets and degraders in each box.

BLIP contains a single hot-cell for delivery of targets to the beam line for irradiation. The building floor layout is shown in Figure 3 and is divided into three distinct areas:

1) the Hot Cell room (where targets are loaded and removed)

2) the Garage room [where monitoring equipment (air sampling for above hot-cell) and Health Physics shielded area for monitoring contamination and the access to target cooling water storage is decayed prior to disposal]

3) the Control Room (where operation of beams is controlled by in-house design LabView software).

Personel access to building is through the Garage (note there are a number of exits door to the building), most of the irradiated targets are removed from the hot cell into a lead cask and transported by fork lift to the TPL for processing. There are no processing capabilities at the BLIP facility. In 2014, in an effort to reduce cost and handling time of moderately activated irradiated materials (foils), a new transfer process was developed that allows the transfer of low level targets in Biodex containers in motor vehicles to the TPL.

The BLIP facility has been upgraded twice, in 1986 and 1996. There are two upgrades in progress that will (and have) improved the beam to BLIP, one to the Linac (Linac Intensity Upgrade) and the other an upgrade to the BLIP beam line (BLIP Raster Upgrade). These upgrade projects are managed by the C-AD Accelerator Division as Accelerator Improvement Projects (AIP’s) and are funded by the DOE Isotope Program Office. The status of these upgrades follows:

Figure 1. Aerial view of Linac relative to BLIP and TPL facilities at BNL

Figure 2. BLIP target shaft Figure 3. Building 931, BLIP, floor layout

1) BLIP Raster Project:

This $4.5M project provides a 5 kHz beam raster system with new beam instrumentation. With this the BLIP targets will be ably to handle the full beam presently available from the Linac, an increase from 115 A (administrative limit) to 142 A (present Linac maximum intensity) and >200 A that could be available with future Linac intensity upgrades. The project began in November 2013 and is on track for a May 2016 early completion date. The new beam line instrumentation was installed before the start of the 2015 BLIP run and, except for one faulty current transformer, all instrumentation performed as planned. The Raster magnet will be installed during the 2015 shutdown period and commissioned in 2016. The components of the Raster Project are shown in Figure 4.

2) The Linac Intensity Upgrade Project:

This $671K project provides for an increase in beam current from the Linac from 125 to 140 A and an evaluation of a potential beam intensity increase to 250 A (X2). The project began in April 2014 and comes with a planned completion date of September 2016. To date, the available current has reached 142 A, so the intensity goal has been exceeded. The evaluation of a possible X2 intensity upgrade is on schedule with all milestones completed on time. If the X2 intensity proves to be feasible with a reasonable cost and schedule this project should become the next major proposed upgrade since with completion of the Beam Raster Project the BLIP targets should be able to utilize the full X2 beam current. A possible timeline is 2016 for a go-nogo decision based on cost and schedule followed by funding beginning in 2017.

Figure 4. Components of the BLIP Raster Upgrade Project

TPL - Chemical processing capabilities

After irradiation targets are transported in a 5280 pound lead shielded container approximately 0.25 mile to the Target Processing Laboratory in building 801. This facility contains 9 hot cells, three 500 gallon tanks in a basement shielded room for aqueous radwaste storage, 6 radiochemistry development labs and two QC/QA labs with a total of 14 fume hoods, and an instrument room with modern analytical equipment for chemical and radiopurity determinations. A layout of the TPL facility is shown in Figure 5 . The TPL has a floor area of 10,776 sq. ft. and is comprised of 6 laboratories dedicated to research, 2 hot-cell for high radiation damage research studies (room 66c) and 3 hot-boxes for processing research and industrial radioisotopes. The main TPL (room 66) area is 1864 sq. ft. and contains a bank of 6 hot-boxes (HB1- HB6) and 1 hot-cell (HC1).

The areas dedicated to manufacture of 82Sr API are outlined below:

1) Quality Control (QC) and Quarantine Lab (Rm 52) is used to quarantine material received prior to QC testing and the storage of starting and intermediate materials. 2) Intermediate laboratory (Rm 58) is used for the preparation of intermediates, washing of components used in the manufacturing process and securing released materials and equipment such as hot-plate stirrers used in the production of 82Sr API. 3) Hot box 2, 4 and 6 (back up hot-cell for 82Sr) are dedicated to processing and dispensing of 82Sr API. The hot cell 1 is shared with other activities such as target can opening, and the packaging and removal of waste. 4) QC Analysis Lab (Rm 68) is used to analyze the 82Sr final product by ICP-OES and Gamma spectrometry. The room is temperature controlled and air is supplied to specifically support the ICP-OES and an ICP-MS. 5) Dispensing and Packaging Area (Rm 66) is used to transfer sealed vials containing 82Sr API to lead pigs and placing them in Biodex containers for transport to customer.

Air supply to TPL areas is provided by air handling unit housed in the mechanical equipment room on the second floor of Bldg. 801. The HVAC is part of the original building construction (1940s). Two new air handler units were installed in FY2011. Outside air is drawn in and initially filtered by 2 inch pleated filter (Merv 8; 3—35% efficient) responsible for filtering large particles. The second in-line is a filter (a 12 inch cartridge filter Merv 18; 95% efficiency) used to remove smaller particles, bacteria and dust. The air handling unit is also used for controlling temperature (at 70ºF) and humidity (to <50%).

The Air-Flow in the TPL is designed to:

1) Protect staff from exposure to volatile radioactivity. 2) Reduce environmental radioactive contamination. 3) Reduce contamination of 82Sr API manufacturing areas.

The hot cells are maintained under negative pressure. The air is exhausted from the hot-cells through the acid scrubber, which is designed to capture volatile radioactive fumes. The vented air then passes through the HEPA filter bank located outside the west wall of Bldg. 801. The TPL (room 66) has a number of radiation monitors, fitted with alarms to alert staff, if there is any migration of radioactivity. Due to exhaust fan configurations for the TPL, only three hot-cell/boxes can be used for processing involving evaporations at any one time. Hence all processing of irradiated targets needs to be carefully coordinated between production and research to ensure no more than three operate at any one time.

This program also is involved in non-isotope work funded by the DOE Office of High Energy Physics and Office of Nuclear Physics. This effort entails irradiating a wide variety of materials in BLIP, chosen as candidates for use as either targets, magnet horns, or collimators in future for very high power high-energy accelerators. After irradiation the materials are transported to our hot cells and measurements of tensile strength, ductility and coefficient of thermal expansion and thermal conductivity are performed. Some recent radiation damage studies were carried out on components of interest to the Facility for Rare Isotope Beams (FRIB) at Michigan State University and the Large Hadron Collider (LHC). These irradiations are only accommodated if they are compatible with ongoing isotope production and research activities. This effort utilizes the hot cell resources available in room 66C (Research Hot Cells in Figure 5) and may in the future be displaced by research needs of the 225Ac project.

Figure 5. The Target Processing Laboratory

Summer School in Nuclear and Radiochemistry

This program also hosts the Summer School in Nuclear and Radiochemistry, funded by DOE and previously sponsored by the American Chemical Society. This is an an intensive 6 week undergraduate lecture and laboratory course with students competitively selected from all over the U.S. Twelve students receive both lecture and lab course credit from Stony Brook University. Two or three German radiochemistry students from the University of Mainz also audit the course. This is a very successful program, now entering its 25th year at BNL. There is a large class room, and chemistry lab available in our building 801 and the students use the low level counting room for the course. Neverthess, there is still a significant national lack of graduate-level training in nuclear and radiochemistry that this undergraduate course does not address. The BLIP program could address this need given the additional necessary resources. Funding for this school was in jeopardy up until late January 2015. DOE successfully argued to restore funding so the school will once again be hosted by BNL this summer.

IV Risk assessment of the BLIP and TPL facilities

The TPL and BLIP facilities are old, and as such require regular and extensive maintenance and/or replacement of components. We have assessed infrastructure and capabilities in both TPL and BLIP to determine areas of single point failure that could result in termination or serious delay in Sr-82 production and R&D activities. Single Point Failures:

1. Linac Tube Inventory

The Linac uses power amplifier tubes (7835’s) that are only available from a single source worldwide. With this it is necessary to maintain an adequate tube inventory to allow operation a few years into the future to guard against the sole source either deciding to not to continue production of the tubes or simply going out of business. Presently 15 tubes are held as spare inventory, paid for by RHIC operating funds. Thirteen of the tubes are dedicated to RHIC operation, and 2 additional tubes provide the same level of risk protection to the BLIP program. The RHIC FY2015 operating budget does not, however, allow for the maintenance of this 15 tube 5-year inventory for combined RHIC and BLIP operation, leaving RHIC and BLIP operations vulnerable to the risk of the 7835’s becoming unavailable. This risk can be mitigated by providing BLIP funds to support the purchase of two 7835 tubes to add to the Special Process Spare (SPS) inventory bringing the total back to 15, at a one-time cost of $520,000. We request that these funds be made available as new funds.

2. ICP-OES

Sr-82 final product is released upon stable metal analysis using ICP-OES (among other tests). Currently we have only one instrument that is capable of performing that task. In an event of an instrument failure, final product release would be delayed until the instrument is repaired. We have a contract for emergency repair with the manufacturer (Perkin-Elmer) which promises someone will be there to do the repair within 24 hours but there is no guarantee that the repair can be acomplished in 24 hours. The most prudent approach is to re-commission the older ICP-OES located in room 2- 57 (at a cost of about $20,000). If that ICP-OES is beyond repair, a new ICP-OES would cost about $120,000 to purchase and install including ventilation. An additional benefit to having two ICP- OES is that one of them could be dedicated to alpha work once Ac-225 work commences at BNL. This would allow for better contamination control between isotope batches. The present plan is to restore the old ICP-OES if possible this year using operations funds. If the device cannot be made operational with a reasonable cost and effort, new funds will be requested to purchase a new instrument.

3. Room 66 Ventilation Panel

The building 801 Accelerator Safety Envelop (ASE) includes credited controls for the ventilation system. One of the criteria is the TPL hot cells, hot boxes, radioactive fume hoods and their associated ductwork must have negative pressure between these facilities and the room and outdoors in order to allow target and radioactive materials processing operations. These systems are maintained by the laboratory Facilities and Operations Division. Air flow is monitored from the Ventilation Panel located in Room 66. The panel’s differential pressure readings are, however, not

9 accurate. In order to help insure compliance with the ASE, and therefore perform radioisotope processing, the panel should function properly so the ventilation can be accurately monitored and to do this we have been advised that new sensors should be installed. All the plumbing would be retained and new differential pressure (DP) sensors on the hot cell/hot box ventilation systems would be installed. In addition, individual DP sensors will be installed on all of the HEPA filters in the bank on the lower roof to monitor the condition of each HEPA filter. This upgrade of the ventilation panel is quoted to be $500,000 by outside contractors. These funds are requested as new funds.

4. Acid Scrubber

Currently the large acid scrubber located in room 2-66A is our only defense against acid fumes corroding ventilation system piping, the HEPA filter bank and filter housing. A new system was installed in 2011 but was plagued with leaks and did not meet design specifications. It was modified and re-installed in FY2012. In event of a breakdown, any evaporation steps performed in hot boxes have to cease. The scrubber also becomes an un-shielded radioactive source if radioactivity becomes airborne and gets trapped in the acid scrubber buffer. Currently, the MIRP group is in the development phase of a new in-cell acid scrubber as the first line of defense against acid fumes. The benefits of having a small-scale acid scrubber include increased reliability and trapping any airborne radioactive fumes within a shielded hot box. The large acid scrubber would act as backup. The large acid scrubber has failed in the past (mostly leaks) with repair times up to a few days. A replacement for the large acid scrubber would cost around $500,000 including decommissioning of the old one. The custom in-cell acid scrubbers cost around $4,000 each to manufacture and install. Two different custom in-cell acid scrubbers have been prototyped and their effectiveness will be evaluated (operations funds) and is the proposed mitigation plan. These should also be fitted with programmable logic controlled hot-plate. This is under development and if successful total fit out for each in-cell acid scrubber with hot-plate and PLC would be $25K, again with operations funds.

5. BLIP-Target Drive Assembly’s and Target Tank

A failure of the target drive assembly or target tank containment is the most significant single point failure associated with BLIP. Without the target drive system targets cannot be inserted or removed from the beam. The present drive system is over 19 years old and has been constantly subjected to very high radiation levels and a corrosive water environment. The electric motors are obsolete with no new direct replacements available. The system needs to be re-designed to allow use of commercially available components. Should one of the target drives fail, such as a broken chain, at least a month (possible longer) in down time would follow.

The stainless steel target tank has also been in the same corrosive and high radiation environment its entire 20 year life. The most likely leak location is at the beam entrance window and spares are available. Window replacement typically takes 3-4 days. However if the target tank were to leak in an inaccessible spot there would be no way to repair it quickly and replacing the tank would take about a year. An estimate of replacing the entire system, target drive and target tank, as a whole would be approximately $500,000. That would include design and installation but would not include disposal of existing tank. To replace only accessible components (chain, motors…) it

10 would be around $150,000. The risk of failure of either the target drive or target tanks is relatively low but the consequences are very high. An engineering study to predict the lifetime of the target tank is planned although it is not clear if such a study can be done with an adequate degree of confidence.

6. Bldg 801 Emergency Generator

The generator supplying power to building 801 (100kW) is not sufficient to continue processing in the event of a power outage. The current generator capacity is enough to power the 3 main ventilation fans on the roof, emergency lights and emergency outlets but not enough to power support lighting and all else for continued processing. Processing then must stop. A generator with a higher capacity or a supplemental generator is needed to support continued processing. The additional power requirements are being evaluated and a request for additional funds to purchase an additional or replacement generator may be forthcoming.

The risk registry for the above single point failures is shown below in Table 1.

Table 1: Risk Registry for Single Point Failures Item Item Risk Impact Mitigation Plan Ops or New # funds 1 Linac Tube * Increased risk to Contribute to the RF New - Inventory RHIC if BLIP tube SPS fund $500K allowed to run 2 ICP-OES (TPL) Medium Delayed or Bring old ICP unit Ops - $20K canceled Sr-82 into service OR OR New - shipment to purchase new ICP $120K customers 3 Room 66 Vent Medium Greater risk of Replace Vent Panel New-$500K Panel (TPL) violating ASE 4 Acid Scrubber Medium Sr-82 processing Develop/implement Ops – few (TPL) delay with (work in progress) thousand potential missed local acid scrubbers shipments to in hot boxes customers 5 Target drive and Low- Possible Replace chain and New-$150K tank (BLIP) Medium termination of a drive motors AND AND Ops. BLIP run get engineering estimate of Tank lifetime 6 Emergency Low Delay in Evaluate additional Ops Generator (Bldg processing, QC, power required to 801 - TPL) shipping of Sr-82 supplement current generator *The tube inventory comes down to an obligation that BLIP has to contribute the Special Process Spare inventory for the RF tubes. This is a DOE decision to make since the decision affects two DOE customers, RHIC and BLIP.

V. Prioritized list of proposed facility modifications and upgrades

Infrastructure upgrades proposed for BLIP and the TPL facilities are listed below by facility. The proposed upgrades do not at this time include those associated with the 225Ac project or include Phase II (doubling of the Linac beam current) of the Linac intensity upgrade. Some details of the 225Ac project as it stands are included at the end of this document. Phase I of the linac intensity is complete in terms of the goal to reach 140 A but the evaluation of the Linac to determine if current doubling is possible/practical is not yet complete (mid-late FY2016 expected finish). If it is determined that doubling the current is possible and costs to do this are within reason we will propose that this project be funded and with that, along with a known schedule, we will revise our 5 year plan accordingly to take into account (such as remediating possible shielding issues) the current doubling. Details of the identified single point failures were discussed above but remediation of the single point failures is included here for completeness.

BLIP Facility

There were two items on the single point failure list for BLIP discussed above, the target drive system and the target tank. The present plan is to replace the target drive system as a preemptive measure to lower the risk of failure due to aging components in a corrosive water bath in a high flux radiation field. The last time this replacement was done was about 16 years ago. Some level of planning is required since some components are obsolete. Planning for this will begin in FY2015. New funds for the replacement of the target drive system are requested for 2017. The replacement can be accomplished during the 2017 shutdown period. An engineering evaluation of the target tank will be done in 2015-16 time period and if the evaluation indicates failure is likely then the tank replacement will become a priority. This project and others are included in the below table. There are numerous small projects planned with costs at the few thousand dollars each that are not included here.

Table 2: Proposed upgrades to the BLIP Facility Space Item Cost Risk Justification Year Ops or New $ BLIP Pistol Grips 49K Med 2015 New for hot cell manipulators, 4 grips (no spares) BLIP Blip water ~100K Med/High In line 2015-16 Ops/New sampling unit monitoring system to detect target leakage and possibly prevent full failure. BLIP Pneumatic 100K Low Reduce rad 2018 New Drive system exposure to BLIP for Hot Cell operator

portal Doors BLIP New Target 150K Med-SPF Pre-emptive 2017 with New Drive System replacement of planning aging equipment in 2015-16 BLIP Upgrade hot 20K Med Extend Pb 2015-16 Ops cell shielding shielding on front face of hot cell to better shield with Raster beam intensity

TPL Facility

There were five items on the single point failure list for the TPL discussed above. The single point failure systems include, in order of mitigation priority, the Linac Tube Inventory, ICP-OES, the Acid Scrubber, Room 66 Ventilation Panel and upgrades to the Building 801 emergency power. Mitigation plans have been proposed for each of the single point failure items and are discussed above. These mitigation projects and other projects are included below in Table 3. There are numerous small projects planned with costs at the few thousand dollars each that are not included here. In addition, there are a few upgrades in the discussion phase that, if realized, would come as an additional request. An example is an upgrade to the TPL Sr-83 dispensing fume hood to include a new fume hood and another hot cell, dedicated to dispensing isotopes.

Table 3: Proposed upgrades to the TPL Facility Space Item Cost Risk Justification Year Ops or New $ TPL Pistol grips 83K Med Improved 2015 New for Sr-82 hot ergonomics Hot box boxes 6 & hot 2&4 already done cell #1 with 2014-15 Ops $, completes retrofits for Sr-82 processing TPL Pistol grips 85K Med Improved 2015 New for HB1, 3 &5 ergonomics TPL Pistol grips 45K Med Improved 2017 Ac-225 for 66C ergonomics TPL Dedicated Sr- 50K Med Better compliance 2015 Ops 82 can opener with cGMP, cross contamination with sharing target can opener with research samples. TPL New waste 50K Med Reduce 2016 New compactor contamination in hot cells and at

waste management facilities, corrects design flaw in present compactor TPL Room 66 500K Med Improve air flow 2018 New Ventilation monitoring in the Panel TPL area Upgrade TPL New hot cells ~5,000K Med Replace the 6 hot 2019-20 New for the TPL boxes in Rm 66 with modern hot cells, less radiation dose, improved ergonomics Bldg 801 Evaluate 0K Low The generator 2015 Ops, requirements supplying power to New if for upgrade building 801 is not solution Bldg 801 sufficient to requires (TPL) continue processing another emergency in the event of a generator power power outage TPL Install floor 50K Low To provide adequate 2015 Ops (66B) storage for Biodex containers prior to shipping. This room is shielded (reduce dose to staff and radiation background in work areas) It will provide shielded area for shipping and receipt. TPL (68) New Gamma 120K Med Replace aging 2016 New Spectrometer detectors plus shielding and DSPEC unit TPL (66) New Portable 80K Low waste 2017 New Gamma characterization, - Spectrometer spectrometry though hot cell door TPL (66) Re- 20K OR Med- Backup for Sr-82 2015 OR Ops OR commission 120K SPF ICP-OES QC, a 2016 New old ICP-OES SPF OR purchase new ICP-OES

TPL (53) Relocate from 400K Low Laboratory 2016 New Rm 52, QC ergonomics and lab and new better alignment fume hood with cGMP TPL (52) Relocate Fe- 100K Med better control of  2016 New 55 dispensing contamination, from hot box better compliance to glove box with cGMP in Rm 52 (follows QC relocation above)

FY2015 request for additional (new) funding - $217,000 Additional funds are requested this year to complete the purchase and installation of new pistol grips for the Hot Cell and Hot Boxes in Room 66 of the TPL and for the Hot Cell at BLIP. Other FY2015 projects listed in the tables will be accomplished/planned using operations funds. Use of the present manipulator grips result in stress on the hands and shoulders of TPL operators. An ergonomic assessment of these manipulators revealed that they require a hand-grip strength of 18 to 35 lbs. to operate. For repetitive use over the TPL processing season this comes with a risk of physical injury to the operators. In early FY 2105 two pairs of hot-boxes (main Hot Boxes for Sr-82 processing) manipulator grips were replaced with pistol grips that require less than 15 lb. to close. Operations funds ($76K split between 2014-15) were used for this work. With these grips a major source of physical stress has been mitigated for these two hot Boxes. The funds required amount to $217K (includes spare grips and is fully burdened) with the breakdowns given in Table 2 & 3. With this all Hot Boxes and the receiving Hot Cell will be outfitted, leaving only the Hot Boxes in 66C to go. Upgrades to the 66C Hot Boxes will be planned and funded through the Ac-225 project. VI. The vision and goals of the five year R&D program

A. R&D Vision

A more robust R&D effort is critically important, not just for the potential benefit from new radioisotopes to be developed, but to be able to attract scientists of the highest caliber to the group work force in the future. In addition, our very success in providing Sr-82 and Ge-68 to the medical community has led to strong growth and increased demand. These products can now be commercially viable. Indeed the US commercial sector is now making Ge-68 for PET calibration sources, and BNL has ceased providing Ge-68 for this purpose. One or more commercial entities are planning to build their own facility to make 82Sr within a few years. This could lead to cessation of DOE production of this radioisotope with severe revenue consequences for the program. Research is needed now to put new useful radioisotopes into the production pipeline.

We seek to take maximum advantage of specific irradiation strengths of BLIP. These are the high beam intensity and high energy capability of the Linac and the ability to devote long periods to “parasitic” low energy irradiations to make long-lived radioisotopes that are impractical for small cyclotrons. The research strategy is to concentrate on three areas of interest;

15 a) Developing radioisotopes for therapeutic and prognostic applications b) Developing radioisotopes for the BLIP low energy slot (downstream of 82Sr array) that was in the past filled with gallium for 68Ge production c) Basic radiochemistry research.

Targeted radiotherapy is the fastest growing area of clinical nuclear medicine. For therapy radioisotopes with both imageable photon and particle emission (beta, auger or conversion electrons, or alpha) [2] are of special interest. These can serve both for needed pre-therapy prognostic imaging and then a larger therapeutic administration of the appropriate dose. This includes appropriate pairs of isotopes of the same element that would do the same thing. These ‘dual-purpose’ radioisotopes that have great potential to enable ‘personalized’ medicine have been coined as “theranostic” isotopes. The imaging study can also determine that the therapy is not advisable if the measured biodistribution shows inadequate tumor uptake or excess uptake in a non- target organ. The radiopharmaceuticals used for imaging and therapy must have the same biodistribution. For example 111In Mab has been used as an imaging surrogate followed by therapy with Y-90 Mab, but careful studies have shown that although the two elements have similar biochemistry, there were striking differences as well. Among the radioisotopes under consideration for use of the low energy slot are 44Ti, 186Re, 191Pt, 195mPt and 47Sc. We also propose to investigate the synthesis and testing of solid supports with different functional groups for metal capture and purification. In this study different metal capturing groups will be synthesized on individual solid supports (e.g. synphase lanterns). The solid supports have applications in metal cleanup, waste treatment, liquid radioactive waste cleanup, radioisotope purification and medical isotope generators. We propose to concentrate our long-term R&D efforts in these areas. B. Specific R&D Plans (in priority order)

225Ac FY15-17 (and beyond)

In the report entitled Compelling Research Opportunities using Isotopes, published April 23, 2009 by the Nuclear Sciences Advisory Committee (Isotopes Subcommittee), recommendation 1 states, “Invest in new production approaches of alpha-emitters with highest priority for 225Ac”. The interest in 225Ac is due to its potential efficacy in treating blood borne cancers, marrow ablation prior to transplant and even difficult to treat infectious disease. The current world wide supply of 225Ac is approximately 1.2 Ci annually and is all produced from decay of the parent 229Th. Present demand assessment by the National Isotope Development Center (NIDC) is at least 50 Ci annually. 225 A new project to investigate the cost and feasibility to make Ac (t1/2 = 10d) by spallation reaction on natural thorium targets at BLIP began in late FY2012. The advantages of this approach include predicted high batch yield, possibility of frequent production runs and year round availability with LANL providing 225Ac when BLIP is off (as is the present case for 82Sr production). The disadvantages include required high proton energy and new radiological safety issues for multiple alpha emitters co-produced. The high energy protons irradiating thorium create a very large number of radioisotopes through spallation and fission, complicating the chemistry. We have performed MCNPX calculations that predict as many as 450 products are formed at levels above 10 µCi.

LANL has recently published cross section data on 225Ac production by proton irradiation of natural 232Th from 40-800 MeV that suggest that Ci-scale production of 225Ac at IPF and BLIP is achievable. Cross section data from the Institute for Nuclear Research in Troitsk, Russia, up to 140 MeV, is similar. This data shows that the cross section and the 225Ac /227Ac ratio improve with increasing beam energy. Therefore the 200 MeV protons available at BLIP give this program a unique advantage.

In FY12 BNL developed a test target, completed safety reviews, and performed three short irradiations at 128 MeV and shipped thorium foils to Dr. Saed Mirzadeh at ORNL for initial development of the difficult chemical separation. In FY13 we demonstrated irradiation of two or three thin thorium foils encapsulated in aluminum for up to 8 days with beam currents up to ~80 µA, using a 138 and 200 MeV proton beam. The 200 MeV run created 113mCi of 225A at EOB, resulting in a shipment of 21mCi of purified 225Ac to University of New Mexico for initial evaluation. In FY14 four, 16 hour thorium irradiations were performed at proton energies on target of 128, 151, 170, and 192 MeV for determination of yield and purity as a function of energy. One 9.25 day irradiation at 192 MeV, 93 uA on a capsule containing three thorium foils was performed resulting in 123 mCi at EOB. Purified 225Ac (35 mCi total) was delivered to three institutions for evaluation. Unfortunately, the target used in the present approach is not considered suitable for curie scale production. Further the production capacity of this joint national program is currently limited to about 40 mCi delivered to users per batch, due to a lack of available suitable Type B shipping containers for the targets and limitations on the radiological inventory at the current processing facility at ORNL.

In order to accelerate and better coordinate the 225Ac research activities of BNL, LANL and ORNL, the DOE/NP Isotope Program, instituted a more formal project structure for this effort. Dr. Kevin John of LANL was named the national project manager. The tri-lab 225Ac collaboration implementation timeline has been established and will be followed based on the overall project management plan and schedule. The use of core R&D funds will be required and is part of the plan to further support critical research aspects of the project. Two critical areas of research have been identified for BNL to pursue and include improvement of (1) part of the chemical separation procedure and (2) thorium target design modifications to allow higher production volumes to be achieved. The multi-step chemical process developed by ORNL achieved excellent removal of fission products and actinides. Separation of actinium from lanthanides (especially La and Ce) was, however, suboptimal due to their similar chemistry. 225Ac losses > 20% were experienced in the final lanthanide separation due to overlap of elution curves. The process is time consuming (4-5d) and will be difficult to scale up from the 10g targets used to date to 100g or more needed for large scale production of 225Ac. A workshop was held at ORNL in May, 2014 to observe the ORNL processing of a BNL irradiated target and discuss the many steps that need to be optimized. Steps in the process that needed significant improvement were identified and the laboratories were charged to take ownership of the various identified problem areas. BNL was charged to develop an improved second anion exchange column which is used in the process to perform a bulk separation of thorium from actinides and fission products. The present anion exchange resin absorbs the bulk thorium and allows the Ac as well as Ba, Cs, Ra and La to be eluted. Currently a large volume column is used for 10 g targets. However scale up to handle 50 to 100 g thorium targets will be very difficult with the current column design. The elution volume is every large and requires most of a day to then evaporate.

A better approach may be to use a small volume column that selectively absorbs Ac, and allows the bulk thorium to pass through. BNL will test a small cation column for thorium removal by investigating various complexing agents (citrate, tartrate, others) to bind thorium and prevent its absorption on the column. Th(IV) forms anionic complexes while Ra(II), Ac(III), and La(III) remain in cationic form. The variables to be studied include effect of pH, bed volume, range of acids for elution of thorium, fission and lanthanide contaminates, using two types of resins (i.e. AG- 50 to MP-50 BioRad). This investigation has been recommended as a high priority project for accelerated development by the DOE 225Ac project review team. The completion of these studies in FY15 will allow a comparison to present ORNL and LANL chemistry processes and should lead to a decision as to an optimal final approach to the problem of bulk separation of thorium from all else followed by integration of the new steps into a revised overall process during FY16.

In addition, core R&D emphasis will be on designing a very high power thick thorium target (~50 g) for production levels of at least 1 Ci of 225Ac. This will include thermal modeling studies, thermal contact resistance studies between Th and various target cladding materials, development of methods to convert available Th into proper forms for targets (e.g. thorium disks), and final target fabrication and testing. This effort will be performed in collaboration with LANL.

Core R&D, will also be used to support related aspects of the 225Ac project. These include routine irradiations and shipments to ORNL to support the material evaluation effort, transportation logistics planning, development of a waste management plan, development of a facility assessment report, development of required ES&H analysis and documentation (e.g. NESHAPS, SAD/ASE, Conduct of Operations plan, etc.), and program management including cost controls and quality assurance plan. If approved, eventual design and construction of laboratory renovations to allow full processing here of BLIP irradiated Th targets would require new 225Ac project funds beyond core R&D.

Competitive R&D (FOA) - As-72 & Cu-67. $719K, FY13-14 with no cost extension to FY16

Other theranostic radioisotopes of interest include 72As, 77As and 67Cu. In response to an Isotope Program Office Funding Opportunity Announcement (FOA) a proposal was submitted entitled “Production of High Specific Activity 72As, 77As and 67Cu for Research and Clinical Applications: Effective design and recycling of targets and radioisotope separation” (CuAs). This proposal is conducted in collaboration with Dr Silvia Jurisson, at University of Missouri and MURR (MU). The CuAs proposal has four sub-projects, two priority projects at each institute.

The CuAs proposal was approved for funding ($750K) in early 2013 and the project was initiated in July of FY2013. Unfortunately, the project has been delayed due to the BNL PI (S. Smith), taking on the Quality Assurance Manager and later Production Manager roles in Aug 2013 and Oct 2013, respectively. A request for a no cost extension to August 2016 was approved on March 9, 2015.

In early 2015, Matt Gott PhD student from Missouri University won a DOE SCGCR scholarship to work at BNL for four months with Smith on the production of 72As and 186Re (to be discussed in more detail later). The revised project schedule submitted to DOE will incorporate this change in effort, however the overall scope of the four projects will stay as approved and outlined below.

Project 1: The objective of this project is to produce high specific activity 67Cu with minimal contamination by 64Cu by assessing yield and purity at 43 MeV.

Project 2: The objective of this project is two-fold: (a) to design a natAs target that is robust at high proton currents and capitalize on the high cross sections of the 72As (p,4n) 72Se reaction; and (b) to evaluate the radiation stability of an anion exchange 72Se/72As generator system containing up to 50 mCi of 72Se recently developed (under DOE DE-SC000385).

Project 3: Reactor production of high specific activity 77As: The objective of this project is to make available a therapeutic radionuclide as a matched pair for the diagnostic 72As. Arsenic-77 can be produced in high specific activity from the beta decay of 77Ge, which is produced from 76Ge via the (n,γ) reaction.

Project 4: The objective of this project is to translate the radioarsenic chemistry developed during the previous DOE funding (DE-SC0003851) using carrier added 76As to the NCA level. This would make available a useful precursor to the community (nuclear medicine and general) for incorporation into a variety of biological targeting molecules (i.e. peptides, antibodies, etc.).

Competitive R&D (FOA) - Basic radiochemistry development $635K, FY15-16

Resins have been used since the 1950’s for the purification of metals from solutions. To date no general method exists to reach into a solution and pull out a specific metal or radioactive isotope. In this study different metal capturing groups will be synthesized on individual solid supports (e.g. synphase lanterns). The solid supports have applications in metal cleanup, waste treatment, liquid radioactive waste cleanup, radioisotope purification and medical isotope generators. More than 15 metal capturing groups can be synthesized on the solid supports. This allows the researcher to tailor the metal capturing group to specific metals for separations. This approach allows freedom to design and test different groups for capturing metals. Characterization will be performed by infra- red spectroscopy, the ability of the modified solid support to capture different metals from various solutions, and capacity studies. Specific studies may examine capturing radionuclides from waste streams such as: 7Be from BLIP cooling system water and eventually 105Rh in 225Ac process waste. The solid supports may be evaluated in a medical isotope generator system such as 113Sn/113mIn (isotope pair is surplus from the Nuclear Chemistry Summer School program at BNL) will be attempted with 44Ti/44Sc as another component of our core R&D. Split-pool techniques may be used to simultaneously capture different metals on different modified solid supports in the same solution.

This effort was embodied in a submission entitled “Development and Evaluation of Non- conventional Materials for Isotope Separation and Medical Isotope Generators” to the most recent Isotope Program Office Funding Opportunity Announcement (FOA). This proposal has succeeded and funding has been awarded in December of 2014.

Other core R&D -Ti-44, FY15-16

A problem and opportunity has been created since the commercial sector has now started producing 68Ge for PET camera calibration sources. Therefore demand for 68Ge from DOE has decreased and

BNL has lost the revenue generated. However, this also frees up the low energy slot in the 82Sr target array that has been almost completely dedicated to gallium target irradiations for 68Ge production for many years. The proton energy at this location varies between 32-22 MeV, depending on the melting and therefore density of RbCl upstream. Note the raster beam to be installed in FY16 will eliminate the deposited power variation across the target face and should provide for a tighter exit energy profile. However energy straggle in the low energy slot created by degrading the proton energy broadens the energy distribution and is unavoidable. This effect is larger at higher incident energy. A potential isotope that could be produced with this energy beam is 57 58 57 58 57 57 Co (t ½ =271.7d) with the Ni(p,2p) Co reaction, or with the Ni(p,pn) Ni beta decay to Co. However we have determined that these reactions cannot achieve adequate product purity in a reasonable amount of decay time so this isotope with the current beam profile and so will not be pursued.

Another isotope that is very attractive for long low energy irradiations is 44Ti. This isotope has a 60 year half-life and decays to short lived 44Sc (3.97h) which emits a positron of 1.97MeV. There is considerable interest in this isotope as the imaging partner with the therapeutic isotope 47Sc, as a “theranostic” pair. This 44Ti/44Sc generator system was first developed in Germany and evoked considerable interest but the quantity available of 44Sc from the generator was too small for evaluation of its utility. Sc-44 can also be produced directly from an enriched 44Ca target using the (p,n) reaction. This method however requires proton energies below 13 MeV and uses the expensive enriched 44Ca material (natural abundance only 2.8%). These two requirements coupled with short half-life of 44Sc constrain centralized production and shipment and makes a 44Ti/44Sc generator approach more practical to pursue at BLIP. The 45Sc(p,2n)44Ti reaction can be utilized on natural Sc, a simple relatively inexpensive target. The cross section reaches a peak of 32mb at ~22- 25 MeV, which is perfect for the low energy slot behind the 82Sr target array. All other Ti impurities created would be much shorter lived or stable. Therefore the purity of the 44Ti can be excellent. Just leaving such a target in beam for an entire BLIP cycle, in effect as a beam stop, would be very cost efficient, especially compared to a dedicated irradiation at a cyclotron. Given the long half-life of 44Ti, this target can be removed to conduct short irradiations of other research targets without significant 44Ti decay loss and thus its production will have little impact on the overall R&D program. The technical approach involves both target and chemistry development. This project will be carried out in collaboration with LANL.

Following the isolation of 44Ti, a 44Ti/44Sc generator design will be developed. An existing system developed by Filosofov et al. Radiochim Acta 98,149-156 (2010) will serve as the starting point for the development. This system is comprised of a solid phase anion exchanger combined with a liquid phase mixture of HCl/oxalic acid. Other possible designs based on new inorganic anion exchangers will be considered and evaluated for long term performance as well.

In FY2016 we propose routine tests of the prepared system at LANL and BNL, including ICP- MS/OES analysis to quantify eluted stable impurities using TLC, HPGe γ-spectroscopy, and storage phosphor autoradiography, to identify potential issues associated with the complexation of eluted 44Sc. Concurrent with this work, we will enlist the assistance of potential university collaborators with experience using 44Sc. If this initial R&D is successful and we determine that marketable quantities of 44Ti can be produced then this work will continue into the future with routine irradiations of natural scandium target “beam stops” concurrent with 82Sr production. The half-life

20 of 44Ti is sufficient for many generations of radiochemists. Since no generator system, even based on inorganic columns, is likely to have a useful lifetime of much more than one year before breakthrough type problems begin, we must eventually develop the ability to receive used generators back from the community for recovery of the 44Ti, purification and reuse in loading of new generators. Other core R&D - Accelerator Production of Platinum (191Pt, 195mPt and 188Pt) and Rhenium (186Re) Radioisotopes, FY15-16

Part (A) Platinum Project is in collaboration with Elizabeth Ricard-McCutchan and Michal Herman and colleagues at National Nuclear Data Centre of the Nuclear Science and Technology Department at BNL and Partha Chowdhury and Christopher Lister, University of Massachusetts Lowell. Their efforts are funded independently from the MIRP Program.

Part (B) Rhenium Project – is collaboration with Silvia Jurisson and PhD student Matt Gott of University of Missouri. Matt Gott efforts (0.17 FTE) are partly funded through DOE SCGST Research Grant (Note the other 0.16 FTE of Matt Gott funded effort will be directed to contribute on the CuAs project).

Part (A) Platinum project

Currently 50% of cancer patients receive platinum agents; collectively they are used to treat a wide range of cancers alone and or in combination with other chemotherapeutic or biological agents such as antibodies. While their mechanism of action is similar, they have different side effects and activities against various cancers. Resistance to these agents is often reflected by a reduction in accumulation of the platinum agent inside the cancer cell. The ability to monitor their pharmacokinetics using their radioactive Pt analogues, in vitro and in vivo would be an invaluable tool for understanding how to optimize treatments (reduce side effect and optimise efficacy) and potentially provide for new theranostic imaging agents.

Research into platinum chemotherapeutics is experiencing a resurgence, largely due to a number of significant events in their drug approval, clinical trials and scientific findings on mechanisms of resistance against these agents.1-5 The ability to monitor their pharmacokinetics using the 195mPt 191 188 189 (t1/2= 4.02 d), Pt(t1/2=2.802 d), Pt (t1/2=10.2 d) or Pt (t1/2=10.87 hr) in vitro and in vivo would be an invaluable tool both for design of effective agents and for preclinical and clinical trials. 195m 193m Additionally, Pt, and Pt (t1/2=4.33d), emit Auger and/or conversion electrons, which at the appropriate dose could be used to kill the cancer cells.

Cross sections of proton-induced nuclear reactions on platinum metal have been reported (2004).6 Data is available up to 70 MeV and show cross sections are suitable for production of 191Pt by natPt(p,pxn)191Pt, (at 20 to 30 MeV cross sections vary from ≈ 8 to 30; at 32 to 53 MeV they range from 80 to 405 mb). For the production of 195mPt the natPt(p,pxn)195mPt cross sections vary from 7 to 21 for 20 to 30 MeV and 30 to 45 mb from 36 to 65 MeV. In addition, the same paper reports a sharp increase in the cross section (up to 90 mb) for the production of 188Pt at 60 to 70 MeV and up to 350 mb in the same region for production of 189Pt. The use of enriched isotopes should provide

21 for even greater production yields. Calculations using the Empire code for protons on platinum metal at 108 and 193 MeV indicate that production of 193mPt (cross section 30 to 22 mb) from enriched Pt-194 and from 195mPt (cross section 18 to 13 mb) from enriched Pt-196 are potential production routes for these two radioisotopes.

Pt-188 with the longer half-life is of interest to use in in vitro and preclinical studies. As no cross section data for protons on platinum metal above 70 MeV is available it is of interest to assess feasibility for production of these Pt radionuclides at proton energies above 70 MeV and up to 200 MeV. We expect to co-produce also Ir and Au radioisotopes and chemistry will need to be developed to isolate the Pt. Initial work by Smith in late FY2014 has shown that this is feasible using similar methods described in recent clinical studies conducted in South Africia7,8 .

The aim of this study is to identify the type and cross section of Pt radioisotopes that can be produced at BLIP using protons up to 200 MeV and to develop a method for separating the Pt radioisotopes. Ultimately the work will assist us to determine which Pt is most cost effective and or of greatest interest to produce at BLIP.

This project is divided into three parts: a) Initially assess the feasibility of proton reactions to make specific platinum radioisotopes at several proton energies from below 40 MeV and above 90 MeV up to 200 MeV. The platinum foils will be irradiated (up to 15 min) and then digested and analyzed for radionuclidic profile. The samples will be analyzed using conventional gamma spectrometry (using Gamma vision) and on a Compton suppressed gamma spectrometer by collaborators at Nuclear Science and Technology Department at BNL. A total of up to six targets will be irradiated at different proton energies concurrently with Sr-82 production and or thorium irradiations to keep cost of tests down. Compatible target arrays will be determined by assessing proton energy loss using SRIM.

b) Cross section data will be correlated with EMPIRE calculations to determine reliability of theoretical models. Collectively these data will be used to optimize approach to large-scale production of platinum radionuclides such as 191Pt, 193mPt, 195mPt and 188Pt and the use of enriched target material for irradiations in FY16.

c) Separation of Pt radioisotopes Substantial amounts of Au and Ir radioisotopes are coproduced on proton bombardment of Pt and it is of interest to separate the Pt radionuclides. Preliminary radiotracer studies will be conducted to purify Pt radionuclides from the Au and Ir impurities, using similar strategies as outlined by Smith et al 2013. Further separation of 191Au may show alternative route for the production of 191Pt.

Part (B) Rhenium Project collaboration with U. Missouri; Silvia Jurisson and Gott (PhD student), FY15

Reactor-produced radionuclides are often of low specific activity because they originate from (n,γ) reactions on the same element. In contrast, accelerator-produced radionuclides are generally of high specific activity (HSA) because the resultant radionuclide is a different element from the target material. There is significant interest in the reactor-produced 186Re however little has been done to

22 produce it in the HSA form using an accelerator. 186Re is a β- emitter with favorable nuclear properties that makes it an ideal therapeutic surrogate for 99mTc. Cross sections have been reported in the literature for the production of 186Re by the 186W(p,n) [1] and 192Os(p,α3n) [2] reactions; however no cross sections are reported for the 189Os(p,α) reaction and little has been done to isolate the product using these targets. The project will investigate the potential of producing 186Re using natural abundant targets to explore the feasibility of the large-scale production of this radioisotope. Prior work at MU focused on the development of target materials, production schemes, and separation methods to isolate Re and recover W/Os target materials for reuse. They have developed novel targets of disulfide species, WS2 and OsS2, which form robust pressed discs and are easy to handle. Both targets have been successfully irradiated for one hour at 10 µA with the 16 MeV protons using the PETtrace cyclotron at MU and natural abundance materials. Tables 1 and 2 summarize resultant radionuclides identified by gamma spectroscopy and their production yields. Further they have developed a low scale separation method for both targets.

The W/Re separation utilizes anion exchange chromatography to isolate the Re and recover the W target material. Because the Os is highly toxic, all work will be conducted in a fume hood and or a hot-cell. The Os/Re separation involves liquid-liquid extraction and ion exchange chromatography to isolate Re. For the former, a specialized distillation apparatus fitted with two base traps has been designed to ensure the distillation is contained and any volatiles not captured in the receiving flask are neutralized. The Os is recovered by distillation of the volatile tetroxide (OsO4) species. There is an added advantage of this approach; if any Os is captured in base solution of the traps, the solution will change colour providing for a visual indication of any significant losses.

nat Table 1. WS2 irradiation with 14 MeV protons at 10 µA for 1 hour Isotopes 181Re 182Re 182mRe 183Re 184Re 186Re t1/2 (h) 20 12.7 64.08 1680 912 89.232 Yield (µCi/µAh) 1.363 1.733 10.298 0.156 0.144 0.524

nat Table 2. OsS2 irradiation with 16 MeV protons at 10 µA for 1 hour 16. t (h) 1/2 64 10.5 41.28 316.8 283.2 89.232 17.004 24 Isotopes 186Ir 187Ir 188Ir 189Ir 189Ir 186Re 188Re 189Re Yield 0.3 4.99⋅10 4.19⋅10 6.58⋅10 (µCi/µAh) 00 14.3 1.00 0.900 0.134 -4 -4 -4

Initial work will be conducted with natural Os as a proof of principle approach. The energy will be carefully monitored to optimize preferential production of 186Re. Should we be able to optimize the beam profile, we will then consider options for using enriched Os-189 at a later date (another FY). The use of enriched 189Os will allow us to reduce the impurities and increase the production yield. Unfortunately, the thermal properties of the disulphide Osmium and Tungsten target materials are not well matched to the BLIP beam profile so test irradiations will be conducted with W and Os foils, which have very high melting points and good thermal conductivity.

Target arrays will be designed to irradiate the Os and W foils (up to three each for up to 30 min) concurrently with Sr-82 target array and/or as part of the As target irradiations at low currents (of

CuAs project). The target arrays will be designed so optimum proton entry energy is at 24 MeV for Os and 15 MeV for W. Because the energy profile of the BLIP beam can be quite varied, (depending on entry energy) initially we will be looking to gain the optimum yield based on the characteristics specific to BLIP. This will involve modeling the beam profile at various energies and also evaluating various target arrays to devise the best conditions for optimize 186Re yield and reduce impurities. The Os foil will be digested using 12% NaOCl in a similar manner to that successfully performed at University of Missouri.

The aim of this study is to identify optimum energy and target material for the production of high specific activity 186Re.

This project is divided into three parts: a) Design target arrays compatible for irradiation of W and Os foil concurrently with approved RbCl and As target arrays.

b) Determine the yields of 186Re and other radiocontaminates and correlate experimental data with available theoretical data.

c) Use established methods to test separation efficiency of 186Re from W and Os target foils.

References: 1) Lapi et al.; Appl. Radiat. Isot. 2007, 65, 345-349. 2) Szelecsenyi et al.; J. Radioanal. Nucl. Chem. 2009, 282, 261-263. 3) Qaim et al.; Radiochim. Acta 2012, 100, 635-651.

Other core R&D -Other radioisotopes FY17-20

Sc-47 is another potential theranostic beta emitting radionuclide. It has nuclear properties that are useful for radiotherapy with low to moderate energy beta emissions (600 and 439 KeV) and a gamma emission of 159.4 keV, very similar to that of 99mTc and thus ideal for currently used SPECT cameras. The production involves the 48Ti(p, 2p)47Sc reaction at proton energies below 30 MeV. It can then form a theranostic pair with 44Sc from the 44Ti/44Sc generator described above. Both these efforts will be initiated in collaboration with the University of Missouri later in the five year period if core R&D funding levels permit. Note that this is another avenue to exploit available beam time in the low energy slot at BLIP downstream of RbCl targets used for Sr-82 production.

There are fission products of interest that are coproduced in reasonable yield in the spallation 105 111 irradiation of Th. In particular Rh (t1/2 =35.4h) and Ag (t1/2 = 7.47d) may be worth pursuing. Both are medium energy beta emitters with imageable photons and have potential for radiotherapy. In this case there would be no need to develop and irradiate a target, but an efficient chemical separation from the soup of radioisotopes in the Th target solution will be required.

The Nuclear Science Advisory Committee (Isotopes Subcommittee) is presently preparing an update to their report from 2009. The new report should be published later this year. We will certainly attempt to address high priority radioisotope development recommendations that are suitable for our capabilities.

VII. The integration of R&D and Production Activities

The proposed research will start in general with low level studies performed with stable surrogates or tracer amounts of radioactivity, sometimes purchased. This work is located in one of the group research radiochemistry laboratories and has no impact on ongoing routine production. When a project requires irradiation at BLIP, scheduling of beam time is required. In early stages only small amounts of radioactivity are needed so irradiations will be short, a few minutes to a few hours. In many cases the research irradiations can be performed parasitically with routine production of 82Sr without any impact on yield. For example 44Ti will be irradiated downstream of the RbCl targets used to make 82Sr. There is only a short cessation of beam (minutes) in order to install the research target and then to remove it. The 186Re and Platinum radioisotopes research effort would be similar. At the other end of the energy spectrum we irradiate thorium targets to produce 225Ac at maximum BLIP energy of 200 MeV. In this situation degraders placed downstream of the thorium are arranged to reduce the proton energy to that needed for effective production of 82Sr. In this manner both isotopes are irradiated simultaneously. However there is a reduction in flux reaching the RbCl targets of approximately 18% due to nuclear reactions in the thorium target and degraders. However since 225Ac irradiations are at most 10 days, while 82Sr irradiations are 14-21 days, the net impact is at most 13% on a 82Sr batch. When possible the Th irradiations are scheduled during a 21 day 82Sr run, which limits the maximum yield impact to 9% for that batch. It is not expected that there will be more than 3 three such 225Ac irradiations in each of the next several years so that the total impact on 82Sr production will still be small. All research targets do require the use of the hot cells in the TPL. The TPL and BLIP staff assist with packaging, leak testing and opening of target cans and transfer of the contents to the hot cells (#1,3,5) for processing of research targets. Competition for TPL staff time to support this work is minimized by staggered schedules of research and routine processing. The recent (this month) hiring of an additional hot cell chemist will help to ameliorate this situation.

VIII. Justification and/or cost benefit analysis for proposed initiatives

Summary of projects by year:

FY 2015:

New Funds –FY 2015: 1) $500K: Purchase two 7835 power tubes to be added to the C-AD special process spare inventory. a. Brings C-AD tube inventory to 5 years supply b. Allows BLIP to continue to receive beam from the Linac in the event of loss of tube supplier (a realistic possibility). Gives C-AD 5 years to adapt alternate RF technology to enable continued operation of the Linac for RHIC/eRHIC and BLIP.

2) $271K: New pistol grips for the hot cells and boxes Benefit: Ergonomic advantage – The new grips relieve stress on TPL operator hands and shoulders caused by the present manipulator grips. Two of the Hot Boxes used in 82Sr

processing were outfitted with these grips using FY 2014-15 operations funds. The reduction in required hand grip strength is up to a factor of two.

Operations Funds – FY 2015:

1) Re-commission old ICP-OES if practical and cost effective (~$20K). Otherwise purchase a new ICP-OES in FY 2016 with New Funds ($120K). a. This will provide backup for the newer ICP-OES used for QC of 82Sr. b. Removes a single point failure.

2) Install floor in room 66B, a shielded room.

a. Will provide safe, well shielded, storage for Sr-82 filled Biodex containers awaiting shipment to customers. b. Reduce radiation exposure to TPL workers and ambient radiation levels in the TPL area.

3) Engineering for a new automated BLIP cooling water gamma analysis unit to be constructed and installed in 2016 (New Funds). Cooling water sampling is done to detect target failures so the sooner the failure is detected the better. Benefits: a. Reduced risk of activated water exposure to BLIP operators b. More frequent sampling and sampling during weekends and holidays. c. With early detection possibly prevent full target failure.

4) Upgrade lead shielding on front face of the BLIP Hot Cell. A one inch layer of shielding was added in 2014 to shield two weak spots on the front face of the BLIP Hot Cell. This project will extend the shielding to cover the front face. a. Reduced radiation exposure to BLIP operators b. Prepare for higher levels of radiation that will come from full utilization of the Raster system

5) Dedicated 82Sr target can opener. The present can opener is shared between 82Sr and R&D targets. a. Reduce risk of cross contamination b. Better compliance with cGMP

6) Implement local acid scrubbers in the 82Sr production Hot Cells as primary acid scrubbers for strontium processing with present acid scrubber as backup. a. Removes single point failure b. Reduction in general radiation levels above the Hot Cells in the ventilation system.

7) Evaluate the cost/benefit for an upgrade to the TPL emergency generator to allow processing to continue in the event of an extended power failure. a. If implemented would eliminate a single point failure

8) An engineering study to predict the lifetime of the BLIP target tank is planned although it is not clear if such a study can be done with an adequate degree of confidence. a. The tank is 19 years old and has been exposed to high levels of radiation in a corrosive water environment. b. This tank is a single point failure with low probability of failure but with serious consequences (1 yr+ downtime)

9) Develop optimized RbCl targets to take advantage of the increased beam intensity available from the Rastered beam in 2016.

FY 2016:

In 2016 both the Raster and Linac intensity upgrade projects should be completed. With these upgrades the BLIP targets can be subjected to the maximum current available from the Linac (presently 142 A – 23 % above the present administrative limit placed on RbCl targets) and up to 250 A should doubling of the Linac beam current prove to be feasible and affordable. One of the deliverables from Phase I of the Linac Intensity Upgrade Project is an assessment of the feasibility, cost and schedule of doubling of Linac beam current. If the answers to these questions are favorable then the highest priority project going forward will be a X2 intensity upgrade for the Linac. With this the production of both 82Sr for the commercial sector and 225Ac for R&D and possible commercialization can be doubled. Some modifications to the BLIP targets and the TPL and BLIP facilities will be required to accommodate the increased radiation burden that comes with this. In addition, the facility Safety Assessment Document (SAD) will have to be updated.

New Funds – FY 2016: 1) $120K: Purchase of new ICP-OES for QC of 82Sr and other isotopes – New Funds needed only if re-commissioning of the old ICP-OES is not successful (a 2015 project) a. This will provide backup for the newer ICP-OES used for QC of 82Sr. b. Removes a single point failure.

2) ~$100K: Construction of a new automated BLIP cooling water gamma analysis unit interlocked with beam delivery to be designed in FY 2015. Cooling water sampling is done to detect target failures so the sooner the failure is detected the better. a. Reduced risk of activated water exposure to BLIP operators b. More frequent sampling and sampling during weekends and holidays. c. With early detection possibly prevent full target failure.

3) ~$50K: New radioactive waste compactor. a. Corrects a design flaw in the present compactor (lid closing) b. Reduces contamination in Hot Cells and at the waste Management Facility

4) $400K: QC laboratory relocation from room 52 to room to room 53 with new fume hood a. Will provide improved ergonomics with an optimally configured laboratory b. Better alignment with cGMP

5) $100K: Relocate 55Fe dispensing from a Hot Cell to a glove box in Room 52 (follows QC lab relocation above) a. Better alignment with cGMP (removes possible contamination source) b. ~Absolute control of beta contamination

6) $120K: New Compton suppression gamma ray spectrometer system. a. Will provide state-of-the art suppression of troublesome background that comes with QC of 82Sr. in particular for improved accuracy with reasonable counting times for measurement of the 83Rb/82Sr ratio.

FY2017

This should be the last year for Stage I of the 225Ac project. With Stage 1 Key Performance Objectives met by the end of FY 2017, there should be an understanding of the viability of proceeding to Stage II with the project with the shipments of 50-100 mCi of 225Ac to the medical community on a regular basis. Planning for the next stage will continue along with shipments of BLIP irradiated thorium to Oak Ridge for processing and distribution.

Phase I of the Linac Intensity Upgrade Project should be completed by late FY 2016. A deliverable in this project is an assessment of an upgrade of the Linac beam current by about a factor of 2, to 240 A. If the X2 intensity increase proves to be feasible with a reasonable cost and schedule this project (Linac Intensity Upgrade – Phase-II) will become a priority for a funding start in 2017.

Presently identified projects for FY 2017 follow:

New Funds – FY 2017:

1) Linac Intensity Upgrade – Phase II to 240 A. 2) $150K: Pre-emptive replacement of the BLIP target drive system, assumes design work in 2015-16 complete. a. Replaces aging components in beam and corrosive water environment for 21 years in 2017 b. Replaces all accessible components, chain drive system, motors etc. c. Reduces risk of a single point failure

3) ~$500K: If the engineering study of the tank done in 2015-16 indicates that the BLIP target tank is at a substantial risk of failure due to exposure to a high radiation, corrosive environment for the past 21 years, then this project will become a priority. a. Reduces risk of a catastrophic single point failure

4) $80K: New portable gamma spectrometer a. Replaces aging gamma spectrometer b. Portable to use at TPL or BLIP as needed

FY 2018

If Phase I of the 225Ac project was successful and Phase II is approved then implementation of upgrades planned in FY 2015-17 to the BLIP and TPL facilities will begin. Upgrades anticipated include: a. General shielding upgrades to hot cells in BLIP and the TPL and target transport cask b. Radiation protection and air monitoring upgrades c. Design work for room 66C in the TPL d. Begin execution of room 66C design including modifications to accommodate a Type B container

This stage is expected to extend through FY 2020.

Presently identified projects for FY 2018 follow:

New Funds – FY 2018:

1) $500K: Upgrade to the Room 66 ventilation panel. a. All the plumbing would be retained b. Install new differential pressure (DP) sensors on the hot cell/hot box ventilation systems c. Install DP sensors to monitor the condition of each HEPA filter in the bank on the lower roof d. Reduces risk of a single point failure e. Reduces risk of violating the C-AD Accelerator Safety Envelope

FY 2019-20

The 225Ac project may be into the last two years of Phase II. At this time the TPL facility may be undergoing upgrades to make possible higher level 225Ac production (Phase III) in 2021. New Funds – FY 2019-20: 1) $5,000K: New Hot Cells in TPL. Replace old and out-of-date hot cells with modern start-of-the art hot cells a. Safety and ease of maintenance, a. Manipulator repairs from front of cells instead of on top b. Ease of cleaning c. Access to sides and back b. cGMP compliance a. Eliminate cross-contamination between cells b. Independent transport between cells c. Optimized shielding for accommodating increased Linac beam intensity with Linac Intensity Upgrade – Phase-II d. Modern hot cells with easy access front and back for maintenance with a cell to cell transfer track.

Other possible projects under discussion:

BLIP-II, a new beamline and new hot cell laboratory

There is a defunct beamline and target station, previously called the Radiation Effects Facility (REF), that is a spur off the BLIP beam line. As a follow on to the Raster and Linac I&II upgrades, we are considering installation of a second BLIP beam line and target station in this existing infrastructure. The REF area is larger than BLIP and can easily accommodate a hot cell for target insertion/removal, as well as power supply racks, control system electronics, target cooling system, storage space and an office. This target station could operate simultaneously with BLIP but at a different and lower proton energy, spanning 37-200 MeV. This eliminates the competition for beam time that currently exists between R&D irradiations that are incompatible with on-going routine production. Pulse by pulse energy switching capability in the Linac already exists and is routinely used to accommodate both BLIP and RHIC needs. In order to maintain this level of flexibility with the new beam line and have this new target station operate simultaneously with BLIP, but at different proton energy as BLIP it will be necessary to replace the DC magnets and power supplies in the BLIP beam line with pulsed devices, so that high and low energy beams could be switched pulse by pulse to either BLIP or BLIP-II. BLIP, together with BLIP-II, would have the unmatched capability to simultaneously irradiate 8-16 targets at energies from 37-200MeV at intensities up to 240μA. The rough order of magnitude cost is $20M (FY14 $) which includes pulse-by-pulse rastered beam to a new target station with hot cells and a control room. A layout of this facility is shown below in Figure 6.

Figure 6. BLIP-II

VIIII. Base Level Staffing Issues

“Base” is defined as FTE’s supported by congressional appropriations and by isotope sales (revolving fund). The present staffing (Feb 2015) is allocated as follows (not including the new Director):

The “base” includes the FTE’s in the blue (6.8 FTE - infrastructure and core R&D) and green boxes (4.2 FTE - isotope production and dispensing). The total “base” FTE count is then 11.0. Support for infrastructure and core R&D comes from the appropriations (FY 2015 budget authority (6.5 FTE)) plus carry forward from FY 2014 (0.3 FTE) with support for isotope production and dispensing (4.2 FTE) from the DOE revolving fund. BLIP and TPL “Base” Staffing: 5.0 FTE appropriations, 4.2 FTE revolving fund = 9.2 FTE

a) TPL: (3.8 FTE base appropriations, 3.5 FTE revolving fund = 7.3 FTE total)

There are 9 Hot Cells/Boxes, many fume hoods, assorted analytical equipment, a cold chemistry laboratory, 5 research labs, 1 QC laboratory for quarantine and analysis of starting and intermediate materials and a gamma-spec/ICP QC laboratory. Lethal levels of radiation are present and disposal of radioactive waste, both liquid and solid, is a big issue. All work related to Sr-82 production is performed with strict compliance with cGMP, which comes with a significant QA/QC effort. This level of effort is considered the minimum for efficient operation of the TPL and BLIP facilities for production and dispensing of research and cGMP compliant radioisotopes with some support for R&D efforts. b) BLIP: (1.1 FTE base appropriations, 0.7 FTE revolving fund = 1.8 FTE total)

BLIP is very technical in nature with targets 30 ft underground immersed in rapidly flowing cooling water with a “blow-torch” proton beam and comes with a Hot Cell and beam monitoring and control equipment. Lethal levels of radiation are present and short lived airborne emissions amounting to several curies per hour are emitted from the BLIP stack. This is the minimum staffing level required to maintain a safe and efficient work environment. c) TPL and BLIP, issues, cross-training, personnel levels:

A number of resignations and retirements have occurred in recent years and for a period the program was quite shorthanded in certain specialized areas. However last year, FY14, and this year. FY15 we have initiated an extensive cross training program within the Production Team. Starting the end of FY13 and during all of FY14 staff experienced extensive training in the development of quality documents and in cGMP practice and guidelines. For critical functions such as operation of manipulators for Sr-82 processing, in particular dispensing and handling of target digestion, we have two high skilled individuals on hot-cell manipulations and a third, hired this month, is presently in training with support from another hot cell chemist who, due to health reasons, no longer does critical hot cell work with manipulators. With the new hire we have a critical number of hot cell technicians to carry on the work in the event one (or two with added stress) of the group is sick or away. In addition, since processing or R&D support is not full time, cross-training of one of the techs for BLIP work is being done to help alleviate a manpower shortage at BLIP in the event that one of the two BLIP operators is away. Other cross-training in 2015 includes cross-training of one of the two BLIP operators in areas such as Shipping, Packaging and operations at BLIP. Further members of the production team (TPL Operators) have acted in the Production Manager role during FY14-15 in the absence of the Production Manager.

With this staff the critical functions for the TPL and BLIP facilities are covered for the next few years. Succession planning is in order for one TPL/BLIP operator. A new hire in FY 2016 would be desirable in order to provide a year or so of overlap. Research and Development Staffing: “Base” = 1.8 FTE appropriations There are presently four full time PhD staff members in the group, Drs. Medvedev, Fitzsimmons, Smith and Mausner, performing multiple roles including BLIP and TPL facility management, production management, quality control and assay, and research. In addition Dr. Mausner serves on national committees for NNSA and NSAC. All desire to have a role in isotope research. In FY2015 the total PhD labor actually involved in research is 2.57 FTE. However, only 1.57 FTE is supported by core research funds, with the remainder supported by the Ac-225 project and competitively awarded R&D grants (FOAs) on As-72 and Cu-67 production and on basic radiochemical separation science. In addition assistance from radiochemical technician staff (~0.45 FTE) and department engineering staff (~0.2 FTE) is needed to perform the research, of which only 0.25 FTE is supported by core R&D funds. The mechanical engineer is not a permanent group member, but is required to provide critical target design input on a continuing basis and is therefore a pivotal part of the needed base R&D funding. These manpower levels and the staff allocation to the individual projects were presented at the budget briefing at DOE in February 2015. The critical tasks to be completed by the core R&D staff effort in FY2015 are the ongoing development of large scale Ac-225 production (chemistry, target design, facility assessment, transportation analysis, ES&H analysis etc.), development of Ti-44 (chemistry and target design), and the preliminary development of Pt isotopes and Re-186 (both efforts in collaboration with U. Missouri). Without the extra funding from the Ac-225 project (revolving fund) and competitively awarded grants (FOAs) there is not enough core salary support to keep the base scientific staff intact. In addition the support staff levels for R&D are considered less than optimum as the tempo of new isotope development is too slow. Staff level of 2.57 FTE permanent PhD, with a postdoc, assisted by 1.0 FTE of radiochemical support staff would be considerably more productive. The total of 0.45 FTE of technician staff presently used to help with all the research activities actually consists of 5 different individuals temporarily diverted for short periods from priority production and facility maintenance functions. The proposed isotope initiatives for FY15-19 include development of Ac- 225, Ti-44/Sc-44 generator, As-72, Cu-67, Re-186, Pt isotopes, Sc-47, Rh-105, and Ag-111. This is an ambitious plan that will need more technician support in order to accomplish in a timely manner. Additional new initiatives as recommended by the NSAC Isotope Subcommittee would also require more assistance. It would be considerably more efficient for research if a technician with a primary responsibility to support the R&D effort became part of the base staffing instead of very short intermittent assistance from the production staff. This position could also provide temporary assistance with facility maintenance functions as time permitted. In this manner the total base staff for R&D is recommended to be about 4.0 FTE, whereas the present level supports only 1.8 FTE. Succession planning for the R&D Group Leader is in order. The guidance from DOE is if this individual or the present Production Manager leaves, then, since we will be hiring a new Director, the position will not be filled. All candidates for the new Director position come with a strong R&D background so this should work. Hopefully the new Director will be on board soon so that an

33 extended overlap period will be realized. If both the R&D Leader and Production Manager were to leave, a new scientist with expertise in nuclear physics should be recruited. The total in FY 2015 for the “base” R&D support is 1.8 FTE and will only support a minimal R&D program. Without additional funds added to the base other sources of funding such as FOA’s or the Ac-225 Project are critical to maintaining a robust R&D program. There are presently issues with using Ac-225 Project funds to support R&D Scientists that apparently can only be resolved with additional funds added to the core R&D budget. Quality Assurance and Quality Control: “Base” Staffing: 0.9 FTE appropriations, 0.9 FTE revolving fund = 1.8 FTE (plus support from R&D group as needed) Quality Assurance and Quality Control for the Isotope Group is a responsibility of the CAD ESSHQ Division. Included in this division is the QA/QC Management Group which a CAD QA Representative and includes QA and QC individuals assigned to CAD from the laboratory Quality Management Office (QMO). QC work using the gamma spectrometers and ICP-OES is performed for all Sr-82 batches by an individual assigned to the QA/QC Management Group with support from two Isotope Group R&D Scientists. When the R&D Scientists are performing this function they formally answer to the CAD QA Representative. The breakdown of support for this effort follows:

Isotope Group QA/QC 2015 2016

C-AD Org Burden 0.75 0.40 Charged to Isotopes, QMO 1.80 1.00 Isotope R&D Support 0.40 0.10

Total 2.95 1.50 Total charged to Isotope Program 2.20 1.10

The expectation is QA/QC requirements will ramp down to the FY 2016 level by the end of FY 2015 and will remain at this level at least until we get to the point where we are processing thorium (Ac-225 Project) in large quantities. The present somewhat elevated FTE requirement is due to a concerted effort to become fully cGMP compliant with Sr-82 production. We have made an offer to one of the Isotope Group Director candidates. Once this person is on board there may be changes made to the plans proposed in this response.