99m

Tc PRODUCTION PROCESSES: AN EXAMINATION OF PROPOSALS TO ENSURE STABLE NORTH AMERICAN MEDICAL SUPPLIES

Submitted by Margaret Cervera Department of Environmental and Radiological Health Science

In partial fulfillment of the requirements for the Degree of Master of Science Colorado State University Fort Collins, Colorado Spring 2009

Introduction As a nation we are fearful of things we do not understand and producing a radioactive medical treatment from material used to create nuclear weapons is little understood and therefore generates great fear. The United States (US) currently relies on technetium-99 metastable (99mTc) for a large number of medical diagnostic procedures with an ever increasing need, especially as the population ages. Supplies of 99mTc reach the United States via Canadas National Research Universal (NRU) reactor which is the sole large scale molybdenum-99 (99Mo) production facility in North America. This process currently depends upon multiple stages of cooperation that are susceptible to disruption at any time. The production of 99mTc begins with shipping uranium-235 (235U) to Canada, irradiation of manufactured targets in a high neutron flux, removal of 99Mo fission products from the reactor and radiochemical separation of the 99Mo. The 99Mo-99mTc generator can then be manufactured, shipped to a radiopharmacy and finally 99mTc is eluted for mixture to a final dosage form. Many agencies realize the urgent need for domestic production of 99mTc but the ability to implement currently approved processes do not exist and changing the manufacturing process is a complex scientific and regulatory issue. For many people radioactivity in any form conjures visions of movie monsters, nuclear accidents such as Chernobyl and Three Mile Island and nuclear war. Society hears that weapons grade high enriched uranium (HEU) is being shipped around and out of the country and they are concerned; What if it is stolen? Will domestic fissile materials be used against us in an attack reminiscent of the Oklahoma City bombing or September 11th attacks? Will citizens be exposed to deadly radiation and require

evacuation from their homes? Will families face cancer as a result of any accidents involving transport or nuclear material? Where is the waste going to be stored and will it leak into my drinking water? In many ways these are valid concerns since accidents and acts of negligence have occurred with radioactive materials although generally with more limited consequences than many people believe. The technical aspects of generating
99

Mo, or any other radioisotope used for medical or research applications will be a

challenge to present to the public in a way that will answer to concerns but not confuse people further. To a certain extent the publics concerns can be alleviated by education and openness. The purpose of this paper is to provide an insight into, and comparison of, the current state of production, the possible changes that are being considered and the infrastructure and scientific issues that will need to be resolved for the United States to supply this vital medical isotope.

Importance and Use of 99mTc Tc-99m is the most commonly used medical isotope for medical imaging. It is involved in about 70% of all nuclear medicine procedures. Activities, in dosage form, for one brand, TechneLite, can range from just over 2 MBq/kg (0.05 mCi/kg) for pediatric thyroid imaging to 1110 MBq (30 mCi) for blood pool imaging of the heart (BristolMyers Squibb 2005). One of the highest use applications is for cardiac stress tests performed on over 40 million patients since 1991 (Bristol-Myers Squibb 2003). One brand of 99mTc, Cardiolite, used in stress tests, generated sales of $304 million from January 2007 to September 2007, not including physician and additional treatment costs induced with each scan (Ghose 2008). Sales of 99Mo, the precursor to 99mTc, are projected

by the Society of Nuclear Medicine (SNM) to increase 15% over the next decade (Atcher 2008) with Bio-Tech Systems market research predicting 7.5-9.4 % growth per year between 2006-2012, or 50-70% increase during that time (Committee 2009). Patent expiration and the entry of generics into the market are sure to have some effect on these projections.
Diagnosing Brain Disorders >57,000 brain scans per year 69,000 projected in 2010 Imaging Lungs for Blood Clots >2,070,000 lung scans per year 2,350,000 projected in 2010 Scanning Bones for Infection >2,825,000 bone scans per year 3,255,000 projected in 2010

Treating Thyroid Cancer >608,000 thyroid imaging and therapy per year 652,000 projected in 2010

Diagnosis and Monitoring of Cancer >818,200 cancer images per year 2,053,000 projected in 2010 Diagnosing Coronary Artery Disease >8,092,500 cardiology scans per year 13,407,500 projected in 2010

Figure 1: Sample Medical Uses of 99mTc (Atcher 2008: data Bio-Tech Systems, images Journal of Nuclear Medicine)

The absorbed radiation dose to specific organs of reference man (70 kg) is estimated by the manufacturer and is provided as a package insert with the formulation kit. Since
99m

Tc is a gamma emitter the radiation dose is generally whole body although due to

pharmakinetics localized organs will concentrate 99Tc at differing rates. Estimated absorbed doses (D) range from 1.8 mGy (breast) to 55.5 mGy (upper large intestine wall) due to the intravenous injection of 1110 MBq (30 mCi) of Cardiolite used for a stress

test (Bristol-Myers Squibb 2003). For reference, the whole body limit for the public is 1 mGy/y and to a radiation worker is 50 mGy/y. Both limits are in addition to that received from background and as a result of medical procedures. Tc-99m is an ideal radiopharmaceutical useful to medical applications because of an effective (inside the body) half-life (T1/2~ 6 h) long enough to complete a study with adequate concentrations remaining within the organ of interest, but also short enough to keep patient doses to a minimum. The short half life insures that a patient undergoing an outpatient procedure has cleared the 99mTc from all organs, by decay or excretion, approximately six hours from injection (Bristol-Myers Squibb 2003). The primary photon emitted, at 140 keV with 89% yield, is energetic enough to escape the body without significant attenuation (ICRP38 1999). The photon is detected by a gamma camera in which scintillators (plastic or NaI-Tl crystals depending upon brand) convert the energy of the photon into flashes of light which are converted by photomultiplier tubes into electrical pulses and are counted electronically.
99

Mo beta 1.2 MeV decay Emax =

99m

Tc IT (or IC) (gamma)

99

Tc

T1/2: 99Mo 67 hr
99m 99

Tc 6 hr

Tc >105 yr (essentially stable)

Figure 2: Decay of 99Mo

Due to its short half-life 99mTc cannot be produced directly since it will decay away in shipping before reaching the patient. Therefore it is eluted with sterile saline from a resin column containing its parent isotope 99Mo. Mo-99 is currently generated for use in the US as a fission product of uranium-235 (235U). The remainder of this paper will

discuss the status and challenges of producing 99Mo on an adequate scale with a focus on the emerging and proposed process changes.

Current Supply Processing Abbreviation NU LEU Name natural uranium low enriched uranium high enriched uranium weapons grade
235

U Content 0.7% 20%

HEU HEU

> 20% 85%

Table 1: Uranium Enrichment Grades

The current system of producing 99Mo utilizes ~ 93% 235U as a requirement of the approved drug application on file with the Food & Drug Administration (FDA). Enrichment to 93% is not performed commercially in the US as HEU is generally used for nuclear weapon production. As a result the HEU used for 99Mo production is shipped from the Y-12 National Security Complex (Y-12) in Oak Ridge TN as it is removed from defense stockpiles (Mangusi 2000). HEU is then shipped to Chalk River Laboratories (CRL) in Canada to be manufactured into targets. Published Nuclear Regulatory Commission (NRC) records indicate shipments of HEU from the US to Canada for 99Mo production totaling from 10-25 kg per year (NRC). At NRU MDS Nordion manufactures HEU targets, formed as pins of uranium aluminum alloy within an aluminum cladding. These targets are then inserted via irradiation ports into the National Research Universal (NRU) reactor at CRL. The NRU reactor operates with neutron fluence (th) of approximately 21014 to 31014 n cm-2s-1. Up to 20 targets may be irradiated at any one time and can remain within the reactor for

five to seven days. The 99Mo is generated as a fission product of 235U and will occur in about 6% of all fissions (Reed 1953). Targets are monitored to determine removal at optimum times. The time of removal is determined based on the buildup of 99Mo from the fission of 235U. Due to an equilibrium, additional irradiation is not productive as the 99Mo will be lost due to decay as it is generated and therefore approximately 97% of the 235U remaining in the target will become waste (Committee 2009). The targets are removed after irradiation, allowed to cool in water for up to half a day, then are transferred to an associated hot cell facility (so named for its ability to handle the great heat and intense radiation of the targets) in shielded casks. Processing then must proceed quickly to minimize 99Mo losses due to radioactive decay. Approximately 1% of the generated 99Mo is lost to decay per hour after irradiation. For reference, the Cintichem reactor (which produced 99Mo in the US until 1989 when the reactor was shut down) typically yielded 600 Ci of 99Mo per target irradiated (Vandegrift 2007). Although processing equipment must be housed within a heavily shielded facility, the equipment itself is actually benchscale and has a footprint similar to that of a large dining room table (Committee 2009).
Ingrowth of Mo-99 vs Thermal Neutron Fission of U-235
U-235 Activity

Mo-99

10

15 t (days)

20

25

30

Figure 3: Buildup of 99Mo in Reactor

Figure 4: Babcock & Wilcox hot cell facility (B&W)

At the hot cell facility the cladding is punctured and gaseous fission products are removed, such as 133Xe and 131I, which are also valuable medical isotopes. Hot nitric acid dissolves the target assembly, forming a nitrate solution containing uranium, molybdenum and other fission products. This solution is then poured through an alumina column (Al2O3) that adsorbs the nitrates. The column is washed with additional nitric acid to elute excess uranium and other fission products but which leaves the molybdenum bound within the column matrix. The addition of sodium hydroxide will elute the purified 99Mo (Saha 1998). This process typically yields recovery greater than 85-90% (Committee 2009). The removed 99Mo is shipped immediately to Mallinckrodt (dba Covidien) in Maryland Heights MO, or Bristol-Myers Squibb Medical Imaging (dba Lantheus Medical Imaging) in North Billerica, MA, where they then manufacture the generator. Manufacture includes adsorption of ammonium molybdate on Dowex-1 anion exchange resin and washing with concentrated HCl removes any other impurities. The 99Mo is pH adjusted to form ammonium molybdate ((NH4)6Mo7O24) and is eluted from the column with dilute HCl (Saha 1998). The alumina column utilizes positively charged beads which adsorb the 99Mo as 99MoO42- (Zolle 2006). The column is

autoclaved for sterility. Additional purification and testing per pharmaceutical regulations is performed before the generator is packaged. The column has a higher affinity for the
99

Mo than the 99mTc ensuring that the 99mTc is preferentially eluted from the column.

Elution of 99Mo, or breakthrough, does occur. The amount of breakthrough is a quality control parameter of the manufacturer (Radioactivity 2009). The NRC regulates the amount of 99Mo that may be given to humans to no more than 0.15 kBq 99Mo per 1 MBq of 99mTc (0.15 Ci 99Mo per 1 mCi 99mTc) and that, upon receipt of the generator, the concentration of 99Mo in the first elution is verified to conform to the limit (Permissible 2007). Due to the short half-life (~66 hour) of 99Mo this process must take place quickly. Most nuclear medicine departments rely on continuous, multiple shipments of
99

Mo/99mTc generators per week to meet treatment demands. This supply chain is

currently capable of supplying 99Mo /99mTc from reactor extraction to patient in less than 48 hours (assuming no delays from any individual step). Industry practice currently sells bulk 99Mo as six day curies which is nominally defined as the activity of the 99Mo in the generator six days after leaving the producer. Current weekly demand (2nd quarter of 2008) is estimated at 6000 six-day-curies. This weekly demand equates to about 40,000 Ci of 99Mo at end-of-irradiation (out-of-reactor) (Robertson 2008). At the hospital or clinic a radiopharmacist will calculate the amount of 99mTc that the decaying 99Mo has generated based on the transient equilibrium that exists between the two species. The 99mTc is eluted from the column with sterile saline (0.9% NaCl), as sodium pertechnetate (Na99mTcO4), and then is mixed with other reagents, according to

commercial kits like Cardiolite, into final patient dosage forms. The column is re-used, or milked, until all the 99Mo has decayed and the column is exhausted.

Figure 5: Elution of Generator Column (generalized) (Sampson 1994)

Figure 6: Decay-growth Relationship in a 99Mo-99mTc Generator (Saha 1998)

10

Figure 7: General Stages of 99Mo Production from Irradiation to Patient. (Making 2008)

Proposed changes to current supply processes

The most pressing change to the development of a 99Mo source in the US is switching the targets from HEU to LEU, but other options are being considered as well. Other means of producing 99Mo include photo fission of 235U, neutron activation of 98Mo, and photo neutron interactions of 100Mo . Construction of new reactors or conversion of existing reactors or the possible use of accelerators to meet increasing demand is also a focus of study as well as the use of alternate radionuclides or imaging protocols.

11

Using LEU Instead of HEU

Converting existing reactors to LEU targets would significantly reduce the security concerns that surround the current supply process. The Schumer Amendment to the Energy Policy Act of 1992 restricts the export of HEU to research and test reactors, of which NRU is one, for any reason unless they can prove that they cannot use LEU as target material (Schumer 1992). Currently, NRU can only utilize targets manufactured using HEU due to the availability of waste storage capability and, mostly, FDA drug approvals, but research is progressing towards conversion to LEU targets. Clearly the change from HEU to LEU targets would seem to be simple, but there are technical and regulatory hurdles to overcome. Substituting LEU directly in place of HEU targets is possible. However, it would reduce the 99Mo yield to approximately 20% of that generated from the HEU. This is due to the reduced number of 235U atoms available to fission (table 1). The lower yield can be overcome by irradiating five times more targets in the reactor. A reactor designated for
99

Mo production could be designed to have the space available to irradiate many more

targets than current reactors can hold due to other user demands on them. Unfortunately, irradiating five times more targets would result in five times the volume of separation wastes which could quickly become a storage and disposal problem. Using LEU targets would also increase the generation of fissile 239Pu due to neutron capture by the higher proportion of 238U. Generating 239Pu, a fissile and long-lived isotope, is also a national security concern. However plutonium is generally insoluble, and can therefore be separated from liquid wastes and ultimately be used to make mixed-oxide (MOX) fuel for nuclear power plants (see NRC Fact Sheet: Mixed Oxide Fuel).

12

Figure 8: Production of 239Pu Resulting from Neutron Capture by 238U

The increase in waste volumes is an important issue. If current target dissolution processes are maintained the waste storage facilities may not be able to accommodate a five-fold increase. Waste facility modification is one possibility for NRU however its also possible that in making certain changes they may not need to make that investment. It is possible that storage tanks are currently operating below capacity and by converting liquid wastes to solid form, waste storage will not be impacted (Committee 2009). Instead of irradiating more targets, the targets themselves could be altered to contain more LEU (increase the target volume). This approach would solve the issue of throughput in the reactor but could be limited by space restrictions in the reactor. Changing the composition of the target itself to contain more 235U by changing the density of the LEU target could also compensate for the reduced yield of 99Mo. Current targets incorporate a uranium-aluminum alloy, with uranium density of approximately 1.6 g/cm3. Converting to uranium metal could yield a higher density of uranium of about 8 g/cm3. The change in density would approximate the mass of 235U given the difference in enrichment (Committee 2009). Argonne National Laboratory (ANL) has been testing a LEU metal foil target within aluminum, nickel or zinc fission barriers that are encapsulated within a cylinder of aluminum cladding. Using foils, these targets, test irradiated in Indonesia, have been compatible with both acidic and alkaline dissolution processes (Vandegrift 1997). Commercial production using LEU targets is undergoing testing at the University of Missouri Research Reactor (MURR) which operates a maximum flux of 6 1014 n cm-2 sec-1(Committee 2009).

13

The main difficulty in utilizing LEU foils has been the method to manufacture the foils themselves. The LEU foils have been manufactured using three differing methods, by casting: pouring molten metal into molds, hot-rolling: heating the metal above its recrystallization temperature and then rolling it out to form sheets, or cold-rolling: rolling the metal out at room temperature to maintain its crystal structure. The casting method has produced irregular targets that, although useable, would make qualifying the uniformity of the targets more difficult and possibly more expensive to produce. Hot- and cold-rolling are both very labor intensive and therefore expensive to produce but result in better target uniformity (Committee 2009). After irradiation, a target of LEU or HEU must be chemically processed utilizing one of only two processes that are FDA approved: MDS Nordion or Cintichem. The (proprietary) MDS Nordion acid-dissolution process is in use for the isotope generated from NRU. The Cintichem process was purchased by the Department of Energy (DOE) from Cintichem Inc. upon the decommissioning of their Tuxedo NY reactor and is the focus of proposed modifications to convert to an LEU target for US supplies. According to available sources both processes are quite similar to each other, however a specific description of the MDS Nordion process is unpublished (Committee 2009). Ensuring that changes to chemical processing suitably achieve the removal of contaminating fission products is the focus of chemistry process research for LEU targets. The prime contaminants are isotopes of iodine (I), rhodium (Rh) and silver (Ag). Researchers from Argonne National Lab (ANL), and the Universities of Illinois and Texas have performed tests focusing mostly on the dissolution of the LEU foil targets in nitric acid as opposed to a mixture of nitric acid and sulfuric acid to avoid the generation

14

of sulfate species that can be corrosive in some storage situations (Gause 1982). Irradiation and processing of foils for the generation of 99Mo has been tested in multiple countries with cooperation and funding from the International Atomic Energy Agency (IAEA). Testing of LEU foils and a modified Cintichem process with acid target dissolution are US, Indonesia, Poland, Chile, Korea, Libya, Pakistan, India and Romania (Goldman 2007). Results confirmed that utilizing LEU foils and a modified acid dissolution process are feasible alternatives to the current processes. Argentina has been producing 99Mo utilizing LEU foils dissolved under a modified Cintichem process with alkaline conditions for their smaller scale domestic imaging needs. The Argentinean process was able to ultimately recover 92% of the available 99Mo but less than 10% of the contaminating 131I. The 131I is chemically reduced and therefore adsorbed onto the alumina column in addition to the 99Mo instead of being removed during purification (Vandegrift 2007). The differences in contamination purification efficiency that exist, dependant upon acid or alkaline dissolution, will likely determine the process ultimately chosen if LEU foils are used to generate US 99Mo supplies. It is not a requirement that a solid form of LEU is irradiated to generate usable 99Mo. A possible source of domestic 99Mo is the Medical Isotope Production System (MIPS) plan proposed by Babcock & Wilcox (B&W). They have proposed to build an aqueous homogeneous reactor (AHR), also known as a solution reactor, which will utilize a LEU fuel salt dissolved in acid and water. Various solution forms are possible: uranyl nitrate (UO2(NO3)2), uranyl sulfate (UO2SO4), or uranyl fluoride (UO2F2). In this reactor the uranium in the solution is both reactor fuel and target material. This system would eliminate the necessity to manufacture or encapsulate a target and un-fissioned uranium

15

can be recycled back into the reactor instead of being removed as waste. The extraction process itself would not differ markedly from the existing adsorption to an alumina column that has already been in use. B&W has estimated that a reactor could generate approximately 1100 six-day Ci assuming a 26 hour processing time. They also have estimated a total waste volume of less than 5 m3 each year consisting generally of alumina column wastes (Reynolds 2007).
Photo-fission of 238U

An accelerator can be utilized to generate 99Mo by the photo-fission of the 238U present in natural uranium. In this method a high intensity beam of photons is generated and directed at 238U (Freeman 2008). This results in nearly the same 6% fission yield for
99

Mo, however the cross section for 238U is about 1000 times smaller than the neutron

capture cross section for the fission of 235U ( 600 barns for thermal neutron capture, 37 barns for the production of 99Mo assuming 6% fission yield) therefore a very large photon source would be required (Committee 2009).
Using Molybdenum Instead of Uranium

Eliminating uranium from the process is also a possibility by using other isotopes of molybdenum and converting them to 99Mo. Four reactions are possible: 98Mo(n,)99Mo (neutron activation) occurring inside a reactor, 100Mo(,n)99Mo (neutron emission),
100

Mo(p,pn)99Mo and 100Mo(p,2n)99mTc which require an accelerator.

Neutron Activation of 98Mo

The activation of enriched 98Mo (natural molybdenum ~ 24% 98Mo) is currently in use by small producers in Kazakhstan and Romania. The reaction, 98Mo(n,)99Mo (neutron activation), requires thermal (~ 0.025 eV) or epithermal (0.025 1.0 eV)

16

neutrons. Although this method does generate the desired 99Mo, not all the 98Mo is activated- analogous to the un-fissioned 235U from the MDS Nordion irradiations. This presents a problem in the purification to pharmaceutical specifications. Mo-99 produced in this way is not carrier-free, as it contains 98Mo that behaves chemically identical and acts as a contaminant. Thus, the 99Mo produced is termed low specific activity and would require larger generators, and by extension larger shielding around the generator, to produce the same activity required for a medical procedure. The FDA also limits the amount of 99Mo that can breakthrough during the final dosage form elution process. The potential exists for increased elution of undesirable 98Mo when formulating patient dosages which, beyond potential danger to a patient, limits the useful lifetime of the larger generator as it will need to be discarded due to breakthrough levels. As an aside, this method does not produce the secondary fission products that are of medical use, namely 131I and 133Xe (Committee 2009).

99

Mo carrier - free : SA = Mo with 10%

98

4.17 10 23 1.76 1016 Bq/g = = 4.8 10 5 Ci/g 5 10 99 * 2.4 10 s 3.7 10 Bq/Ci 4.17 10 23 1.34 10 3 Bq/g = = 3.6 10 8 Ci/g 5 19 0.9(99 * 2.4 10 s ) + 0.1(98 * 3.2 10 s ) 3.7 1010 Bq/Ci

99

Mo : SA =

Figure 9: Specific Activity Effect of 98Mo Contamination

Accelerator Reactions of 100Mo

The accelerator produced methods explored do have merit. However all three would require extensive investment in accelerators that can generate very high intensity beams of protons (500 A) or electrons, to create photons, with sufficient energy to overcome the significantly smaller cross sections involved in these reactions. It has been calculated

17

that the 100Mo(p,pn)99Mo reaction would require about 100 cyclotrons, assuming currently used cyclotron production values (Committee 2009). The final method, 100Mo(p,2n)99mTc, results in the direct production of 99mTc which has the significant disadvantage of time. Since the 99mTc has such a short half life (~6 hours) any need to ship the generator over distances would reduce the usefulness to the end-user and, by extension, the patient.

Other Challenges

The current system of shipping HEU from Y-12 in Tennessee to NRU in Canada, and shipping 99Mo back to the US occurs with many points of contention and supplies are in almost constant jeopardy. Security concerning fissile materials that could be stolen and used as an improvised nuclear device (IND) or dirty bomb is a current fear concerning the use of HEU worldwide. Domestically, pharmaceutical companies must appeal to the Department of Energy (DOE) and the Nuclear Regulatory Commission (NRC) in order to secure defense stockpiled HEU from Y-12. Shipping itself is carried out under military supervision with permission from the Department of Transportation (DOT). All three agencies must grant approval for the raw material (HEU) to be shipped. Delays have occurred in the past due to reluctance of the various agencies to ship HEU to a private enterprise out of direct US control (Mangusi 2000). Legally, the Schumer Amendment to the Energy Policy Act of 1992 states that HEU cannot be exported from the US with very few exceptions allowed one of them being no approved alternative to the use of HEU such as that for generation of 99Mo (10CFR110). As a result of these confounding factors,

18

periodic challenges to NRU and Cintichem (when in operation) regarding the transport HEU have arisen (Tilyou 1989). Another serious hurdle to overcome in the development of domestic production capability or changes to current processes is the approval for human use by the Food & Drug Administration (FDA). The production of any pharmaceutical, including medical radioisotopes, can only be performed according to a documented series of steps submitted and held by the FDA as a Drug Master File (DMF). Any changes to any step in the process will require an amendment to the DMF and subsequent approval by the FDA. The initial approval, such as would be required for a new manufacturer like B&W or MURR, includes a New Drug Application (NDA) which outlines all parameters for the manufacture of the drug (Brown 2005). Before any product can be given to patients, three complete production runs must be performed and evaluated for safety, efficacy and purity according to current Good Manufacturing Practices (cGMP) (21CFR210, 21CFR211). Even changes to an existing NDA or DMF requires an evaluation to ensure changes do not deleteriously affect drug safety, efficacy and purity. The product is tested against internal protocols but must conform to accepted pharmacopeial standards such as those covered in the United States Pharmacopeia (USP), the European Pharmacopeia (EP), Japanese Pharmacopeia (JP) or others. Some standard testing parameters are pH, concentration, radiochemical and radionuclide purity (Sodium 2009). Although extensive testing prior to process conversion should establish that 99Mo generated will perform no differently than the current process, the FDA will review all submitted data to determine the actual performance. This qualifying requirement adds considerable costs beyond infrastructure. These include protocol and system development

19

for the three qualification runs, raw materials testing, production costs of the three complete and typical-sized production runs, materials to complete the assembly of generators, final testing of the completed generators for all three runs and the costs associated with analyzing, compiling and completing the NDA. Each manufacturer will have to independently navigate this process which has been estimated to be at least $250,000 (Brown 2005). An FDA presenter to the National Academy of Science (NAS) suggested review lead times ranging from 4-18 months before approval although they could be extended significantly if FDA determined that human clinical trials would be required (Committee 2009).

Figure 10: FDA Regulatory Process (adapted from Brown 2005)

Another major stumbling block to domestic production is the capital investment that would be required. Estimates of costs and timelines vary extensively since no new reactor facilities or isotope separation facilities have begun construction in the US for over two decades.

20

Construction Criticality Start Date Univ. Texas-Austin 1986 1992 Watts Bar 1 1973 1996 Comanche Peak 1 1974 1990 Comanche Peak 2 1974 1993 Seabrook 1 1976 1990 Limerick 1 1974 1990 Table 2: Recent US Reactors Reactor Name

A facility dedicated to isotope production utilizing solid or liquid targets would need to construct a reactor in addition to hot cell and waste stream facilities. Commissioning a new reactor for isotope production is a lengthy process. Internationally, start of construction to commission of a reactor has been 6-8 years based on the ETRR2 in Egypt, FRM II in Germany and OPAL in Australia. An existing reactor, such as MURR, would need to create the capability to chemically separate the 99Mo in an associated hot cell. Construction and commissioning of a new processing facility could take 3-5 years and has been estimated to cost $30 million to $40 million by the director of MURR, Ralph Butler (Committee 2009). Time estimates given are minimums and delays are always a possibility due to regulatory demands or design/construction changes (Committee 2009, Reynolds 2007). An example of the challenges to a new reactor facility is the Canadian MAPLE (Multipurpose Applied Physics Lattice Experiment) experience. Two reactors, MAPLE I and II, were planned and constructed to supply the worldwide 99Mo demand from one reactor and to utilize the other as a backup and research reactor. Costs projected to complete the MAPLE reactors (to replace the aging NRU) were estimated to be $130 million. During the testing phase MAPLE I was discovered to posses a positive

21

temperature coefficient of reactivity. The temperature coefficient of reactivity, or multiplication factor, describes the number of neutrons available per generation per degree change in coolant temperature. A positive value indicates that there are more neutrons available as each fission generation progresses and the power of the reactor will increase as the temperature increases. A negative value indicates that there are fewer neutrons available for each subsequent generation and the power of the reactor will decrease as the temperature increases. The reactors were designed to have a temperature coefficient of reactivity of -0.12 m MW-1 but testing measured +0.28 m MW-1. Where is the effective multiplication factor and is dependant upon the absorption cross section of the fuel and moderator, the enrichment of the fuel (the MAPLE reactors were designed to utilize HEU fuel), the arrangement of the fuel rods and the coolant capabilities. This means that the inherent safety requirements of the reactor design were not met. Additional investigation could not determine the cause of the positive temperature coefficient of reactivity and in mid-2008 the project was cancelled (Magnus 2008).

22

The Four Factor Formula: = f p

Symbol Name Meaning Dependence

Reproduction Factor (eta) The thermal utilization factor The resonance escape probability

The number of fission neutrons produced per absorption in the fuel.

fuel enrichment composition and geometry of fuel (reactor design) moderator/fuel ratio (reactor design) cross section ratio, moderator/fuel ratio, fuel geometry (reactor design) -

Probability that a neutron that gets absorbed does so in the fuel material.

Fraction of fission neutrons that manage to slow down from fission to thermal energies without being absorbed.

The fast fission factor

The multiplication factor

Table 3: The Four Factor Formula - Temperature Coefficient of Reactivity

Babcock & Wilcox (B&W) assumes that five years will be required from conceptual design (which has begun) to commercial operation for their AHR. They have formed a partnership with a pharmaceutical company, Covidien, to assist with production and processing practice with B&Ws AHR design. An AHR has never been built at the proposed scale in the US and as such budget projections, based on experience, are lacking. The directors of MURR have also indicated their intention to commercially produce 99Mo and have solicited funding for studying the design and construction of facilities (Scully 2009).

23

A recurring theme with regard to developing any definite plans for the construction of domestic isotope production is securing capital from companies or federal budgets. Obtaining adequate funding is a major barrier to production. Government and private enterprise, including the medical community, seem to realize the importance of supplying
99

Mo. Unfortunately, funding for such projects will likely be hampered by the current

economic crises and investments of such huge amounts of money may not be deemed appropriate or truly urgent until some recovery occurs. Waiting for funding will, obviously, put the ideal timelines out of grasp extending the time until the US can depend on its own isotope supply.

Other Treatment Options

There are other treatment options available to practitioners when supplies of

99

Mo/99mTc are limited. Since cardiac and bone scanning account for ~75% of 99mTc

applications the examination of alternate treatment modalities will focus on replacements in those areas. The main competitors to 99mTc are thallium-201 (201Tl), positron emission tomography (PET) utilizing rubidium-82 (82Rb), nitrogen-13 (13N) ammonia, or fluorine18 (18F) as tracers and computed tomography (CT). The largest competitor to 99mTc for cardiac perfusion studies is 201Tl. Thallium-201 can be used as a replacement for 99mTc but they are often utilized in conjunction with each other. Thallium-201 is produced by irradiating a natural thallium target in the external beam of the 60 Brookhaven cyclotron with 31 MeV protons (Lebowitz 1975). The nuclear reaction is 203Tl(p,3n)201Pb. The 201Pb decays to 201Tl in 9.4 hours. Thallium201 is not considered an ideal isotope for imaging because it decays to mercury-201

24

(201Hg) and emits multiple characteristic x-rays resulting in lower quality images. It also tends to concentrate in the kidneys due to its longer half life (73 hours) resulting in a higher radiation dose to that organ than may be acceptable (Committee 2009).

Figure 11: Decay and Emissions from Tl-201 (Lombardi 2006)

The tracers used in PET include rubidium-82 (82Rb), which is cyclotron produced requiring 500 MeV protons. The nuclear reaction is 85Rb(p,4n)82Sr. The 82Sr (T1/2 ~ 26 d) decays to 82Rb (T1/2 ~ 75 s) within a 82Sr/82Rb generator (similar to the 99Mo/99mTc generator). Since the half life of the 82Rb is so short the generator is milked by continuous infusion directly into the patient. Use of 82Rb with PET is limited by generator availability and insurance / Medicare reimbursement. Additionally, radiation doses to medical personnel who administer the tests can be significantly higher, possibly limiting the number of tests which could be performed at a center (Schleipman 2006). Ammonia with 13N is also used. This form of nitrogen has a 10 minute half life and therefore is made within a hospitals cyclotron. Obviously this limits treatment to geographical regions with cyclotron availability. Fluorine-18 (18F) is actually superior to
99m

Tc for bone scanning however it has limited cardiac use since it is currently not a

reimbursable treatment. The use of PET has increased dramatically, however it is estimated that the bulk of treatments with 99mTc are performed in private cardiology

25

practices which may not make the significant investment that adding PET will entail. The investment includes significant equipment costs, additional training in interpretation and additional personnel including medical physicists (Committee 2009). Computed tomography is cited as a possible replacement for diagnoses with 99mTc. For many cardiac diagnosis needs however this will not be a replacement since CT does not provide adequate images of the coronary artery due to interferences with calcium deposits. CT also provides little or no information about myocardial ischemia (reduced blood supply to the heart muscle) or left ventricular function without additional chemical staining. Often CT is used to complement the use of 99mTc instead of as a replacement (Committee 2009).

Conclusions

The real issue is how desperate this nation is for a stable supply of 99Mo. Although many people may not think beyond what the co-pay will be when they are prescribed a nuclear medicine procedure, practitioners are concerned with supply. The SNM surveyed their members about the impact and response to 99Mo shortages. They generated 479 responses to questions about type and location of practice as well as their ability to supply all the 99mTc prescribed to the patients in their care. Confirming the requirement for stability in 99Mo supply is the 49% of patients whose procedures were postponed and the 19% of procedures that were cancelled outright. In addition, 21% of patients were given a different isotope from that originally prescribed with physicians turning mostly to
201

Tl or to non-nuclear procedures such as CT, magnetic resonance imaging (MRI) and

catheterization (Society 2008). Although it is possible that some of these patients were

26

not impacted negatively from the changes to their treatment plans, it is also likely that some were. A negative impact would be to health, insurance reimbursement, scheduling or trust in the abilities of their care providers. Additional challenges are constantly evolving. For example, in response to the National Academy of Science report, Medical Isotope Production Without Highly Enriched Uranium, released in January 2009, Representative Edward J. Markey (D-Mass) has stated his intent to introduce legislation to pressure change to eliminate HEU in the generation of 99Mo and also to ensure supply reliability (Congressman 2009). As of this writing no legislation has been introduced. It is unknown how any additional legislation would impact the building of a significant source of 99Mo in the US. More active and consistent support for changes to the supply chain comes from the IAEA and the global nuclear community who financially support and test the experimental changes explored throughout this paper. It seems that there is a favoring of converting worldwide production to the utilization of LEU with only minor consideration given to other production methods - although this may be more of a political drive rather than a technical necessity. Regardless, more time and money has already been invested in research to ensure that conversion to LEU will be successful. Given that LEU appears to be the preferred raw material for a domestic production facility I am intrigued by the possibilities of the AHR system. This reactor designs ability to use the uranium in uranyl nitrate both as target material and as reactor fuel appears economical to me. I also prefer its ability to essentially recycle the unfissioned uranium back into the reactor as this could dramatically reduce the amount of waste that would require further processing or long-term disposal or security. I am

27

optimistic that the B&W / Covidien partnership can ultimately succeed in navigating the NRC licensing and FDA approvals to achieve their goal of producing a majority of the US demand for 99mTc. There are many hurdles to ensuring stable US supplies: security, economy, infrastructure and the technical changes to processing procedures in moving away from HEU. Ensuring that the supply can be achieved while ensuring homeland security and environmental safety is also important. Of ultimate importance however is supplying
99

Mo/99mTc to patients in a prompt and dependable manner because it is important to the

health and longevity of the American population.

28

29
Figure 12: Quick Review of Processes

Bibliography

Amersham Health, Medi-Physics, Inc. Ceretec: Kit for the Preparation of Technetium Tc99m Exametazime Injection. Brochure. Arlington Heights: Author, 2005. Atcher, R. W., R. W. Brown, and J. P. Norenberg. "Mo-99 Production." An Outlook on New Sources of Mo-99 and Other Medical Radionuclides. Proc. of 2008 International Meeting on Reduced Enrichment for Research and Test Reactors, Washington DC. Oct. 2008. Society of Nuclear Medicine. Jan. 2009 <http://interactive.snm.org/docs/SNM poster low res 1001.pdf>. Babcock & Wilcox Technical Services Group, Inc. "B&W Names R&D Lead for Medical Isotope Initiative." Press release. Lynchburg, VA. 25 Feb. 2009. Bristol-Myers Squibb Medical Imaging. Cardiolite Kit for the Preparation of Technetium Tc99m Sestamibi for Injection. 2003. Bristol-Myers Squibb Medical Imaging. TechneLite Technetium Tc 99m Generator. Brochure. North Billerica: Author, 2005. Brown, R. W. "Mo-99 Production." The Radiopharmaceutical Industry's Effort to Migrate Toward Mo-99 Production Utilizing LEU. Proc. of 2005 International Meeting on Reduced Enrichment for Research and Test Reactors, Boston MA. Nov. 2005. Council on Radiopharmaceuticals and Radionuclides (CORAR). Jan. 2009 <http://www.rertr.anl.gov/RERTR27/PDF/S8-2_Brown.pdf>. Brown, Roy W. "Drug Master File Development and FDA Filings for LEU-Produced Medical Radionuclides." NAS Committee on the Production of Medical Isotopes Without HEU. Keck Center, Washington DC. 11 June 2007. Bushberg, Jerrold T., John M. Boone, and Edwin M. Leidholdt. The Essential Physics of Medical Imaging. 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 2002. Chandra, Ramesh. Nuclear Medicine Physics: The Basics. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 1998. Committee on Medical Isotope Production Without Highly Enriched Uranium. Medical Isotope Production Without Highly Enriched Uranium. Rep. 14 Jan. 2009. National Academy of Sciences. 14 Jan. 2009 <http://www.nap.edu/catalog.php?record_id=12569>. "Congressman Edward Markey - Jan. 14, 2009 - Report: Nuclear Bomb Materials Can Be Eliminated From Production Of Medical Supplies." Congressman Edward Markey - Home. 14 Jan. 2009. 6 Feb. 2009 <http://markey.house.gov/index.php?option=com_content&task=view&id=3511 &Itemid=141>. Conner, C. "Mo-99 Production." Progress in Developing Processes for Converting Mo-99 Production from High- to Low-Enriched Uranium - 1998. Proc. of 1998 International Meeting on Reduced Enrichment for Research and Test Reactors, Sao Paulo Brazil. Oct. 1998. Chemical Technology Division, Argonne National Laboratory. Jan. 2009 <http://www.rertr.anl.gov/Mo-99-98/CConner.pdf>. Covidien. "B&W and Covidien to Develop U.S. Source of Key Medical Isotope." Press release. Mansfield, MA. 26 Jan. 2009. CRP on Production of Mo-99 from LEU or Neutron Activation. International Atomic Energy Agency. 26 Feb. 2009 <http://www.iaea.org/OurWork/ST/NE/NEFW/rrg_Mo99.html>. 30

Diamond, Bill. "Yields of Mo-99 from Alternate Production Methods." Oct. 2008. TRIUMF: Canada's National Laboratory for Particle and Nuclear Physics. Nov. 2008 <http://admin.triumf.ca/facility/5yp/comm/Diamond.pdf>. Dunn Lee, Janice, comp. Proposed License to Export HEU to Canada for Use in the NRU Reactor to Produce Medical Radioisotopes. Rockville: Nuclear Regulatory Commission, 2001. Federal Register, Pg 48921 Vol. 61, No. 181 (1996). Freeman, Tami. "Medical Isotope Supplies: A Game Plan for the Future." Editorial. Medical Physics Web. 8 Dec. 2008. 19 Feb. 2009 <http://medicalphysicsweb.org/cws/article/opinion/36974>. Gause, E. P., L. G. Stang, D. R. Dougherty, E. Veakis, and J. Smalley. Characterization of Radioactive Large Quantity Waste Package of the Union Carbide Corporation. Rep. no. BNL-NUREG-30247R. Upton NY: Brookhaven National Laboratory, 1982. Ghose, Carrie. "Generic Drug Could Mean More Money for Cardinal Health." Columbus Business First 21 Mar. 2008. American City Business Journals Inc. Jan. 2009 <http://www.bizjournals.com/columbus/stories/2008/03/24/story3.html>. Goldman, Ira N. "Mo-99 Production." Fostering New Sources of Mo-99 for International Nuclear Medicine Needs - The Contribution of the IAEA Coordinated Research Project on Molybdenum-99 Production from LEU or Neutron Activation. Proc. of 2008 International Meeting on Reduced Enrichment for Research and Test Reactors, Washington DC. Oct. 2008. International Atomic Energy Agency. Jan. 2009 <http://www.iaea.org/OurWork/ST/NE/NEFW/documents/ResearchReactors/RE RTR_2008_Mo99_Paper_Goldman.doc>. Goldman, Ira N., Natesan Ramamoorthy, and Pablo Adelfang. "Mo-99 Production." Progress and Status of the IAEA Coordinated Research Project: Production of Mo-99 Using LEU Fission or Neutron Activation. Proc. of 2007 International Meeting on Reduced Enrichment for Research and Test Reactors, Prague, Czech Republic. Sept. 2007. International Atomic Energy Agency. 18 Feb. 2009 <http://www.rertr.anl.gov/RERTR29/PDF/6-3_Goldman.pdf>. Homogeneous Aqueous Solution Nuclear Reactors for the Production of Mo-99 and Other Short Lived Radioisotopes. Tech. no. TECDOC-1601. Vienna, Austria: IAEA, 2008. Hot Cell Facility. Babcock & Wilcox Company. B&W Technical Services Group, Inc. Hot Cell Facility. 25 Mar. 2009 <http://www.babcock.com/services/laboratory_management_and_services/hotcell .html>. International Commission on Radiation Protection: Radiation Dose to Patients from Radiopharmaceuticals. Publication no. 80. 3rd ed. Vol. 28. Annals of the ICRP, 1999. International Commission on Radiation Protection: Technetium-labeled MIBI Tc-99m. Publication no. 80. 3rd ed. Vol. 38. Annals of the ICRP, 1999.

31

Jarousse, C., P. Colomb, M. Febvre, N. Morcos, and P. Anderson. CERCA Mo-99 Annular Cans Target Manufacturing Development for ANSTO. Tech. 22 Mar. 2004. European Nuclear Society. 16 Dec. 2008 <http://www.euronuclear.org/meetings/rrfm2004/Presentations/210_Jarousse.pdf>. Lebowitz, E., M. W. Greene, R. Fairchild, P. R. Bradley-Moore, H. L. Atkins, A. N. Ansari, P. Richards, and E. Belgrave. "Thallium-201 For Medical Use." Journal of Nuclear Medicine 16 (1975): 151-55. Lombardi, Max H. Radiation Safety in Nuclear Medicine, Second Edition. 2nd ed. CRC, 2006. Lyman, Edwin. "Using Bilateral Mechanisms to Strengthen Physical Protection Worldwide." Editorial. Nuclear Weapons & Global Security. 26 Aug. 2008. Union of Concerned Scientists. 26 Feb. 2009 <http://www.ucsusa.org/nuclear_weapons_and_global_security/nuclear_terrorism /technical_issues/strengthening-protections-for.html>. Magnus, Ben. "Over Budget, Overdue and, Perhaps, Overdesigned." Canadian Medical Association Journal 178 (2008): 813-14. Canadian Medical Association Journal. 20 Mar. 2008. Canadian Medical Association. 12 Jan. 2009 <http://www.cmaj.ca/cgi/content/full/178/7/813>. Making Medical Isotopes: Report of the Task Force on Alternatives for Medical-Isotope Production. Rep. Vancouver, BC, Canada: TRIUMF, 2008. Mangusi, John. "Application to USNRC for License to Export Nuclear Material (10CFR110)." Letter to Ronald D Hauber. 23 Oct. 2000. Nuclear Regulatory Commission Reading Room. 2001. United States Nuclear Regulatory Commission. 15 Jan. 2009 <http://www.nrc.gov/reading-rm/doccollections/commission/secys/2001/secy2001-0047/attachment2.pdf>. MDS Nordion. Sr-82 Fact Sheet. Brochure. Ottawa, ON, Canada: Author, 2008. MDS Nordion. Tl-201 Fact Sheet. Brochure. Ottawa, ON, Canada: Author, 2008. "Mo-99/Tc-99m Generators: From Reactor to Patient." Monthly Scan 11 (July 2006): 12. Radiopharmacy, Inc. July 2006. 16 Dec. 2008 <http://www.radiopharmacy.com/files/July2006.pdf>. Mushtaq, A., Massod Iqbal, Ishtiaq H. Bokhari, Tariq Mahmood, Tayyab Mahmood, Zahoor Ahmad, and Qamar Zaman. "Neutronic and Thermal Hydraulic Analysis for Production of Fission Molybdenum-99 at Pakistan Research Reactor-1." Annals of Nuclear Energy 35 (2008): 345-52. "NRC: Electronic Reading Room." NRC: Home Page. United States Nuclear Regulatory Commission. <http://www.nrc.gov/reading-rm.html>. Permissible Molybdenum-99, Strontium-82, and Strontium-85 Concentrations, 10 CFR 35.204 (2007). Preliminary Draft Report of the SNM Isotope Availability Task Group. Rep. June 2008. Society of Nuclear Medicine. Dec. 2008 <www.snm.org>. "Radioactivity." United States Pharmacopeia. Vol. 31. Rockville: United States Pharmacopeial Convention, 2009. 340. Reed, George W., and Anthony Turkevich. "Uranium-235 Thermal Neutron Fission Yields." Physical Review 92 (1953): 1473-481.

32

Reynolds, W. Evans. "Babcock & Wilcox Medical Isotope Production System." Medical Isotope Production. United States Nuclear Regulatory Commission, Rockville MD. Dec. 2007. Reynolds, W. Evans. "Babcock & Wilcox Medical Isotope Production System Status." Medical Isotope Production System Status Update. United States Nuclear Regulatory Commission, Rockville MD. Oct. 2008. Robertson, David. "University of Missouri and MU Research Reactor Center." DOE Isotope Production & Applications Workshop on Nation's Need for Isotopes: Present and Future. Rockville MD. Aug. 2008. Isotope Production and Applications. Dept. of Energy Office of Science for Nuclear Physics and Office of Nuclear Energy. Dec. 2008 <http://www.sc.doe.gov/np/program/docs/Isotope Worksession Presentations/Working Group 2/MURR.pdf>. Saha, Gopal B. Fundamentals of Nuclear Pharmacy. 4th ed. New York: Springer, 1998. Sampson, Charles B. Textbook of Radiopharmacy: Theory and Practice. 2nd ed. Taylor & Francis, 1994. Schleipman, A. Robert, Frank P. Castronovo, Marcelo F. Di Carli, and Sharmila Dorbala. "Occupational Radiation Dose Associated With Rb-82 Myocardial Perfusion Positron Emission Tomography Imaging." Journal of Nuclear Cardiology 13 (2006): 378-84. ""Schumer Amendment" to the Energy Policy Act of 1992." Reduced Enrichment for Research and Test Reactors (RERTR) [Nonproliferation]. 25 Jan. 2009 <http://www.rertr.anl.gov/REFDOCS/EPACT92.html>. Scully, Sarah. "MU Research Reactor poised for global production of medical radioisotope -." Columbia Missourian. 9 Jan. 2009. 25 Mar. 2009 <http://www.columbiamissourian.com/stories/2009/01/09/MU-Research-ReactorRadioisotope/>. Society of Nuclear Medicine. Isotope Shortage Survey Final Results. Raw data. Http://interactive.snm.org/docs/Isotope Survey Results 11-3-08.pdf. 3 Nov. 2008. "Sodium Pertechnetate Tc 99m Injection." United States Pharmacopeia. Vol. 31. Rockville: United States Pharmacopeial Convention, 2009. 3336. Stabin, Michael G. "Effective half life of technetium-99m tests." Health Physics Society. 10 Oct. 2003. 10 Mar. 2009 <http://www.hps.org/publicinformation/ate/q3040.html>. 10 CFR 110.42(a)(9), 134 (1992). 21 CFR 210 21 CFR 211 Tilyou, Sarah M. "DOE's Suspension of Enriched Uranium Shipments at Savannah River Puts Mo-99/Tc-99m Supply in Jeopardy." The Journal of Nuclear Medicine 30 (1989): 1139+. United States. Department of Public Health. Food and Drug Administration. Guidance for Industry: Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products. Rockville: Center for Drug Evaluation and Research, 1997. United States. Environmental Protection Agency. Environmental Impact Statement for Proposed Medical Isotope Production. 129th ed. Vol. 60. Washington DC: Federal Register, 1995.

33

United States National Nuclear Security Administration. Office of Global Threat Reduction. "Strategic Plan." Press release. Jan. 2007. United States Department of Energy. 10 Mar. 2009 <http://nnsa.energy.gov/nuclear_nonproliferation/documents/GTRI_StrategicPlan .pdf>. Vandegrift, G. F., and Et Al. "Mo-99 Production." Full-Scale Demonstration of the Cintichem Process for the Production of Mo-99 Using a Low-Enriched Target. Proc. of 1998 International Meeting on Reduced Enrichment for Research and Test Reactors, Sao Paulo Brazil. Oct. 1998. Argonne National Laboratory. Jan. 2009 <http://www.rertr.anl.gov/MO99-98/GVandegrift1.pdf>. Vandegrift, G. F. "Mo-99 Production." Converting Targets and Processes for FissionProduct Mo-99 From High- to Low-Enriched Uranium. Proc. of 1995 International Meeting on Reduced Enrichment for Research and Test Reactors, Paris France. Aug. 1995. Argonne National Laboratory. June 2008 <http://www.rertr.anl.gov/MO99/GVandeg897.pdf>. Vandegrift, G. F. "Mo-99 Production." Progress in Chemical Processing of LEU Targets for Mo-99 Production - 1997. Proc. of 1997 International Meeting on Reduced Enrichment for Research and Test Reactors, Jackson Hole WY. Oct. 1997. Argonne National Laboratory. Jan. 2009 <http://www.rertr.anl.gov/Fuels97/GVandegrift.pdf>. Vandegrift, George F., Allen J. Bakel, and Justin W. Thomas. "Mo-99 Production." Overview of 2007 ANL Progress for Conversion of HEU-Based Mo-99 Production as Part of the U.S. Global Threat Reduction - Conversion Program. Proc. of 2007 International Meeting on Reduced Enrichment for Research and Test Reactors, Prague, Czech Republic. Sept. 2007. Argonne National Laboratory. 18 Feb. 2009 <http://www.rertr.anl.gov/RERTR29/PDF/62_Vandegrift.pdf>. Vandegrift, George F. "Mo-99 Production." Facts and Myths Concerning Mo-99 Production with HEU and LEU Targets. Proc. of 2005 International Meeting on Reduced Enrichment for Research and Test Reactors, Boston MA. Nov. 2005. Argonne National Laboratory. Jan. 2009 <http://www.rertr.anl.gov/RERTR27/PDF/S8-1_VandeGrift.pdf>. Zolle, Ilse. Technetium-99m Pharmaceuticals Preparation and Quality Control in Nuclear Medicine. New York: Springer, 2006.

34