Nuclear Energy Research Advisory Committee (NERAC) Subcommittee

Nuclear Energy Research Advisory Committee(NERAC)

Subcommittee forIsotope Research & Production Planning

Final ReportApril 2000

Table of Contents

Page

Transmittal Letter ---------------------------------------------------------------------------------------------------------------------------- 4

Charge to the Subcommittee -------------------------------------------------------------------------------------------------------------- 6

Executive Summary------------------------------------------------------------------------------------------------------------------------- 9

Introduction ---------------------------------------------------------------------------------------------------------------------------------- 11

Use of Isotopes in Research, Medicine, and Industry --------------------------------------------------------------------------- 11

How Isotopes are Supplied ------------------------------------------------------------------------------------------------------------ 13

Reactor and Accelerator Production and Hot Cell Processing of Radioisotopes --------------------------------------- 13

Markets and Users of Radioisotopes --------------------------------------------------------------------------------------------- 14

Federal Support for Isotope Production and Processing --------------------------------------------------------------------- 15

Stable Isotopes ------------------------------------------------------------------------------------------------------------------------- 17

Problems with Radioisotope Supply ------------------------------------------------------------------------------------------------ 17

Iodine-124, a Long-Lived Isotope for Positron Emission Tomography --------------------------------------------------- 17

Bismuth-212 and -213, Alpha-Emitting Isotopes for Cancer Therapy ---------------------------------------------------- 19

Copper-67, an Isotope for Radiolabeling Monoclonal Antibodies --------------------------------------------------------- 21

Recommendations -------------------------------------------------------------------------------------------------------------------------- 22

Discussion of Short-term Recommendations-------------------------------------------------------------------------------------- 22

Discussion of Long-term Recommendations -------------------------------------------------------------------------------------- 25

Site Evaluations ----------------------------------------------------------------------------------------------------------------------------- 27

Evaluation Procedure and Criteria -------------------------------------------------------------------------------------------------- 27

Site Assessment Results ---------------------------------------------------------------------------------------------------------------- 29

Observations ------------------------------------------------------------------------------------------------------------------------------ 30

Comments and Recommendations on the Fast Flux Test Facility for Isotope Production -------------------------------- 31

NERAC Subcommittee for Isotope Research and Production Planning------------------------------------------------------- 32

Site Visit Reports

Appendix A: Missouri University Research Reactor -------------------------------------------------------------------------- A-1

Appendix B: International Isotopes, Inc. ----------------------------------------------------------------------------------------- B-1

Appendix C: Brookhaven National Laboratory -------------------------------------------------------------------------------- C-1

Appendix D: Oak Ridge National Laboratory ---------------------------------------------------------------------------------- D-1

Appendix E: Los Alamos National Laboratory --------------------------------------------------------------------------------- E-1

Appendix F: Sandia National Laboratory ----------------------------------------------------------------------------------------- F-1

Appendix G: Pacific Northwest National Laboratory ------------------------------------------------------------------------ G-1

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4 NERAC Subcommittee for Isotope Research and Production Planning

5Charge to the Subcommittee

7Charge to the Subcommittee

EXECUTIVE SUMMARY

Isotopes, including both radioactive and stable isotopes,make important contributions to research, medicine, andindustry in the United States and throughout the world.For nearly fifty years, the Department of Energy (DOE)has actively promoted the use of isotopes by funding (a)production of isotopes at a number of nationallaboratories with unique nuclear reactors or particleaccelerators, (b) nuclear medicine research at thelaboratories and in academia, (c) research into industrialapplications of isotopes, and (d) research into isotopeproduction and processing methods. The radio-pharmaceutical and radiopharmacy industries have theirorigin in these DOE-funded programs. Currently, morethan 12 million nuclear medicine procedures areperformed each year in the United States, and it isestimated that one in every three hospitalized patientshas a nuclear medicine procedure performed in themanagement of his or her illness.

Refocus the Office of Isotope Programs on thesupply of radioisotopes and stable enrichedisotopes for research within its mission to servethe national need for a reliable supply of isotopeproducts and services for research, medicine,and industry.

Limit commercial isotope production to productswhere the DOE has a unique productioncapability and where other market supplies arenot sufficient to meet U.S. demand.

Establish an Isotope Review Panel to review andrecommend proposals to produce isotopes tothe Director of Isotope Programs. The Panelshould identify isotopes of interest and preferredsites for production, including alternative supplyoptions, and provide other advice as requested.

Consolidate existing radioisotope processingcapabilities.

Contract with the academic and private sectorsto accomplish the primary focus and mission.

Expand innovative research in diagnostic andtherapeutic nuclear medicine by increasingfunding for the Advanced Nuclear MedicineInitiative.

Increase the funding for academic training tosupport the primary focus and mission.

Begin conceptual design of a dedicated cyclotronto support the mission to serve the national needfor a reliable supply of isotope products andservices for research, medicine, and industry.

Short-Term Recommendations (the next five years)

1.

2.

3.

4.

5.

6.

7.

8.

Promote the greatest synergism among thenational labs, academia, and industry to fulfillthe Isotope Program's mission.

Acquire a dedicated, single-mision, isotopeproduction and processing facility that would befully operational by 2010. The facility shouldinclude a cyclotron and a reactor both dedicatedto isotope production based on off-the-shelfdesigns.

Maintain a stable/enriched isotope inventory forresearch purposes.

Ensure an adequately sized and properly trainedwork force to meet national isotope needs.

Implement a contingency plan to guarantee anuninterrupted radioisotope and stable isotopesupply for the country's research needs.

Long-Term Recommendations (the next ten years)

1.

2.

3.

4.

5.

All of this is enabled by an abundant supply of isotopesthat can meet the changing needs of a vigorous andgrowing research community. If the widespread uses ofradioactive materials are not maintained throughresearch, it will not be possible for this country to sustain,much less expand, our high standard of living andadvanced industrial economy.

Recent levels of federal appropriations, averaging about$20 million per year, have not permitted the DOE’sisotope supply to adequately keep pace with thechanging needs of the research community. It is nowwidely conceded that limited availability of specificradionuclides is a constraint on the progress of research.The problem is especially apparent in a number ofmedical research programs that have been terminated,deferred, or seriously delayed by a lack of isotopeavailability.

The Nuclear Energy Research Advisory Committee(NERAC) convened a Subcommittee for Isotope Researchand Production Planning in January 1999 to study theissue of isotope availability. The Subcommittee visitedseven isotope production sites: five within the nationallaboratory system and two outside producers. A numberof recommendations, both short- and long-term, weremade regarding the supply of isotopes:

9Executive Summary

NERAC Subcommittee for Isotope Research and Production Planning10

Final Report

FINAL REPORT

Introduction

Beginning with the Atomic Energy Act of 1954, theDepartment of Energy (DOE) and its predecessororganizations, the Energy Research and DevelopmentAgency (ERDA) and the Atomic Energy Commission(AEC), have actively promoted the use of isotopes byfunding (a) production of isotopes at a number ofnational laboratories with unique nuclear reactors orparticle accelerators, (b) nuclear medicine research at thelaboratories and in academia, (c) research into beneficialindustrial applications of isotopes, and (d) research intoisotope production and processing methods. Theradiopharmaceutical and radiopharmacy industries havetheir origin in these DOE-funded programs. Currently,more than 12 million nuclear medicine procedures areperformed each year in the United States, and it isestimated that one in every three hospitalized patientshas a nuclear medicine procedure performed in themanagement of his or her illness. Although the fundingfrom various federal agencies has been especiallysuccessful in both medical diagnostic and therapeuticarenas, it is now widely conceded that limited availabilityof specific radionuclides is a constraint on researchprogress in this exciting area.

The lack of radionuclides significantly inhibits progressin evaluating a host of promising diagnostic andtherapeutic drugs in patients with debilitating and fataldiseases, examining fundamental basic science questions,studying human behavior and normal growth anddevelopment, and exploring the aging process and theproducts of transgene expression. This report assessesthe current status of radioactive and stable isotopeavailability for research, medicine, and industry in theUnited States and makes recommendations to theDepartment of Energy that will ensure the long-termcapabilities of the country to provide this neededresource.

Use of Isotopes in Research, Medicine, andIndustry

Isotopes, including both radioactive and stable isotopes,make important contributions to research, medicine, andindustry in the United States and throughout the world.Overall, the biomedical community uses more than 200radioactive and stable isotopes for research, drugdevelopment, and diagnosis and treatment of humandiseases. The research leads to the development ofcompletely characterized radiolabeled compounds thatpermits a physician to target a specific organ or cell typeby selecting the appropriate radiopharmaceutical. It isinteresting that 80–90% of all drugs that receive Food andDrug Administration (FDA) approval go through a researchand development process that uses radioisotopes. Why?

The Annular Core Research Reactor (ACRR) core at Sandia NationalLaboratory during operation at 2MW.

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NERAC Subcommittee for Isotope Research and Production Planning

Because studies in which the proposed new drug islabeled with a radioactive tracer tells us where the druggoes, the rates of transfer, how long it remains in the body,and how, where, and at what rate it is excreted. Theradioactive tracer technique measures kinetic functionswithin the human body without disturbing the normalfunction one wants to assess. Without the use of theseradioactive markers the FDA approval process wouldtake much longer and be more complicated andexpensive than it already is.

Another category of research is based on the use of stableisotopes. When stable isotopes are separated andenriched, and then introduced into a system understudy—whether biological or physical—they can be usedto trace accurately the movement of materials or reactionof chemical constituents. Such isotopic tracers give riseto sensitive and nonintrusive measurements inenvironmental and life sciences, and chemicalengineering.

While much less focused on research, isotopes are at workin industry, too. A number of important categories ofuses exist: Industrial radiography plays a central role inensuring public safety by nondestructively examiningwelds and searching for flaws in pressure vessels, piping,bridges, airplanes, ships, etc. The DOE and a DOE-commercial partnership are two of a half dozeninternational suppliers of iridium-192 for this type ofradiography. Radioisotope instruments have beendeveloped for a number of highly sensitive chemical,elemental, and physical analyses of materials. Radiationprocessing is widely used to sterilize medical productsand food around the world, creating a considerabledemand for cobalt-60. Industrial radioisotope gaugingcomprises a broad set of methods for determining thethickness, concentration, density, or weight of a productundergoing continuous production, like papers and thinfilms. There are also specialty uses of radioisotopes forunique applications, such as the tritium-poweredrunway safety lights at airfields and the smoke detectorsfound in most homes.

The fact that the uses of radioactive materials areubiquitous in our society, giving rise to enormouseconomic and health benefits,1 is generally unappreciatedby most Americans. The medical and health usesimprove the quality of life and save lives by earlydiagnosis and treatment of disease. At the same time,the costs of medical care are significantly reduced by theuse of radioactive materials. The industrial uses improvepublic safety and increase the quality while reducing thecost of everyday products. If the widespread uses ofradioactive materials are not maintained throughresearch, it will not be possible for this country to sustain,much less expand, our high standard of living andadvanced industrial economy.

A technician processing iridium-192 in a hot cell operated by InternationalIsotopes of Idaho, Inc. on the Idaho National Engineering and EnvironmentalLaboratory. This commercial partnership with the government supplies mostof the iridium-192 and high activity cobalt-60 used in the U.S. today.

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1 “Economic and Employment Benefits of the Use ofRadioactive Materials,” Management Information Services,Inc., March 1994.

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How Isotopes are Supplied

To understand the supply of radioisotopes, it is helpfulto consider the major ways that they are produced, whoproduces them, and who uses them. It is also importantto consider the pricing and costs for isotopes and thepolicies on federal production. These are discussed inturn below. At the end of this section, the supply of stableisotopes is mentioned briefly.

Reactor and Accelerator Production and Hot CellProcessing of Radioisotopes

The two major means of radioisotope production are withnuclear reactors or particle (typically proton)accelerators. Most radioisotopes can be made via onemethod or the other, but not generally both. Thus, thenation’s supply must have both types of productioncapabilities. In general, an isotope production reactorshould have as high a neutron flux as possible, bedesigned to offer regions with a choice of high thermalor fast neutron flux, afford easy access of small targets inand out of the reactor, and operate nearly constantlywithout other demands or program priorities. Anaccelerator should have a high average beam current ofprotons of a reasonably high energy (roughly 30–100MeV), afford flexible arrangements for targets, andoperate reliably, that is, without other demands orprogram priorities.

Both reactor and accelerator production share a commonneed for chemical processing of the targets afterirradiation or bombardment. The processing recoversthe desired radioisotope product from the target,separates out the impurities, and brings the radioisotopeto the desired chemical state and physical form for use.This typically requires small- to medium-size hot cellslocated near the production facility, with a substantialinfrastructure for chemical processing, radioactivematerials handling and shipping, and waste disposal.

A third means of “production” is the separation ofdesired isotopes from existing stockpiles of transuranicmaterials or other long-lived radioactive isotopes. Anexample of this is thorium-228, the parent of bismuth-212, which can be separated from stocks of uranium-232.This type of production requires hot cells, but requiresneither a reactor nor an accelerator.

The above requirements are generalizations, and manyvariations exist. Current producers of radioisotopes inthe United States and world today include governmentsthat operate reactors and accelerators at nationallaboratories or institutes and commercial companies thatown and operate accelerators. Most importantly, thereare many partnership arrangements where companieslease irradiation space in government reactors or operateprocessing facilities in coordination with the government.

The 85 MW High Flux Isotope Reactor (HFIR) being readied for a operationat the Oak Ridge National Laboratory.

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A few universities also produce radioisotopes, thoughtheir small-scale capabilities or operating schedulesusually limit the supply.

The ideal of a truly commercial supplier—one whosecapital builds the facility and infrastructure and assumesall costs of production, waste disposal, anddecommissioning—is currently only realized among themany smaller accelerator-based producers. This is notlikely to change in the future. Rather, commercialpartnerships with governments are found throughout theworld and will continue to be the primary means ofproduction well into the future. Indeed, thecommercialization projects that the DOE has recentlyconducted successfully are all aimed appropriately atbuilding partnerships, not at selling off or shutting downtheir unique production facilities.

At all DOE production sites, the radioisotope productionmission shares the reactor or accelerator with otherdiverse programs for nuclear science, energy, or defense.In all cases, the other sponsors are much larger than theisotope production and exercise considerable influenceon the facility schedules and priorities. This “parasiticproduction” often yields a lack of priority forradioisotopes, especially for the smallest customers.Many examples of this problem are presented in the SiteVisit Reports. In its recommendations, the Subcommitteeobserves that the only complete solution to the problemsof parasitic production is to take steps to providededicated, yet modest, facilities for radioisotopeproduction in the future.

Markets and Users of Radioisotopes

Radioisotope suppliers generally operate in two differentmarkets: Bulk radioisotopes are sold to pharmaceuticalmanufacturers and distributors (in the case of medicaluse), or to equipment or sealed-source manufacturers(in the case of industrial use). Bulk radioisotopes areusually not sold directly to the end users. Rather, theybecome an integral part of the product that thepharmaceutical or equipment manufacturers offer. Onthe other hand, specialty radioisotope sales to end users,such as researchers preparing for experiments, aretypically small quantity orders. The U.S. governmentconducts both types of business. The bulk radioisotopesales are often referred to as “commercial sales,” whilethe specialty radioisotope sales are often referred to as“research sales.” As indicated above, commercial salescan be to either medical or industrial customers. DOE’scommercial sales are almost evenly divided between thetwo. Research sales are much more frequently made tomedical researchers, though a few industrial researchersalso purchase small quantities of radioisotopes.

The DOE sales of radioisotopes during recent years havebeen predominately by commercial. By dollar volume,over 95% of the sales were bulk isotopes for medicine

Commercial Sales: Sales of large ("bulk") quantitiesof radioisotopes to pharmaceutical companies ordistributors, or to equipment or sealed-sourcemanufacturers. The DOE prices these orders at fullcost-recovery. The DOE produces commercial salesonly when there is no U.S. private sector capabilityor foreign sources are insufficient to meet U.S. needs.

Research Sales: Sales of small quantities of specialtyradioisotopes to end users usually engaged in medicalresearch (though there are some physics, chemistry,agriculture, biology, and industry researchers as well.) The DOE prices these orders to produce a reasonablereturn to the government but not discourage their use.

Full Cost-Recovery: Pricing based on the entire costof an activity. This includes all the direct labor andnonlabor costs associated with the activity, and indirectcosts normally allocated to the direct costs as well. Itdoes not include any profit nor any costs unrelated tothe work performed.

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Final Report

(notably strontium-82, germanium-68, and others) andindustry (notably iridium-192, californium-252, andothers). Less than 5% were for research sales, thoughthe number of shipments of specialty isotopes greatlyoutweighs the number of bulk radioisotope shipments,and the kinds of radioisotopes supplied to researchersare much more diverse.

The market changes, of course, to reflect increasingdemand for successful new radioisotope products andthe decline or replacement of existing products. Only afew of the research isotopes will become successful newmarket entries, and their applications will grow andeventually shift into commercial use. Accordingly,pricing and supply policies need to reflect the marketstatus of each isotope. The DOE policy is that commercialisotopes are sold on a full cost-recovery basis. Also, theDOE will only produce commercial isotopes when thereis no U.S. private sector capability or when foreignsources do not have the capacity to meet U.S. needsreliably. These policies are appropriate. DOE issometimes reluctant, however, to cease its production ofisotopes that the market could reliably furnish. This isbecause DOE’s production of commercial isotopes bringssignificant revenues to the production sites, which helpsto maintain their infrastructure.

At the other end of the market spectrum, researchisotopes must be managed carefully. The DOE policy isto provide research isotopes at prices that support areasonable return to the government but not discouragetheir use. Also, the DOE attempts to provide all isotopesrequested, subject to production capability, inventory,and financial restraints. Again, these policies areappropriate, but difficult to follow because they involvemany subjective decisions and tradeoffs. Also, isotopesgradually shift their focus from research to commercial,and sometime even revert their status. A number of theSubcommittee’s recommendations deal with moreeffective means to make equitable decisions with regardto which research isotopes to supply and to assist withevaluations of isotope status and production across thespectrum from research to commercial.

Federal Support for Isotope Production andProcessing

Federal appropriations for the DOE’s Isotope Programare $20.5 million in FY 2000. Of this, $10.5 millionsupports operations and production of isotopes. Theremainder funds two major initiatives ($8 million for theIsotope Production Facility at Los Alamos NationalLaboratory and $2 million for the Advanced NuclearMedicine Initiative). In recent years, sales of isotopeshave averaged about $10 million per year, which can beaccessed from a revolving fund account and are typicallyused to fund operations, thereby augmenting the federalappropriations. Thus, the total operations funding is

The Missouri University Research Reactor (MURR) during operation at10 MW.

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U.S. and Russian scientists work together at the Los Alamos NationalLaboratory Hot Cell Facility on a campaign to make strontium-82 generators.

about $20 million per year, which is divided among fiveDOE sites. At this level of support, the Subcommitteefound that the sites have difficulty maintaining theirinfrastructure and giving support to the production ofresearch isotopes. There needs to be robust support forisotope production because it is a vital contributor to U.S.economic competitiveness and well-being.

D. Allan Bromley, Ph.D., Sterling Professor of Sciencesand Dean of Engineering at Yale University, formerpresident of the American Association for theAdvancement of Science and former presidential scienceadvisor during the Bush Administration, cited a list ofchallenging research problems in an editorial in Sciencesupporting legislation that would maintain U.S.industrial competitiveness. He went on to state:

“In all these cases, the role of government shouldbe to uncover ideas that have the possibility ofovercoming the technological barriers. Then, asindustry nears those barriers, it can pursue themost promising possibilities. It is a symbioticrelationship: industry is attentive to immediatemarket pressures; the federal government makesriskier investments that assure long-termcompetitiveness. Industry invests in the present; thegovernment invests in the future.”2

Many, including David Baltimore, Nobel Prize winnerin physiology and medicine and president of Caltech,have pointed out that within the next 50 years arevolution in biotechnology could bring breathtakingadvances in health, longevity, food supplies, and evenenergy supplies. Such developments will depend onrobust federal support and an assured supply ofradioisotopes.

Congress has acknowledged its responsibility to fundresearch and to provide policies that stimulate private-sector investment in research and development (cf., H.R.578 and S. 2217). The House bill was based on principlesoutlined in the 1998 report, Unlocking Our Future—Towarda New National Science Policy,3 authored by Rep. VernonEhlers (R-MI), Vice Chair of the House ScienceCommittee. The Senate bill promoting federalinvestment in R&D was sponsored by Senators Bill Frist(R-TN), John Rockefeller (D-WV), Pete Domenici (R-NM)and Joseph Lieberman (D-CT), and passed unanimously.

Although there is no consensus about how U.S. scienceand technology policy should be promoted, therecommendations of the Ehlers’ report are noteworthy.Among these are that Congress should give high priorityto stable and substantial federal funding for fundamentalscientific research, and that the Federal governmentshould invest in fundamental research across a widespectrum of disciplines in science, mathematics, andengineering. The Subcommittee believes that the DOElong-term goal to have a reliable isotope supply system

Aerial view of the 800 MeV, 1 mA proton linear accelerator at the Los AlamosNeutron Science Center (LANSCV).

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2 D. A. Bromley, “Staying Competitive,” Science, 285:833,August 1999.

3 Report to Congress by the House Science Committee,www.house.gov/science/science_policy_report.htm,September 24, 1998.

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in place that would enable scientists to bring theircreative ideas into practical use safely, quickly andefficiently is appropriate, be it basic science research,clinical medicine, or industrial endeavors. The discoveryand dissemination of new knowledge should continueto be a core mission, and basic science and the applicationof basic science to clinical research discoveries to improvethe diagnosis and treatment outcomes should be a crucialcomponent of that mission. The Office of IsotopePrograms, in providing a federal system for the reliablesupply of stable and radioactive isotopes for research,will be an important aspect of fulfilling the federalresponsibility to support biomedical research.Substantial justification for all the recommendations isincluded in the Ehlers’ report, which has been stronglyendorsed.4,5

At the current level of appropriations for isotopeproduction, this Subcommittee makes severalrecommendations in the spirit of making the best use oflimited funds. At the same time, the Subcommittee alsomakes several strong recommendations that call forvigorous increases in support and changes in the long-term strategy that, if implemented, would strengthen theavailability of isotopes well into the 21st century.

Stable Isotopes

The single supplier of stable isotopes for DOE is OakRidge National Laboratory. The production of stableisotopes has, during past years, been based on theirextensive capability for electromagnetic separation withcalutrons, a technology that is now over 50 years old.While this capability was put on standby several yearsago and has only operated intermittently since then, theinventory of stable isotopes at Oak Ridge is fairlyextensive. In recent years, a foreign supply of stableisotopes from stocks and ongoing operations in theformer Soviet Union have emerged. A number ofalternative technologies have been proposed within thenational laboratories that potentially offer much loweroperating costs with an acceptable level of throughput.The Subcommittee recommends that these alternativesbe more fully assessed and plan for the support of anappropriate technology choice for resumed supply ofstable isotopes in the future.

Problems with Radioisotope Supply

The difficulties experienced by researchers resulting froma lack of isotopes or high costs associated with isotopesin their research are significant and ongoing. Threeexamples are presented:

Iodine-124, a Long-Lived Isotope for PositronEmission Tomography

The increasing amount of clinically relevant informationavailable from PET, in particular from fluorine-18 labeledfluorodeoxyglucose (FDG), has contributed to the

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The large scale electromagnetic separators (Calutrons) at the IsotopeEnrichment Facility (IEF) of Oak Ridge National Laboratory. They are theonly large-scale separator of stable isotopes outside of Russia.

4 E. Bloch and C. M. Vest, “Congress and U.S. Research,”Science, 283:1639, 1999. Vest is President of MIT and also ViceChairman of the Council on Competitiveness, where Bloch isa Distinguished Fellow.

5 F. D. Raines, “Making the Case for Federal Support of R&D,”Science, 280:1671, 1998. Mr. Raines was Director of the Officeof Management and Budget from September 1996 to May 1998.


expanding interest in additional positron emittingradionuclides for exploration of basic research studiesand clinical applications. However, the half-life (T1/2) offluorine-18 is less than 2 hours and limits the period ofobservation whenever fluorine-18 is used. The spectrumof physiologic processes that could potentially be studiedgrows as the number of alternative positron-emittingradionuclides increases. In this context, longer-livedradionuclides, such as bromine-76 (T1/2 = 16 hr) andiodine-124 (T1/2 = 101 hr) provide the opportunity toimage for longer times, which has advantages forstudying “slow” physiological processes and providesadditional time for clearance of nonspecific radioactivity.Iodine-124 was initially identified in a report resultingfrom a collaborative effort between Brookhaven NationalLaboratory and the Sloan-Kettering Cancer Institute inthe 1950s.

Many research scientists have the opinion that,concurrent with the technical improvements being madeon the intrinsic resolution and reconstruction of imagesobtained with positron emission tomographs, thereshould be an increased availability of a variety of short-lived, radiolabeled substrates possessing the uniquepotential to serve as indicators of in vivo alteration ofbiochemical processes. In oncology, the application ofPET holds promise through the extension of the metabolicimage to pathologic process identification and enhancednuclide-directed treatments. Many clinical investigatorswho prefer iodine-124 radiolabeled compounds for theirclinical trials appreciated this fact. However, the lack ofa reliable source of iodine-124 has hampered progressfor nearly a decade.

A recent example of the potential use of iodine-124 is ingene therapy trials to enhance chemotherapy effects inpatients with brain tumors. A major step in themanagement of patients undergoing gene therapy is thedetermination of the distribution, intensity, and durationof function of the transplanted gene, which usuallyrequires a biopsy to obtain tissue for examination.Repeated biopsy sampling of vital organs or tissues, e.g.,brain, heart, is not feasible. Dr. Ronald Blasberg and co-workers at the Memorial Sloan-Kettering Cancer Centerhave developed an elegant yet simple technique forassessing marker gene transfer and gene expressionusing noninvasive quantitative nuclear medicineimaging. The best radioactive label for the markersubstrate is iodine-124, which has not been available toresearch groups interested in perfecting the procedurefor human use.

Although other isotopes of iodine (such as fission-product iodine-131 and reactor-produced iodine-125) arereadily available, the availability of iodine-124 is limitedbecause it is difficult to make. While there have beenseveral reports in the literature over the past decade thatindicate iodine-124 can be prepared from low- to

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Imaging of gene expression can be achieved by selection of a “marker gene”and “marker substrate” combination. An animal bearing five RG2 tumorsis shown at the top: the tumors developed after S.C. injection of four clonesderived from the HSV1-tk transduction (RG2TK#16, RG2TK#4, RG2TK#32,and RG2TK+) plus a RG2 wild-type cells (naive). PET imaging wasperformed 24 hr. after I.V. injection of [124-I]-labeled (FIAU), a substratethat is selectively phosphorylated and trapped in HSV1-tk transduced cells.Highly significant relationships were observed between the magnitude of [124-1]-FIAU accumulation (in-vivo) and the level of HSV1-tk gene expressionas determined by two independent measurements. (from Blasberg, RG, et al.,Memorial Sloan Kettering Cancer Center).

RG2TK#4 RG2 naive

RG2TK+

RG2TK#32 RG2TK#16

Cancer Research 58: 4333 (1998)

0.0 -

2..0 -

1.0 -

% Dose / g

1.5 -

0.5 -

Summed CoronalImages

RG2TK+

RG2TK#4 RG2 naive

RG2TK#16RG2TK#32

Axial Images

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medium-energy proton cyclotrons using an enrichedtellurium target, production of this radioisotope forinvestigators has not been undertaken. The problem withthe supply of this isotope could be overcome byincreasing the priority for its production by the Office ofIsotope Programs.

Bismuth-212 and -213, Alpha-Emitting Isotopes forCancer Therapy

Ovarian carcinoma has the highest mortality of anygynecologic cancer. The major reason for this dismaloutcome is late detection and the fact that most patientshave disease outside the pelvis at diagnosis. Peritonealspread is an important feature in the natural history;failure to control disease within the peritoneal cavity isa major cause of treatment failure. None of theconventional therapies are of proven value.Radionuclide therapy with chromic phosphate has beenused for years, but its effectiveness is still controversial.Similar to x-ray therapy, this form of therapy has beenmost successful against microscopic disease with 5-yearsurvival rates of 80% being reported for stage I and IIdisease. However, neither form of radiation has proveneffective against diseases that are resistant tochemotherapy.

Since 1987, Dr. Jacob Rotmensch and associates at theUniversity of Chicago and Argonne National Laboratoryhave been investigating alpha-emitting radionuclides, aclass of isotopes having radioactive properties that makethem attractive for therapy. Unlike conventional formsof radiation such as x-rays and phosphorus-32, theseradionuclides have high-linear energy transfer, aredensely ionizing, and their effect does not depend onthe presence of cellular oxygen.

Early investigations focused on lead-212 (T1/2 = 10.6 hr),which was obtained from thorium-228 and its daughter,bismuth-212 (T1/2 = 1 hr). These investigatorsdemonstrated in vitro that lead-212 was more effectivethan x-rays against human carcinoma cells grown inmonolayers and then showed that alpha-emittingradionuclides have the ability to eradicate microscopiccancer in animals. The studies demonstrated that leadcolloids cured animals inoculated with an ascites-producing tumor that simulated ovarian cancer and hasreal potential for treating microscopic diffuse peritonealmetastasis in patients with ovarian cancer.

Bismuth-212 was also evaluated. This radionuclide isattractive for development for therapy because it has ahalf-life of only one hour. All the experiments performedwith lead-212 were repeated using bismuth-212.Although the Rotmensch group developed a method toproduce clinically significant quantities of bismuth-212,further work was required to refine this method beforeclinical trials could be initiated. However, in 1997 theonly supplier of bismuth-212 generators, a DOE facility

A health physicist monitors the dose rate at the window of a dedicated glovebox at MURR, while a research technician formulates the Sm-153-labeledEDTMP which will be used to treat a dog with bone cancer.

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at Argonne National Laboratory, stopped production.

The attraction for using alpha-emitters prompted severalgroups to explore development of another alpha-emittingradionuclide, bismuth-213. The advantages of thisradionuclide are that there is no gamma-ray emissionduring the decay process, and the half-life is 42 minutes;therefore, there is less radioactivity exposure topersonnel.

Radiolabeled monoclonal antibodies are showingincreased promise for oncology diagnosis as well astherapy applications. The ideal treatment plan includesa short-lived, radiolabeled monoclonal antibody imagedfor clinical staging followed by radiation dosimetry andpost-treatment with the monoclonal antibody complexedwith a therapeutic radionuclide for management ofunresectable, metastatic disease. The goal ofradioimmunotherapy is, therefore, the delivery of a largeradiation dose to the tumor over a finite time period,while limiting dose-rate effects and radiation damage tonormal tissue such as bone marrow. Clinical experienceswith several monoclonal antibodies have shownpromising results in patients with lymphoma orleukemia, where there is rapid access to malignant cells.An increase in effectiveness of the particular radiolabeledmonoclonal antibody could be achieved through thecareful matching of the specific radionuclide withconsideration for the biological half-life of the monoclonalantibody. Preclinical evaluations of alpha particle-emitting bismuth-213 labeled antibody constructs havedemonstrated the specificity and potency of these agentsin a variety of cancer systems. The transition of abismuth-213 radiolabeled antibody from a preclinicalconstruct to a clinical drug represented a difficult task,which involved developing reliable and validatedmethods to provide multiple activity quantities of a pureimmunoreactive agent that met pharmaceuticalstandards to treat patients.

Although an FDA Phase I clinical trial involving targetalpha particles has been initiated by Dr. David Steinbergat Memorial Sloan-Kettering Cancer Center withbismuth-213 chelated to the anti-CD33 monoclonalantibody HuM195 for therapy of myeloid leukemia, theprogress and determination of the full potential of thisexciting new therapeutic approach has been seriouslyslowed because of restricted quantities, and frequentlya complete lack of availability, of the parent radionuclide,actinium-225.

The supply of bismuth-212 and -213 depends uponexpensive handling and chemical separations of parentisotopes from existing stocks of transuranic elements.

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The 200 MeV proton linear accelerator at Brookhaven National Laboratoryis used for high energy physics research and isotope production.

Several of Oak Ridge National Laboratory’s hot cells are used in the processingand packaging a wide variety of medical and industrial isotopes.

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The problem with their supply could be overcome withfunding for processing campaigns.

Copper-67, an Isotope for RadiolabelingMonoclonal Antiodies

Dr. Andrew Raubischek of the RadioimmunotherapyGroup at the City of Hope National Medical Center hasdeveloped a series of antitumor monoclonal antibodiesthat appear to be most promising for the treatment ofboth solid tumors and hematopoietic malignancies. Inaddition, the group has developed novel chelating agentscapable of binding copper to a number of antibodies.Drs. Sally and Gerald DeNardo at the University ofCalifornia Davis have shown favorable clinical responsesusing the limited copper-67 that had been madeavailable. While the characteristics of this isotope makeit an ideal candidate for cancer therapy, the majorimpediment to clinical trials has been the lack of anadequate supply.

Copper-67 can be made by the accelerators at Los Alamosand Brookhaven, but these facilities only produceisotopes parasitically and are subject to short operatingschedules. The problem with the supply of this isotopecould be overcome in the short-term by increasedfunding to lengthen the operating schedules, and in thelong-term by the provision of a dedicated cyclotron forcopper-67 and other research isotopes.

21

The recently refurbished Hot Cell Facility at Sandia National Laboratory has12 cells which are connected together to accomodate processing ofmolybdenum-99. Sandia was given the mission to produce a backup supplyof this commercial medical isotope in 1996, and began a major upgrade of itsfacilities. However, the program was halted in 1999 as other commercialsupplies were brought online before its completion.


Recommendations

The Subcommittee has reviewed the recommendationsof the 1998 DOE Expert Panel6 and endorses them.

The Subcommittee makes the followingrecommendations to address current and future needsfor improvements in the supply of isotopes. Therecommendations are presented as short-term, whichcover the next five years, and long-term, which coverthe next ten years. Each recommendation is discussedin turn below.

Discussion of Short-term Recommendations

1. Refocus the Office of Isotope Programs on thesupply of radioisotopes and stable enriched isotopesfor research within its mission to serve the nationalneed for a reliable supply of isotope products andservices for research, medicine, and industry.

The Subcommittee finds that there are insufficientresources and priority for research isotope production.The primary programmatic focus of Isotope Programsshould be on the supply of radioisotopes and stableenriched isotopes for research to fulfill the program’smission “to serve the national need for a reliable supplyof isotope products and services for medicine, industry,and research.” Isotope Programs is in the process oftransition from a strict reliance on the revolving fundand focus on revenue-producing isotopes, to yearlyappropriations to support a research mission. In theforeseeable future, substantial budgetary limitations forIsotope Programs require that the program focus moreon supporting the research community with a consistent,reliable supply of radioisotopes rather than commercialproduction. In addition, the existing supply of stableenriched isotopes needs to be maintained both forresearch tools in and of themselves as well as for targetsfor the production of research quantities of radioisotopesin reactors and accelerators. In the cases of both stableenriched isotopes and radioisotopes, examples have beendocumented of research suffering because of shortagesor interruption in supply. These shortfalls have had adeleterious effect on the progress of nuclear medicineresearch in particular as well as other areas of sciencesupported by isotopic tools.

2. Limit commercial isotope production to productswhere the DOE has a unique production capabilityand where other market supplies are not sufficientto meet U.S. demand.

Commercial isotope production at DOE facilities shouldbe limited to areas where these facilities represent aunique capability and are needed to meet U.S. demand.For isotopes with sufficiently strong suppliers in themarket, Isotope Programs should pursue the process ofcommercialization. To this end, Isotope Programs needs

Refocus the Office of Isotope Programs on thesupply of radioisotopes and stable enrichedisotopes for research within its mission to servethe national need for a reliable supply of isotopeproducts and services for research, medicine,and industry.

Limit commercial isotope production to productswhere the DOE has a unique productioncapability and where other market supplies arenot sufficient to meet U.S. demand.

Establish an Isotope Review Panel to review andrecommend proposals to produce isotopes tothe Director of Isotope Programs. The Panelshould identify isotopes of interest and preferredsites for production, including alternative supplyoptions, and provide other advice as requested.

Consolidate existing radioisotope processingcapabilities.

Contract with the academic and private sectorsto accomplish the primary focus and mission.

Expand innovative research in diagnostic andtherapeutic nuclear medicine by increasingfunding for the Advanced Nuclear MedicineInitiative.

Increase the funding for academic training tosupport the primary focus and mission.

Begin conceptual design of a dedicated cyclotronto support the mission to serve the national needfor a reliable supply of isotope products andservices for research, medicine, and industry.

Short-Term Recommendations (the next five years)

1.

2.

3.

4.

5.

6.

7.

8.

22

6 “Expert Panel, Forecast of Future Demand for MedicalIsotopes,” http://www.ne.doe.gov/nerac/isotopedemand.pdf, March 1999.

Final Report

to assess thoroughly the production activities andmarkets, including the impact on facilities, operations,staff, etc. Isotope Programs should propose realisticapproaches to the posed risks to the commercializationentities, and actively match companies with theappropriate skills, staff, and business plans. For eachcommercialization project, a transition plan should bedeveloped and acted upon to transfer smoothly theproduction or processing activities and accommodate thetransition of the laboratory staff and capabilities into newresearch directions with appropriate and sufficientfunding. Successful transition of the laboratory staff andfacilities into new research areas with appropriate andsufficient resources would create valuable motivationand incentive for successful commercialization.

3. Establish an Isotope Review Panel to review andrecommend proposals to produce isotopes to theDirector of Isotope Programs. The Panel shouldidentify isotopes of interest and preferred sites forproduction, including alternative supply options,and provide other advice as requested.

The Subcommittee anticipates that an increasedemphasis on research isotopes will be difficult to achievewithout a means to find a consensus of opinion in theuser community on which isotopes are to be produced.The Subcommittee recommends that an Isotope ReviewPanel be created to make production decisions and actas a resource to review key aspects of Isotope Programsactivities.

The Isotope Review Panel should be a standingcommittee of researchers from academia, governmentand industry. The Panel should meet as needed andmake overall isotope production decisions based oncurrent and anticipated research needs, estimatedproduction capacity and costs, and the overalloptimization of facility and resource usage. In addition,the Panel should make key recommendations on isotopecommercialization, outsourcing, and collaborativeefforts. The Panel should also serve as a resource toIsotope Programs for review of its progress, as well aspeer review of research priorities.

4. Consolidate existing radioisotope processingcapabilities.

The Subcommittee recommends that processingcapabilities at the five existing radioisotope productionsites (Brookhaven, Los Alamos, Oak Ridge, PacificNorthwest, and Sandia) be consolidated in order toreduce redundant capabilities and increase the effectiveuse of resources. The site visits conducted by theSubcommittee indicate that there is an excess ofprocessing capabilities, especially hot cells andprocessing equipment, relative to their system-wide use.In addition, the limited budget of Isotope Programs isinsufficient to support continuous operation of the key

production facilities. Rather than continuing isotopeproduction as a small-scale operation, subject to theschedules, funding, and priorities of other programs, itis recommended that Isotope Programs work toward amore cost-effective and reliable supply based on as fewas two reactor and two accelerator sites. It isrecommended that a special panel of experts be convenedto evaluate the needed steps to consolidation.

5. Contract with the academic and private sectors toaccomplish the primary focus and mission.

As a part of consolidation, the use of productioncapabilities at universities or other private sector entitiesshould be sought. The site visits to representativefacilities determined that they offer cost-effective andflexible irradiation services for reactor- and accelerator-based products. The continuation and possibleexpansion of collaborative production with sites in othercountries also could become an important factor.

The Subcommittee encourages Isotope Programs to availitself of the cost-effective, established facilities within theprivate and academic sectors in order to accomplish itsmission of providing a reliable supply of isotope productsand services. The Subcommittee recognizes that theinclusion of the private sector and academia in its isotopesupply system will result in a network of radioisotopeproviders that will better meet the demand for researchisotopes. It must also be anticipated that the impact ofoutsourcing, technology transfer and commercializationcan lead to a reduction of Isotope Programs revenue. Acontingency plan within the DOE must be created toallow for reestablishment of credentials and efforts tooffset the effect of each successful transfer to the privatesector. Also, the contract process should ensureexpedited response to DOE proposals and award ofcontracts.

6. Expand innovative research in diagnostic andtherapeutic nuclear medicine as provided by theAdvanced Nuclear Medicine Initiative.

The Subcommittee reviewed the Advanced NuclearMedicine Initiative (ANMI), submitted as part of the FY2000 budget proposal. The Subcommittee judges thisinitiative to be of the highest merit to the IsotopePrograms and recommends expansion of the ANMI toallow more projects to be added each year. Further, itwill be important to establish and maintaincommunication between the ANMI and programs withinthe National Institutes of Health and the Food and DrugAdministration.

This initiative will employ a peer-reviewed selectionprocess to identify high priority research grant proposalsin nuclear medicine science and will seek to makeradioisotopes available for research at prices thatresearchers can afford. The recommendations of the

23


Isotope Review Panel should play a major role in thisprocess. Nuclear medicine science will include proposalsto optimize radioisotope production and processingtechniques. The Subcommittee recommends that thisinitiative focus the program funding on research to applyradioisotopes that would be useful for the treatment ofboth malignant and important nonmalignant humandiseases.

The Advanced Nuclear Medicine Initiative shouldencourage the training and education of students innuclear medicine science by supporting scholarships,fellowships, and sponsoring internships at the nationallaboratories and universities (vide infra).

7. Increase the funding for academic training tosupport the primary focus and mission.

It is increasingly evident that the cadre of personnel withexpertise in isotope production and processing isshrinking rapidly, primarily due to retirement. In fact,some believe that the present generation of trainedprofessionals in this field has not reproduced itselfsufficiently to sustain isotope production processing atan appropriate level beyond the year 2020.

In a report prepared for the DOE in 1992 by ProfessorGregory Choppin, Professor of Chemistry at Florida StateUniversity, titled “Status of Graduate Programs inRadiochemistry and Nuclear Chemistry,” Prof. Choppinconcluded that radiochemistry and nuclear chemistrygraduate programs had declined. Laboratory facilitieshad deteriorated, and faculty, students, and support forresearch were insufficient to support most programs. Thenumber of viable radiochemistry programs in 1992 wasprobably eight. Furthermore, the number of doctoraldegrees granted by all programs has averaged fewer thaneight annually during the previous three years, with evenfewer Master’s degrees during the same period. AChemical and Engineering News report on March 13, 1995,tabulated that there were eight doctoral degrees grantedin the previous year. The deteriorating trend reportedin the 1989 National Academy of Science/Institute ofMedicine report, “Training Requirements for Chemistsin Nuclear Medicine, Nuclear Industry and RelatedAreas,” has been persistent.

The “Education and Training of Isotope Experts Report”(June 1998) for the Subcommittee on Energy andEnvironment of the House Committee on Science bymembers of the Senior Scientists and Engineers groupof the American Association for the Advancement ofScience concluded that too few isotope experts werebeing prepared to fulfill the functions of government,medicine, industry, technology, and science. If thesituation is not reversed, the study predicted thesefunctions would face a national crisis, including slowedprogress in medicine and some technologies, an impacton national security, and probable losses in quality health.

The Subcommittee observes that previousrecommendations to support graduate and postgraduatetraining have not been addressed, and now a desperatesituation exists in the disciplines of nuclear andradiochemistry, where scientists and faculty for isotopefields, including nuclear medicine, radiopharma-ceuticals, and radiation safety are educated. Nuclear andradiochemistry are nearly disappearing from researchand faculty positions in universities and colleges becauseexperienced graduates are not available to replace thoseretiring. The major reason for this decline is believed tobe the long inattention to alarms about disappearingfederal support for these programs.

In view of this critical situation it is imperative that theDepartment of Energy increase funding for academictraining to support the primary focus of IsotopePrograms. Such training should be an integral part ofthe Advanced Nuclear Medicine Initiative (ANMI), theNuclear Energy Research Initiative (NERI), and theNuclear Engineering Education and Research Program(NEER). Moreover, all of the isotope production andprocessing facilities, both present and future, should beadequately funded to incorporate academic training asan important component of their responsibilities. Specificforms of support should include undergraduatescholarships, internships, graduate fellowships, researchassistantships, and postdoctoral research assistantships.Efforts should be supported at all facilities to provideon-the-job training for technicians, engineers, andscientists as well as for cross-training to allow fordevelopment of expertise in more than one area. Byspreading the responsibility for academic trainingthroughout the grant awards structure and isotopeproduction and processing facilities, the nation can beassured of a work force adequately trained andmaintained.

8. Begin the conceptual design of a dedicated cyclotronto support the mission to serve the national needfor a reliable supply of isotope products and servicesfor research, medicine and industry.

The existing isotope production program relies onmultiprogrammatic facilities where isotope productionaspects are not the primary mission. Thus, theavailability of radioisotopes for the research communityis limited by the operating schedule of these facilities.This is especially true for the accelerator-producedradionuclides that rely on the accelerators at Brookhavenand Los Alamos National Laboratories. During 1999,these accelerators were used in a parasitic mode for lessthan 20 weeks per year. The incremental cost fordedicated radioisotope production at these accelerators,as they are currently configured, is prohibitive. TheSubcommittee recommends the purchase of a highcurrent multibeam cyclotron by 2005. The energy of thecyclotron should depend upon other existing accelerator

24

Final Report

capabilities for these radionuclides at greater than 40MeV. The Isotope Review Panel should be charged withthe task of choosing the specifications for the cyclotron.The siting of the cyclotron should undergo carefulconsideration with respect to long-termrecommendations for combining radioisotopeproduction capabilities at a single site. To meet the timeschedule, a conceptual design for the cyclotron shouldbe initiated during FY 2000.

Discussion of Long-Term Recommendations

1. Promote the greatest synergism among the nationallabs, academia, and industry to fulfillthe Isotope Program’s mission.

Isotope Programs should adopt a strategy to conductworld-class research and development in support of itsmission by promoting the greatest synergism among thenational laboratories, academia, and industry. Forexample, the development of strontium-82 generatorsfor PET imaging leveraged the research and developmentcapabilities of Los Alamos National Laboratory, BaylorUniversity, and Bristol-Myers Squibb Co. Relationshipsof this type create a network of collaborators in a virtuallaboratory of capabilities. The benefits of such a strategyyield significant cumulative effects and a broaderresearch program despite budgetary limitations andlimited facilities.

2. Acquire a dedicated, single-mission, isotopeproduction and processing facility that would befully operational by 2010. The facility shouldinclude a cyclotron and a reactor both dedicated toisotope production based on off-the-shelf designs.

Plans for acquiring a dedicated radioisotope productionreactor should be initiated so that both the cyclotron andreactor radioisotope production facilities will meet theradioisotope needs of the U.S. research community by2010. As the most economical solution, theSubcommittee recommends siting the cyclotron andreactor at the same location.

3. Maintain a stable/enriched isotope inventory forresearch purposes.

Isotope Programs should maintain a stable/enrichedisotope inventory for research purposes. TheSubcommittee recognizes that commercial entities willpursue a supply of enriched stable isotopes for theproduction of their products. Several stable and enrichedisotope products, e.g., oxygen-18, the target material forproducing fluorine-18, for which there is increasingdemand because of the increasing number of researchand clinical coincidence gamma camera and PET studiesbeing performed, are available primarily from non-U.S.sources. Oxygen-18 is also used in lower enrichment,but in greater quantity, in nutrition studies. In October1999, a representative of the major Russian supplier of

Promote the greatest synergism among thenational labs, academia, and industry to fulfillthe Isotope Program's mission.

Acquire a dedicated, single-mision, isotopeproduction and processing facility that would befully operational by 2010. The facility shouldinclude a cyclotron and a reactor both dedicatedto isotope production based on off-the-shelfdesigns.

Maintain a stable/enriched isotope inventory forresearch purposes.

Ensure an adequately sized and properly trainedwork force to meet national isotope needs.

Implement a contingency plan to guarantee anuninterrupted radioisotope and stable isotopesupply for the country's research needs.

Long-Term Recommendations (the next ten years)

1.

2.

3.

4.

5.

25


stable isotopes to the U.S. reported a significant numberof requests for increasing quantities of oxygen-18 duringthe past year.7 There are some researchers who believethat, in addition to oxygen, there will also be a shortageof stable isotopes used for nutritional and biomedicalresearch, e.g., calcium, magnesium, and selenium. Thisdemand will drive a continuing supply of those isotopes.The research community depends on those supplies thatare in inventory at ORNL. The Subcommittee is awareof, but did not review in detail, the August 1999 reportby A. Weitzberg, “The Future of Stable IsotopeProduction in the U.S.,” prepared for DOE. We believethe technical quality and the various analyses are likelyto be proven valid, but offer no position on the specificrecommendations in the report. The Subcommitteerecommends that Isotope Programs conduct anassessment of the low capacity enrichment capabilitieswithin the national laboratories that can be used toreplenish small quantities of those research isotopes thatare exhausted. In parallel, the program shouldinvestigate alternative sources of those isotopes and usethe production channel that will ensure long-termavailability of those isotopes. Provided that adequatebudgets are available for research, limited funds shouldbe made available for research into enriched stableisotope production using technologies other thanelectromagnetic separation.

4. Ensure an adequately sized and properly trainedwork force to meet national needs.

To ensure an adequately sized and properly trainedworkforce to meet national needs, long-term academictraining in isotope production and processing shouldpermeate the entire gamut of funding programs, suchas ANMI (Advanced Nuclear Medicine Initiative), NERI(Nuclear Energy Research Initiative), and NEER (NuclearEngineering, Education and Research Program), as wellas continue as an integral component of the mission ofisotope production and processing facilities. In addition,the Department of Energy should make a concerted effortto revive radiochemistry and related programs atacademic institutions. These programs have beenallowed to contract almost into nonexistence. If this trendis not reversed, then no programs will exist to sustainour national needs in this important area.

5. Implement a contingency plan to guarantee anuninterrupted radioisotope and stable isotopesupply for the country’s research needs.

It is important that contingency planning be performedand implemented by Isotope Programs that act toguarantee isotope supplies in the long term. This mustinclude consideration of facility retirement and/orredirection, potentially major changes in the agreementsunderlying parasitic production, successful consolidationof processing capabilities, and the timing anduncertainties of bringing new, dedicated facilities online.

26

7 “Report on The Supply and Demand of Oxygen-18 EnrichedWater,” A report of the ad hoc committee of the North AmericanAssociation for the Study of Obesity, Jan. 21, 1999.

Final Report

Site Evaluations

Evaluation Procedure and Criteria

The Subcommittee selected four areas of critical concernfor evaluation: (1) production of reactor radioisotopes,(2) production of accelerator radioisotopes, (3) currentgood manufacturing practice (cGMP) capabilities, and(4) education and training. To gather current informationand status, seven sites were identified, and site visit teamswere formed to gather information and report on eachsite. The seven sites included the five DOE nationallaboratories currently engaged in isotope production orresearch (Brookhaven, Oak Ridge, Los Alamos, Sandia,and Pacific Northwest), as well as two representativenonfederal producers of isotopes. The two nonfederalproducers were the Missouri University ResearchReactor, the largest university research reactor and mostactive producer of radioisotopes in academia, andInternational Isotopes Inc., an emerging entrant into high-energy accelerator operations in the United States andcommercial partner for reactor isotope production andprocessing at the Idaho National Engineering andEnvironmental Laboratory.

To prepare for each visit, the questions listed in theCharge to the NERAC Subcommittee and additional siteevaluation questions (see box) were sent to the managerof each production facility, and written responses werereturned. These were reviewed during the visit. Eachsite team prepared a Site Visit Report, which was sharedwith the site visit manager. The manager reviewed thereport for factual content and possible ambiguity andreturned comments to the site-visit chair. The site-visitteam then finalized their report. Five Site Visit Reportswere subsequently reviewed, discussed, and approvedat a first meeting of the full Subcommittee held on June22–23, 1999. The remaining two reports were reviewed,discussed, and approved at a second meeting of the fullSubcommittee held on September 28–29, 1999. Duringthese meetings, the full Subcommittee established theshort- and long-term recommendations.

The seven Site Visit Reports, with the written responsesto the site evaluation questions, are included asappendices to this Final Report.

The Subcommittee felt a brief summary comparison ofthe sites would be useful. To accomplish this, criteriawere developed within the four areas of critical concern.The criteria are listed in the following table, and thescoring of each production site was discussed by the fullSubcommittee to produce the final ratings.

High thermal neutron fluxfor attaining high specificactivity, and high energyneutron flux for producing(n, p) reactions

A broad flux profile withavailability of high neutronenergy regions and thermalflux traps

Reactor availability (Percentof time in operation):>98% (excellent), 97-90% (good), 89-80% (fair),<80% (poor),<50% (marginal)

Easy access to the reactorcore, including duringreactor operation with ashuttle system

High proton energy

High beam Current

Accelerator availability(percent of time in operationfor isotope production):>90 (excellent, 90-80% (good), 80-70% (fair),70-50% (poor),<50% (marginal)

Production ofReactor Radioisotopes

Production ofAccelerator Radioisotopes

Overall Site Evaluation Criteria

Current good manufacturing practice (cGMP)

Availability and conditionof the products

Availability and conditionof hot cells

Logistics and personnel

Ability to attract studentsand operating personnel

University affilations

Internships

Processing Capabilities Education and Training

27


Site Evaluation Questions

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

How well does the Department's existing five-site production infrastructure serve the current need forcommercial and research isotopes?

What is the physical condition of the isotope processing facilities and equipment?

What capital investments are needed to assure the near term operability of the facilities?

If additional resources are needed, are they practical, e.g., technically rational, easily integrated into existinginfrastructure, quickly implemented and supportable? Will any portion be sustainable over time by localfinancial and personnel resources?

What is the availability of the primary nuclear facility (accelerator or reactor) over the next five years, e.g.,HFIR outage, LANSCE program changes?

What understanding exists at each site about the priority of isotope production to serve isotope customers?

How much influence does each site manager have in planning the use of multi-purpose facilities?

What cost-containment measures are being pursued?

What "licensing" issues need to be addressed?

What unused or underused capacity, e.g., personnel, facilities, could be mobilized to support growth in isotopedemand?

Summarize customer inquiries received during the past two years. What percent was filled, referred to otherfacilities, rejected? Explain unfilled requests.

How does each site manager rate customer satisfaction for his site? For the overall program?

Kindly detail how you set the price of a mCi of a radioisotope? the detail should show if the cost is fully loadedor incremental, and should include labor, materials and parts, facility rental and amortization costs, listing of allthe actual overhead charges, waste disposal (a major cost), and all other costs that are tagged to the cost ofproducing, marketing, selling, and distributing of the product (e.g., customer service, distribution, ordering).

Illustrate the above question for the following radioisotopes: In-111, P-32, I-123, I-125, and several researchradioisotopes.

What process, mechanism, and organizational structure do you have for the timely distribution of the producedproduct?

What processes, mechanism, organizational structure do you have for customer service?

Will you sign contracts that guarantee delivery at the contracted time of delivery and where the contract haspenalty clauses for non-timely delivery of the specified product?

What should be the long-term role of Government in providing commercial and research isotopes?

28

Final Report

Site Assessment Results

A summary of site profile assessments is presented intwo tables. The tables overview and compare each site’scapabilities. These tables are based on theSubcommittee’s site evaluation experiences. Note thatthe scoring of the factors for sites is based solely on howwell the existing in-house capabilities fulfill the missionfocus recommended by the Subcommittee, i.e., thesupply of research radioisotopes.

The scoring scale is based on a five-point system withfive being considered excellent and one being marginal.An excellent rating for a given category means that thesite must be able to supply research radioisotopes withsuperior capabilities related to that category. In the casewhere no capability exists, it is noted in the table as NoExisting Capability (NEC).

The Subcommittee cannot overemphasize that thescoring of the sites focuses on the current and futuresupply of radioisotopes for research. These assessmentsdo not reflect the enormous contribution that eachnational laboratory has made in the past and will makein the future to the development of the sciences in theUnited States.

Each table represents the Subcommittee’s assessmentrelative to the evaluation criteria for the indicated timeperiod. The first table is based on the Subcommittee’sassessment of the current data collected by the site visitteams. The second table is the Subcommittee’s estimateof the capability of the sites based on their stated budgetprojections and stated projects in planning for the nextfive to ten years. Due to the uncertainty in the statedplans of each facility, the second table should beinterpreted with caution.

Missouri University Research Reactor

Los Alamos National Laboratory

Oak Ridge National Laboratory

International Isotopes Inc.

Sandia National Laboratory

Brookhaven National Laboratory

Pacific Northwest National Laboratory

Rating Scale: 5 = excellent 4 = good 3 = fair 2 = poor 1 = marginal NEC = no existing capability

5

NEC

4

3

2

NEC

NEC

NEC

2

NEC

1

NEC

1

NEC

3

5

3

5

3

4

2

5

4

3

NEC

1

1

3

ReactorIsotopes

AcceleratorIsotopes

cGMPa

CapabilitiesEducation& Training

Assessment of Isotope Capabilities in 1999

Missouri University Research Reactor

International Isotopes Inc.

Los Alamos National Laboratory

Oak Ridge National Laboratory

Sandia National Laboratory

Brookhaven National Laboratory

Pacific Northwest National Laboratory

a.

b.

c.

Current good manufacturing practice.

Based on projected budgets and projects currently in planning and development indicated by the sites.

The Subcommittee did not rate this category because the Subcommittee does not consider the FFTF tobe a viable long-term source of research radioisotopes.

5

3

NEC

4

2

NEC

c

NEC

4

4

NEC

NEC

1

NEC

5

5

5

3

4

4

c

5

4

4

3

3

2

3

ReactorIsotopes

AcceleratorIsotopes

cGMPa

CapabilitiesEducation& Training

Assessment of Isotope Capabilities Estimated in 2005-2008b

29


Observations

The Subcommittee makes several observations: first,research isotope supplies outside the national laboratorysystem offer significant, complementary productioncapability. Second, DOE sites, as an aggregate, have morethan adequate processing capability today. And third,no overall strategy exists regarding the designation ofpreferred reactor and accelerator sites. This leads to theconclusion that the production capability suffers fromfunds being shared by too many sites. It is theSubcommittee’s opinion that the short-term supply ofradioisotopes for research would be adequately servedby as few as two reactor and two accelerator productionsites.

30

Final Report

Comments on the Fast Flux Test FacilityFor Isotope Production

As stated, the role of Isotope Programs in the short andlong term should be to maintain a reliable system thatproduces isotopes for the research community. In limitedinstances, the DOE possesses unique resources, e.g., thehigh flux of fast neutrons and large irradiation volumein FFTF, that could be utilized for the production of someresearch isotopes, but is best suited for commercialinterests who might consider its use for isotopeproduction.

A few of the radioisotopes identified in the FFTFdocuments provided to the Subcommittee fall into thiscategory, notably tungsten-188, the parent of rhenium-188. The team at FFTF and PNNL should be encouragedto pursue commercial production opportunities wherethey exist. It was apparent to the site visit team that thescope of operations at PNNL will require large amountsof funding, both capital expenditures and operationalfunds. This funding requirement necessarily requiresthe isotope production activity to focus on isotopes withlarge demand and mature markets.

The Subcommittee concludes that the FFTF will not be aviable source of research radioisotopes. Anticipatedincome from sales likely will not meet expectationsthereby curtailing operations and reducing the FFTF’scapability to produce research radioisotopes in a timelyand cost-efficient manner. In light of these factors, theSubcommittee recommends that the FFTF not beconsidered as a viable long-term source or researchradioisotopes.

The Subcommittee believes that the production needsof neutron-rich isotopes for research purposes can be metby existing reactors. In particular, the operations at theMissouri University research reactor and the High FluzIsotope reactor are better suited to meeting the demandsof users who need small quantities of research isotopesat irregular intervals. Other neutron sources may alsobe available for research isotope production.

The Subcommittee has reviewed the FFTF business planand will submit their observations and suggestions forissues to be addressed in the EIS review in a separatedocument.

The FFTF is a research reactor located at Hanford that is proposed for operationat 100 MW. The original mission of the FFTF was to support the U.S. liquidmetal reactor technology development program. Although this program endedat about the same time that FFTF commenced in 1982, the reactor continuedoperation for 10 years as a DOE national facility for production of medicalresearch isotopes, the testing of advanced nuclear fuels and materials, andthe development of active and passive reactor safety technologies. The reactorwas shut down in December, 1993, but in August, 1999, the Secretary ofEnergy approved the preparation of a Programmatic Environmental ImpactStatement (PEIS) for expanded civilian nuclear R&D and isotope productionmissions that included the role of the FFTF. A PEIS is now being preparedthat includes environmental impact data for future FFTF missions. Thesemissions include isotope production, reactor safety testing, production ofplutonium-238 as a power source for deep space exploration missions, testingof reactor fuels and instrumentation, and irradiation services related tomaterials testing and transmutation of nuclear wastes.

31


NERAC Subcommittee for IsotopeResearch and Production Planning

ChairRichard C. Reba, M.D.,Professor, Department of Radiology (NuclearMedicine)University of Chicago

MembersRobert W. Atcher, Ph.D.,Bioscience DivisionLos Alamos National Laboratory

Ralph G. Bennett, Ph.D.,Director, Advanced Nuclear EnergyIdaho National Engineering and EnvironmentalLaboratory

Ronald D. Finn, Ph.D.ChiefCyclotron/Radiochemistry Medical ImagingDepartmentMemorial Sloan-Kettering Hospital

Linda C. Knight, Ph.D.,Professor,Diagnostic ImagingTemple University School of Medicine

Henry H. Kramer, Ph.D.,Executive DirectorCouncil on Radionuclides andRadiopharmaceuticals

Sekazi Mtingwa, Ph.D.,J. Ernest Wilkins, Jr. Distinguished Professor ofPhysicsMorgan State University

Thomas J. Ruth, Ph.D.,DirectorPET ProgramTRIUMF

Daniel C. Sullivan, M.D.,Associate DirectorNational Cancer Institute/National Institutesof Health

Joan B. Woodard, Ph.D.,Executive VP and Deputy DirectorSandia National Laboratory

32

Final Report

Appendices

Appendix A: Missouri University Research Reactor

Appendix B: International Isotopes, Inc.

Appendix C: Brookhaven National Laboratory

Appendix D: Oak Ridge National Laboratory

Appendix E: Los Alamos National Laboratory

Appendix F: Sandia National Laboratory

Appendix G: Pacific Northwest National Laboratory


Missouri University ResearchReactor (MURR) Site Visit

Site Visited April 28, 1999

1. Introduction

On April 28, 1999 a site visit team including RobertAtcher (LANL), Ralph Bennett (INEEL), and HenryKramer (consultant) reviewed the operations at MURR.The site visit team heard presentation from EdwardDeutsch, MURR director, and had discussions withseveral other members of the reactor management. Theyalso met with Jack Burns, Vice Provost for Research, atthe Columbia campus.

Mission

The mission of the MURR changed when Ed Deutschbecame director 18 months ago. Dr. Deutsch hasrefocused the mission of the MURR on isotopeproduction activities. Prior to his arrival, the primaryfocus of the reactor was on scattering experiments. Thereactor is also used for materials testing, neutronactivation analysis, and other research activities.

Facilities

The Missouri University Research Reactor (MURR)provides opportunities for research and graduateeducation in the neutron-related sciences that areunmatched at any other U.S. university. The central focusof this research center is a 10 megawatt light watermoderated reactor that is the highest power universityresearch reactor in this country. The reactor providesextensive capabilities for both neutron beam research aswell as irradiation facilities for producing a variety ofisotopes and performing activation analysis.

The reactor has been in operation for 29 years(commencing October 13, 1966), and since 1976 has hada 150+ hour per week operating schedule maintainedmore than 90% of real time. At the end of fiscal year 1995,MURR had a full-time staff of 115 including 25 Ph.D.scientists engaged in research programs. The reactor is aUniversity Research Center, not part of any MUdepartment, and reports to the Vice-Provost for Research.

The operation of the reactor is under the direction of theReactor Operations Manager and operations group whoalso handle in-pool and flux-trap sample irradiationprocedures. This group has close association with theFacility Operations Manager and group responsible forimprovements and maintenance of the reactor andassociated instrumentation facilities. This includes amechanical engineering and design group and completemechanical and electronics shops.

Development engineering of new electronicinstrumentation is provided by the InstrumentDevelopment group. Computer software and hardwaresupport, including the facility-wide computer networkand instrument control computers, is under the directionof the Computer Applications group. Health physicssurveillance and support for the diverse irradiation andlaboratory facilities at MURR are provided by a HealthPhysics Manager and group. Responsibility for all of theoperations and support groups is under the leadershipof the Associate Director of the Center.

Before any experiment is done or performed at MURR,a Reactor Utilization Request must be filled out andapproved. The principle experimenter or assistant fillsout a form where they describe the experiment. Theexperiment is evaluated for radiation safety and reactorsafety. The evaluation is reviewed by the reactor manager,health physics manager and the safety subcommittee.

Beamports

There are six beamports, three 4 inch and three 6 inchports. Beamports “A”, “D” and “F” are 4-inch ports.Beamports “B”, “C” and “E” are 6-inch ports.

Beamports “A” and “F” are located 2 inches below corecenterline and have the highest flux. “F” port canpenetrate the beryllium but does not. “B” and “E” portsare 7 inches below core centerline. “C” and “D” portsare 14 inches below core centerline and are tangential tothe core. This gives the ports good thermal neutrons withless fast neutrons and gammas. “A” port currently hasprompt gamma facility. “B” port has SANS andinterferometry. “C” port has neutron effect studyequipment. “D” port PSD and other material studies.“E” port double and triple axis for material studies. “F”port is neutron beam filter studies.

The pneumatic tube system is used to irradiate samplesrapidly and in small quantity. The system has two 1-1/2concentric pipes which terminate in the graphite reflector.The tubes are operated out of four labs. Two labs assignedto each tube. The p-tubes are used for trace elementstudies in nutrition, geology, archaeology, chemistry,medicine and veterinary medicine. The tubes are usedto make target material to run in the reactor or shippedto another user on or off campus.

The graphite reflector contains 16 irradiating positionswhich vary from a nominal size of 1 inch to 6 inches.These positions are used to irradiate an assortment ofitems like silicon, topaz, gold, sulphur, iridium, teeth,sodium, etc.

The center test hole contains the three tube flux trapsand is MURR’s highest flux irradiating position and themost valuable real estate in the reactor. The test hole is a4-inch aluminum tube which goes through the center of

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Appendix A

the core and is the inner pressure vessel. The restrictionson what can be run are the most strict. The sampleplacement is critical due to the reactivity effects eachsample has which changes with height. These values aremeasured before full-scale runs are performed. Thesamples are restricted by weight, size, how it isencapsulated, what effect it has on system componentsand effect on other samples.

Neutron Fluxes

• Center test hole has an average flux of thermalneutrons of 6.2 x 10E14 nv.

• Beam tubes range from 1 x 10E6 nv to approximately5 x 10E8 nv.

• Irradiation positions have flux profiles from top tobottom with peaks that range from 8 x 10E13 to 1 x10E10 nv.

• Pneumatic tubes have flux rates at 5 x 10E13 nv in rowone to 1 x 10E11 nv in row two.

Products and Services

The Radiation Services Group provides the interfacebetween experimenters and the reactor, and is made upof the Irradiations/Isotope Production, Silicon, Shippingand Gemstones Sections and support staff. The groupreviews experiments to ensure that all safetyrequirements are met, prepares samples for irradiation,processes irradiated materials, and packages and shipsmaterials after irradiation. The group handles theprocessing of production isotopes, silicon and gemstonesthat generates the bulk of the Center’s revenue forresearch work. During FY94, Radiation Servicesperformed work for approximately 57 industrialcustomers, 38 universities and eight governmentagencies.

Two main regions of the reactor used by this group arethe reflector and the flux trap. The flux trap, providingthe area of highest flux, is loaded and unloaded once aweek during reactor shutdown. Samples can be loadedinto the reflector region at any time during the week.Sample size is limited by the diameter of the reflectortubes that hold the samples in the reactor pool. Thelargest tube can hold a five-inch diameter sample.

MURR ships about 2000 shipments per year. Theseshipments are divided among commercial customers andresearch investigators. The material shipped includessome isotopes that undergo processing as well as thosethat irradiated as a service.

2. Relationship to DOE Programs

DOE Office of Isotope Programs (IP)

At present, there is no formal arrangement with IP. Thestaff at MURR has submitted a proposal to IP to conductisotope production activities with funding from IP. Thisproposal is currently under review.

Other DOE Programs

The MURR is fueled by highly enriched uranium. Thereactor is dependent upon DOE to provide the HEU forthis fuel. This amounts to $900K per year in support. Inlight of the fact that HFBR at BNL is in standown, MURRapproached DOE about the possibility of moving someof the scattering work done at HFBR to MURR. Theirproposal was not accepted. MURR, through itspartnership with the Nuclear Engineering program, alsohas interactions through training programs.

3. Relationship to Academic Programs andTraining

Overall, the Missouri University conducts over $380Mof sponsored research per year, and is ranked in the top20 institutions nationwide in terms of researchexpenditures. The Columbia campus has 13 colleges andprofessional schools, and features colleges of medicine,veterinary science, engineering, arts and sciences, andagriculture on its campus. A continuing strength in thebiomedical and life sciences is seen as the major impetusbehind continued operations of MURR. While theUniversity offers a nuclear engineering option with M.S.and Ph.D. students enrolled, there is not a formalDepartment of Nuclear Engineering. The number ofstudents electing the nuclear engineering option is notexpected to grow in the near term.

Radiopharmaceutical Sciences Institute

An interdisciplinary radiopharmaceutical scienceprogram has existed on the Columbia campus for over20 years, involving clinical departments in the School ofMedicine, the Departments of Chemistry and Biology,the College of Veterinary Medicine, the Harry S. TrumanMemorial Veterans Hospital, and MURR. To build thisprogram, Missouri formally established theRadiopharmaceutical Sciences Institute (RSI) in 1999.This recognition formalized the interdisciplinaryprogram, and underscored its importance with a majorfinancial investment to expand and enhance the RSI withfive new tenure track positions to begin in FY 1999 and2000. There are currently 12 RSI faculty, who in totalconduct an average of $1.4M per year of externallysponsored research.

The RSI is an integral part of education and trainingprogram in the biomedical and life sciences. RSI facultyhold appointments in Ph.D. granting departments. An

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average of seven Ph.D. candidates has been supportedeach year on RSI-generated funds over the last decade.The students meet the Ph.D. requirements in theirrespective home departments, and participate in RSIseminars, research presentations, discussion groups, etc.They also interact through laboratory rotations withinMURR and through the conduct of specific experimentsrelevant to their research. The RSI faculty is activelyinvolved in training postdoctoral research fellows,averaging five fellows in recent years. Over fiveundergraduate students are mentored each summer inthe RSI as a part of the Research UndergraduateExperience program.

4. Current Isotope Production

Throughput

MURR makes about 2000 shipments per year. Theseinclude commercial customers and researchinvestigators. The potential to add Good ManufacturingPractice capability would expand the product lineavailable as MURR could ship radiopharmaceuticalgrade material. This involves an added cost to the enduser, however.

Customers

The customer base includes commercial vendors whosell a product that includes the radioisotope producedat MURR, research investigators who use the product inclinical trials, and research investigators who areconducting preclinical and basic research.

Pricing Policies

Dr. Deutsch emphasized to us that pricing has to be doneto recover the costs of operation for the facility. Thispolicy has forced them to narrow the number of isotopesthat can be produced on a routine basis. One casualty ofthis new policy is production of Cu-64. Pricing for largervolume isotopes is done on an individual basis. A pricelist is expected to be available in June 1999.

Product Development

Product development has been excellent. The staff atthe reactor, in collaboration with faculty at MU, hasaggressively pursued external funding to developradionuclides and radiopharmaceuticals. With thesupport of the RSI, this is expected to continue.

5. Future Capabilities and Resource Requirements

Continued Operation

MURR was originally licensed by the Nuclear RegulatoryCommission (NRC) in 1966. Continued operation ofMURR beyond 2001 is contingent upon successful re-licensing by the NRC. Costs associated with re-licensingare estimated to be $8.1M, which includes $1.2M for

safety analysis and license submittal and the balance,$6.9M, for a variety of upgrades and replacements. Thespecifications for upgrades and replacements haveadopted a long-term view, and their successfulimplementation will result in a research reactor that canoperate for many years into the future.

While there was some experience with nuclearintervenors over a TRU electrochemical separationprocess at the facility in the early 1990s, the expectationis that the reactor re-licensing will proceed smoothly.

Expanded Operations or Services�Underway

Modification of the center flux trap in the reactor istentatively scheduled to take place in 1999, althoughfunding is not certain. The redesigned high flux regionwill be partitioned into smaller regions, several of whichwill allow insertion and removal of 0.38" diameterirradiation targets during full power operations, ratherthan during the weekly fuel changeout. This will add asignificant capability to MURR for production of highspecific activity short-lived radioisotopes. Themodification requires NRC approval for a revision toMURR’s Technical Specifications.

Funding is being obtained to build a second high activitygeneral use hot cell. The estimated cost is $200K.Currently, only one high level hot cell exists. There areobvious concerns about operations if this hot cell is notfunctional for some reason.

As a supplier of high quality radioisotope products,MURR is working toward achieving GoodManufacturing Practices (GMP) status for selectedradiopharmaceuticals. This is typically accomplished ona case-by-case basis with the assistance of apharmaceutical partner. One recent example of this was153Sm EDTMP.

Expanded Operations or Services�Proposed

To meet expected demand for research radioisotopeproduction, as many as five additional hot cells areproposed for addition over the next three years. Theestimated cost is $250K per hot cell.

The availability of space for facilities is a continuingproblem for MURR. The MURR facility is fully utilized,and the facility layout does not easily lend itself toexpansion. While land is available nearby for additionalconstruction, it cannot be developed until levees arecompleted to alter the flood plain it occupies. The visionfor facility expansion is to construct a $6M building,possibly as a business incubator, to seed the developmentof products and services based upon the reactor.

A number of studies of power upgrades to the reactorhave been performed over the years. These haveestablished the feasibility of upgrading core power to 20

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Appendix A

(or even 25) MW, from the current 10 MW level. Thestudies project a cost ranging from $15–25M toaccomplish the upgrade. Funds have not been identifiedfor this purpose.

6. General Issues Related to Isotope Supply

Institutional Support

The operational budget for MURR is approximately $8Mper year. This is comprised of roughly $2M from theState of Missouri, $2M from grants and researchcontracts, and $4M generated from operations. None ofthese are considered base funding. With MURR’s centralposition in the future of the University’s biomedical andlife sciences programs, support from the Universityadministration is quite strong. However, the annualoperating funds require a considerable effort to maintainor grow because they are derived from different sources,and because none are considered a base commitment offunds.

While it has elected not to submit proposals in recentyears, MURR may be able to successfully compete forNational Center for Research Resources or ProgramProject Grants from the National Institutes of Health.These are typically on the order of $1M per year in directsupport.

Marketing

MURR makes about 2000 shipments of radioisotopes peryear. About 90% are for biomedical/medical/life scienceapplications, and the remaining 10% are for commercialapplications. Overall, about 60 different isotopes areavailable. MURR’s customer contracting is quite flexible,ranging from simple purchase orders to long-term supplyor partnering agreements. Pricing is set individually foreach routinely delivered product or service. MURR’sapproach to pricing is to consider all costs associated withfilling the order.

MURR is aggressively pursuing radioisotopes sales andapplications services. This includes marketing at nationalmeetings of prospective customers utilizing an exhibitionbooth. A campaign has recently begun to increase severalof its neutron activation analysis services, a few of whichhave a fairly strong forecast growth.

Business Practices

In recent years, MURR has been as much as $2M in debt,largely due to spending on R&D at the facility exceedingrevenues. The prospects are good that this can becorrected, however, as MURR exits the topaz irradiationbusiness and sells off existing stocks. At this point cashflow is positive. The facility runs on a modified cashflow basis, which allows it some flexibility for the pricingof isotopes. Also, it was noted that MURR has someflexibility in using operating funds for capital equipmentpurchases.

An important issue for sources of funding for MURR isthe University policy on overhead charges for researchgrants. This currently is set at 46%, which considerablyreduces the amount available for operations. Analternative to funding radioisotope production at MURRwould be to place a blanket purchase order with MURRfor radioisotopes, which would avoid the generaloverhead charges. Dr. Deutsch noted, however, that thismechanism would require a “pay or take” provision sothat he could hire the staff necessary to supply thoseisotopes.

Waste Management

Waste is handled according to provisions outlined by theState. The cost of radioactive waste handling hasescalated which has had an impact on productiondecisions. These include ceasing Cu-64 production inpart because a waste stream of Zn-65 was created. Long-lived radioactive waste is shipped to sites outside ofMissouri.

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Missouri University ResearchReactor (MURR)

Questions and Answers

1. How well does the Department’s existing five-siteproduction infrastructure serve the current needfor commercial and research isotopes?

In our experience as a back up for MURR it did notserve our needs very well

2. What is the physical condition of the isotopeprocessing facilities and equipment?

The physical condition of facilities and equipmentfor isotope processing at MURR is adequate for thecurrent level of demand. For any expansion of ourcurrent capabilities we’d need capital investmentin several dedicated hot cells.

10 MW Light Water Moderated Reactor: The reactoruses highly enriched uranium, is light watermoderated and cooled, and is beryllium reflected.The reactor is pressurized and is centered 25 feetdown in a water-filled pool. Eight fuel elements inthe fuel zone form the core. Each fuel element isassembled from 24 fuel plates; each plate is asandwich of uranium aluminide fuel withaluminum cladding, held in place by side plates andend boxes. The core has 6.2 kg of 235U fuel. Theactive core is 29.77 cm in diameter and 60.96 cmtall, with an active core volume of 33 liters. At thecenter of the core of the reactor is a neutron fluxtrap with an unperturbed peak flux of 6 x 1014 n/cm2sec.

The reactor has a compact core loaded with 93percent enriched 235U aluminide fuel. The reactordesign is derived from the High Flux Isotope Reactor(HFIR) design, but is simplified for lower poweroperation and ease of maintenance. The fuel iscontained in the pressure vessel, through which thecooling and moderating water flows. All movingparts, such as control and regulating blades, areexternal and visible in the open light water pool.Over the last 20 years, there have been only a fewunscheduled shutdowns typically lasting less thanone day. The extended history of reliable operationof MURR is a major asset to its users, both scientificand technical.

Radioisotope Processing Facilities: Four research/processing laboratories (~350 ft2 each) are dedicatedto processing research radioisotopes radioisotopesand radiopharmaceuticals. All of the labs havehoods connected to MURR’s ventilation system,which is monitored for radioactive releases. There

are six lead shielded gloveboxes for processing upto Curie quantities of some radioisotopes. These cancurrently be used to process Re-186, Rh-105, Lu-177,Re-188, W-188 and others.

A small processing hot cell with two manipulatorsand remotely operated syringe pumps is availablefor processing holmium target, enabling productionof multi-Curies of Ho-166 solution per week. Thiscan be divided and shipped to multiple users.Another lead-lined processing unit with a singlemanipulator and remotely operated syringe pumpsis used for the production of Sm-153 solutions on aweekly basis, enabling the production and supplyof up to 40 Curies of Sm-153 solution per week.

Irradiation Facilities: MURR currently utilizes theflux trap, the graphite reflector region, and the bulkpool facility to irradiate a wide variety of targets toproduce radioisotopes and activated samples fortesting and analysis. A schematic of the irradiationfacilities is included below (Figure 1). The flux traphas a 4.5” annulus and provides a peak flux of 4.5 x1014n/cm2/s. With a 30” vertical length, the flux traphas a maximum usable volume of 477 cubic inches.The current flux trap configuration consists of three1.5” outer diameter (OD) tubes with a total usablevolume of 110 cubic inches of 1.13” OD samples.

Though lower in flux, the graphite reflector regionprovides a much larger volume for irradiations andalso has the advantage of access to targets when thereactor is at full power. The irradiation positionsare approximately 30” tall and have diameters andpeak fluxes as follows: 1ea @ 1.350” OD (8.0 x 1013n/cm2/s); 2 ea @ 1.125” OD (5.0 x 1013 n/cm2/s); 5ea @ 2.350” OD (6.0 x 1013 n/cm2/s); 5 ea @ 3.350”OD (2.5 x 1013 n/cm2/s); 2 ea @ 6.0” OD (1.0 x 1012

n/cm2/s); and 2 ea pneumatically controlled 1.0”OD (5.0 x 1013 n/cm2/s with 4” usable length. Thebulk pool facilities allow for larger or especiallyshielded irradiation positions. Currently there aretwo 4”-, one 5”- and one 6”-diameter positions 30”in length, and a 1.125”-diameter sample, 10”-longlead shielded position. The peak flux for the bulkpool facility is approximately 6 x 1012 n/cm2/s.

3. What capital investments are needed to assure thenear term operability of the facilities?

Relicensing costs and a backup hot cell are requiredfor near term, as well as long term, reliability.Additional hot cells, dedicated to processingradioisotopes for medical applications, are requiredto increase or radioisotope processing and supplycapabilities to meet future demands for clinicalgrade radioisotopes.

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Appendix A

Relicensing of MURR: The State of Missouri and theUniversity of Missouri are making plans now forthe relicensing of MURR with the NRC in 2001.Expenses associated with this relicensing areestimated at $8.1 million and serve to illustrate thecommitments of the State and the University toMURR.

Backup Hot Cell: Steps to obtain/build a secondhigh activity general use hot cell are currentlyunderway. The estimated cost for such a hot cell is~$200,000.

Dedicated Processing Hot Cells: To meet theexpected increase in demand for researchradioisotopes additional hot cells which will allowus to produce clinical grade radioisotopes formedical application are required. We anticipateadding 5 such hot cells over the next 3 years. Theestimated cost for each hot cell, includingmanipulators, is ~$250,000 for a total cost of~$1,250,000 for five such hot cells.

4. If additional resources are needed, are theypractical, e.g., technically rational, easilyintegrated into existing infrastructure, quicklyimplemented and supportable? Will any portionbe sustainable over time by local financial andpersonnel resources?

The relicensing philosophy will be to request thefunds necessary to allow us to provide the reliabilityto operate ~90% of all available hours for the next20 years. We will have done a condition assessmentof all operating equipment and proposed thereplacement and timing of replacement so we cancontinue our historic availability record. This willinvolve both capital investment and ongoingoperating costs be considered for twenty years ofreliable operation.

All additional hot cells and major equipment willbe integrated into our maintenance and replacementprogram to ensure MURR’s long term capability andreliability as a supplier of radioisotopes.

5. What is the availability of the primary nuclearfacility (accelerator or reactor) over the next fiveyears, e.g., HFIR outage, LANSCE programchanges?

Projected to be 90% of all hours available as we haveachieved since 1977.

History: MURR was commissioned in 1966,beginning its operations at 5 MW. In 1970 theoperation schedule was expanded to 100 hours per

week, and in 1974 the power was increased to 10MW, the highest power research reactor on anyuniversity campus in the US. In 1977 the operatingschedule was increased to more than 150 hours perweek. Since then, the reactor has operated morethan 90 percent of all the available hours in the year.Its on-line availability is a remarkable level ofreliability which is unmatched by any researchreactor in the US. The only deviations from thatrecord have been associated with one-weekshutdowns required once every eight years for thereplacement of the beryllium reflector and one 3-day shutdown for change-out of the pool heatexchangers. The beryllium reflector was lastreplaced in September 1997, and replacement willnot be necessary again until 2005. MURR’s reliabilityis a critical factor in meeting the national needs forshort-lived isotopes.

Current Reliability: MURR already serves as areliable national resource for reactor-producedradioisotopes and the primary source of manyresearch radionuclides used in the US. MURRsupplies isotope irradiation and related services toover 300 clients in 45 industries, seven state andfederal laboratories, and over 31 universities. In fact,the reactor was designed from the beginning topermit scientists easy access to neutrons for a varietyof research applications, including activationanalysis, neutron scattering and radioisotopeproduction.

6. What understanding exists at each site about thepriority of isotope production to serve isotopecustomers?

We’ve been serving our radioisotope customers formany years and are now focusing even moreattention and more resources to do more and do itbetter. Recently MURR has shifted its primaryservice mission to providing medical and researchradioisotopes. This focus has become the highestpriority behind the safety and maintenance of thereactor.

7. How much influence does each site manager havein planning the use of multi-purpose facilities?

The Director has total responsibility and authorityfor planning the use of MURR facilities. He has thesupport of the MU Administration to focus MURRefforts into radioisotope and radiopharmaceuticaldevelopment, because these areas providesignificant and unique opportunities for several MUdepartments, including the Medical School,Veterinary School and Agriculture.

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8. What cost-containment measures are beingpursued?

Cost containment and cost consciousness have longbeen ingrained in MURR’s operating philosophy outof necessity. We have never been fully base funded,but have had to depend on our inventiveness andresourcefulness in R&D and service to industry togenerate a significant part of our annual budget.

Management is keenly aware of the importance ofcarefully monitoring and controlling costs. MURR’sminimal base funding forces management’sconstant attention on stretching limited resourcesto maintain reactor reliability and thereby serve ourcustomers which include patients undergoingradiodiagnostic and radiotherapeutic procedures.

9. What “licensing” issues need to be addressed?

MURR Relicensing

MURR was built in the mid-1960s and licensed foroperation by the U.S. Nuclear RegulatoryCommission (NRC) in 1966. MURR’s current NRClicense expires in 2001. Efforts are underway toupgrade the facility infrastructure in preparation forthe new license application. The relicensing effortwill cost $8.1 million and consist primarily ofrelicensing application costs (e.g., safety analysisreport and license submittal) and reactor and facilityupgrades. Examples of reactor and facility upgradesinclude: 1) assessing the condition of the reactor’ssystems, 2) evaluating the integrity of the pool liner,3) replacing reactor instrumentation and controlcomponents and wiring, 4) evaluating and replacinghealth physics instrumentation, 5) improving fireprotection and detection systems, 6) replacing poolwater storage tanks, 7) reconditioning radioactivesumps and drains, 8) replacing the berylliumreflector, 9) updating the pneumatic tube sampleirradiation system, and 10) updating security andsurveillance systems

10. What unused or underused capacity, e.g.,personnel, facilities, could be mobilized to supporta growth in isotope demand?

One fully utilized facility that can be modified(expanded) to provide growth in isotope demandis the flux trap. Engineering and design areunderway to allow access to flux trap volume morefrequently than once/week which is our currentaccess to the high flux volume. We are in the processof increasing our staff and reallocating staff to meetthe increase in demand for isotopes we currentlysee.

Six Barrel Flux Trap: A new flux trap that willcontaining three additional 0.75” OD tubes is shown

in the figure 2 below (cross sectional view). Thecurrent flux trap is classified as a secured experimentwhich can only be removed when the reactor is notoperating. Each of the three new tubes is shown asa tube within a tube. The outer small tube is part ofthe secured flux trap. The inner small tube is sized(0.56” OD will hold 0.38” OD samples) so thereactivity affect of removing or inserting it will bewithin the American National Standard InstituteStandard’s definition of a movable experiment. Thiswill allow samples to be safely removed while atfull power. This modification will require NRCapproval of a revision to the MURR Reactor LicenseTechnical Specification before it can be used as amovable experiment. This approval will enableaccess to the high flux region at any time, givingMURR tremendous flexibility in the scheduling oftargets.

Feasibility studies have also been completed whichindicate that the reactor could be upgraded in powerto 20-25 MW. This would significantly increase ourisotope production capabilities by increasing themaximum flux to over 1x1015 n/cm2/s

11. Summarize customer inquiries received duringthe past two years. What per cent was filled,referred to other facilities, rejected? Explainunfilled requests.

Many of our customer requests for isotopes are longstanding ones (P-32, S-35, P-33). A number of othersare for development of radioisotopes used formedical products (Ho-166, Sm-153, Y-90) and othershave been requested for various R&D needs. We fill>95% of the requests that we receive. Most of theunfilled requests are for isotopes where we have noexisting safety analysis in place and the requestor isnot interested or able to assist with the cost ofanalysis to fulfill their request.

12. How does each site manager rate customersatisfaction for his site? For the overall program?

We don’t have a formal customer satisfactionmeasurement system in place. We look at thenumber of long term users who regularly request alarge fraction of our service and who haven’t movedtheir business to other reactors as a measure of ourability to meet their needs. Our on-line reliability(>90% since 1977 and our access to isotopes on aweekly basis make us a unique supplier to most ofour customers.

13. Kindly detail how you set the price of a mCi of aradioisotope? The detail should show if the costis fully loaded or incremental, and should includelabor, materials and parts, facility rental andamortization costs, listing of all the actual

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Appendix A

overhead charges, waste disposal (a major costs),and all other costs that are tagged to the cost ofproducing, marketing, selling, and distributing ofthe product (e.g.,. customer service, distribution,ordering).

Isotopes provided for commercial use are priced atmarket value which is presumed to cover fullyloaded costs.

14. Illustrate the above question for the followingradioisotopes: In-111, P-32, I-123, I-125, and severalresearch radioisotopes.

Most high volume radioisotopes, such as P-32 andS-35, are provided as part of irradiation services forlarge customers. Those prices are set in accordancewith volume purchase plans from the variouscustomers. We are currently in the process ofrevising the price list for research radioisotopes andplan to have a list available in the first part of June’99.

15. What process, mechanism, and organizationalstructure do you have for the timely distributionof the produced product?

MURR’s Income Generating Operations (IGO)division is dedicated to the processing and deliveryof radioisotopes requested by industry andresearchers. Within IGO resides a mature and testedshipping group that makes over 2000 radioisotope

shipments per year. The variety and quantities ofradioisotopes shipped is far beyond the capabilitiesof any other shipper in the US.

16. What process, mechanism, and organizationalstructure do you have for customer service?

Customer service is provided by customercommunications with the section leaders in IGOirradiations, processing and shipping groups.

17. Will you sign contracts that guarantee delivery atthe contracted time of delivery and where thecontract has penalty clauses for non timelydelivery of the specified product?

MURR typically has not entered into such contracts,but would seriously entertain them.

18. What should be the long-term role of Governmentin providing commercial and research isotopes?

The Federal Government should subsidize theproduction and supply of research (and in somecases commercial) radioisotopes by providing long-term financial commitments to and capitalinvestments in the most cost effective and reliablefacilities available in the US. This list should includenon-DOE facilities such as MURR.

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International Isotopes, Inc.,Site Visit

Site Visited May 7, 1999

1. Introduction

A site visit was conducted at International Isotopes, Inc.,(I3) in Denton, TX on May 7, 1999. Site visitors includedDr. Ron Finn, Memorial-Sloan Kettering Cancer Center,Dr. Tom Ruth, TRIUMF- UBC PET center, and Dr. RobertAtcher, Los Alamos National Laboratory. Mr. Carl Seidel,President of I3 acted as host for the site visit. During thecourse of the visit, we had a telephone conference withthe site manager for International Isotopes operation atthe Advanced Test Reactor in Idaho.

Mission

International Isotopes, Inc. is a company that wasfounded to produce radionuclides andradiopharmaceuticals utilizing accelerators on site aswell as reactors outside of Denton. The company alsohas imaging technology for tomographic imaging andaccelerator technology based on the linac which wasinstalled at the Denton site.

Facilities and Services

The company was founded to exploit resourcesdeveloped in Texas during the construction of theSuperconducting Super Collider (SSC). Th SSC facilitywas partially constructed when DOE canceled theproject. I3 bought assets from the SSC facility, includingthe linac that was built to inject protons into the largeraccelerator. This linac underwent modifications toincrease the beam current to a level that is sufficient forisotope production. The linac was in the process oftesting at an intermediate energy to the proposed finalenergy of 70 MeV. There are hot cells for target handlingin the building above the linac tunnel. In addition, thereare labs equipped for radiochemical work. This buildingis located across town from the main offices and buildingof I3.

I3, in partnership with the University of North Texas(UNT), moved a CP-42 cyclotron from M.D. AndersonHospital in Houston to a site adjacent to the main I3facility. The cyclotron is owned by UNT but is beingleased and operated by I3 staff. During the site visit,initial testing of the cyclotron had produced a circulatingbeam. Since that time, production of Thallium-201 hasbeen undertaken and regulatory approval was obtainedfor its sale. A hot cell was under construction at thecyclotron at the time of the site visit. The intent is toproduce F-18 for local distribution in addition to thelonger-lived commercial products.

I3 has production facilities in Idaho at the Idaho NationalEnvironmental and Engineering Laboratory. They utilizethe Advanced Test Reactor for isotope production. Giventhe inability to remove targets via a pneumatic system,the production is better suited to isotopes with longerhalf lives. However a pneumatic “rabbit” system isplanned for 2001. This operation is focused oncommercial isotope production.

The main facility at I3 has GMP facilities that are designedfor radiopharmaceutical synthesis. The company’sIodine-125 seed manufacturing is conducted there. Inaddition, they have the capacity for several otherproduction lines. There is more than 40,000 sq. feet ofexpansion room for additional radiopharmaceutical andmedical device production lines in the main facility.

Brief History

The company was founded in 1995 and went public withan Initial Public Offering (IPO) in August 1997. Sincethen the company has built or purchased 5 buildings withover 150,000 square feet for production of radioisotopesand radiopharmaceuticals as well as manufacturingequipment (total worth over $45M). The 42 MeVcyclotron is operating and I3 has begun to sell Tl-201made on the machine and processed in the radiochemicallabs under their Drug Master File (DMF). I3 plans tomake F-18 and I-123 from this machine by the end of theyear. They plan to make research radioisotopes on thismachine beginning in the year 2000. The 70 MeV LINACis now operating at 30 MeV and has irradiated sometargets in a preliminary production mode as they bringthe machine up to full current and test each of the sixtarget stations. Tl-201, In-111, Co-57, Pd-103 and severalother radioisotopes are planned for production in largequantities when the LINAC is in full operation next year.They have also begun validation procedures for theproduction of finished radiopharmaceuticals at theirfacility and plan to distribute these products beginningnext year.

Development programs on new imaging systems andother instruments in collaboration with several Texasinstitutions have begun and should produce workingprototypes in the near future.



Currently, there is no programmatic interaction betweenI3 and DOE. The Idaho facility (I4) has a contract to leasespace and facility at the ATR for several more years andthey plan to make improvements to the facility that willallow them to produce short-lived radioisotopes whichwill be shipped to the Denton facility for finalradiopharmaceutical manufacturing.

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Appendix B

In addition they have signed a contract and made initialpayments to the Sandia reactor facility for the productionof I-125 for the next three years. Discussions are beingheld with the facility to produce other radioisotopes.

Other discussion have been held with DOE about usingthe facilities at other laboratories, providing researchisotopes to their customers and acting as a marketingagent for products the DOE labs produce.

Other DOE Programs

I3 bought a company called MacIsotopes. This companyprivatized the isotope production activity at the IdahoNational Engineering Laboratory. This productionprogram centers on the Advanced Test Reactor, a DefensePrograms reactor. I3 has had discussions with the IPconcerning distribution arrangements. In addition, theyhave had discussions with production sites within theDOE labs for isotopes of interest.

The site visitors discussed the potential for the IP topurchase irradiation time on the accelerators at I3. Thisappears to be a viable option until demand increases tothe extent that there is no accelerator time available. Thelikelihood exists, though, that time on the CP-42 couldbe purchased for short irradiations of limited quantitiesof research isotopes.

3. Relationship to Academic Programs andTraining

I3 has a close working relationship with North TexasUniversity. Interactions are primarily focused on theDepartment of Physics, which has a program inaccelerator physics. The University of Texas MedicalSchool at Dallas is in the early stages of developing arelationship with I3. The exact form of this relationshipis not clear at this stage of the interaction. The PhysicsDepartment at NTU plans to use one of the beam lineson the CP42 for proton irradiations. There are discussionsof beginning a training program in radiopharmacy thatwould provide a source of students for I3 in itsradiopharmacy operation. These discussions arecontinuing with U. of Texas and in addition they areplanning an imaging equipment development centerwith Southwest Medical center that will include a clinicfor patient treatment using PET radioisotopes.


At this stage I3 is generating only Thallium-201 from theircyclotron. They are not producing any radioisotopes onthe linac yet. They are preparing radioactive seeds fromradioisotopes acquired from smaller reactors. They havesigned an agreement with Univ. of Missouri ResearchReactor for isotope production. They have also agreedto purchase Iodine-125 from Sandia reactor when they

begin routine production. They have produced F-18 andI-123 on the cyclotron in preliminary test targets and havesold some Tl-201, produced on the cyclotron andprocessed under their DMF. The LINAC has irradiatedsome pre-production Tl-201 targets and will beproducing product for sale by the end of the year.

Throughput

The facilities appear to have the capacity to handle a largenumber of shipments. Their hot cell capacity lookedsomewhat limited for the number of products beingproposed (a total of 4 hot cells with one of these dedicatedto receiving from the accelerator). The hot cell area atthe cyclotron building was still under construction at thetime of the site visit in May 1999. It now has three smallhot cells in the cyclotron building for Tl-201 and I-123production.

Customers

At this point in time they are producing limited quantitiesof accelerator-produced radioisotopes. They have 3contracts that have made public. The Imagyn contractis for the marketing of I-125 brachytherapy seeds. TheBracco contract is for the production and distribution ofa finished radiopharmaceutical . The Gamma Pluscontract is for a joint venture to produce and distributeF-18 FDG for the Dallas Ft. Worth market.

Research and Development (R&D)

Both accelerators require R&D work in the opinion ofthe site visitors. The CP42 that was acquired from M.D.Anderson in Houston has not been run under thedemanding conditions proposed by the I3 team. Whileother CP42s have run and continue to run as productionmachines at other sites around the world (MDS-Nordion,Canada and Amersham, UK) this productive capabilitycame at a price in terms of major upgrades. Theyanticipate that the CP42 will be operating in the 100 to150 µA. They are now irradiating at the 80-100 µA level.

The Linac is based on the original injection acceleratorfor the now defunct Super Conducting Super Collider(SSC). The SSC was designed for low beam currentoperation while the I3 production machine requires highbeam current and relatively high duty factor. This totalreversal of design criteria has been a challenge for theaccelerator engineers and physicists. It is too early todetermine if they have been successful with themodifications.

With respect to research associated with the completedfacility, they plan to start supplying researchradioisotopes to the user community during the secondyear of operation. This would obviously entaildevelopment work. I3 is planning on a targetdevelopment program as well.

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Continued Operation

The physical plant has the capacity to meet the needs ofthe research community for many years to come.However, whether that comes to pass will depend uponthe success of I3 in the commercialization of the proposedproducts over the next few years.


The whole facility is in process at this point in time.Nothing has really been tested in a production mode(other than their seed production facility which makesuse of I-125 purchased from off site). They will beproducing I-125 from the Texas A&M reactor next month.


The facilities in Denton are a recently completed greenfield facility thus the only expansion in the foreseeablefuture would be to meet expectations in terms of designcriteria and operational reliability.



As a commercial entity they have total autonomy.However, they appear to support from the participatinginstitutions such at University of North Texas andUniversity of Texas Medical Branch.

Marketing

Marketing is still under development as yet since theyhave such a limited product line. However, they havebeen quite successful in raising money for the creationof the company so one assumes that they understandthe market place. The assembled team certainly hasextensive experience in producing and distributingradioisotopes.

Waste Management

Almost all the waste is segregated and held for decay.Other longer lived waste is properly stored for periodicremoval to approved waste burial sites.

International Isotopes, Inc.


No Q&As were submitted.

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Appendix C

Brookhaven National Laboratory(BNL) Site Visit


1. Introduction

On May 11, 1999, a site visit to Brookhaven NationalLaboratory (BNL) was conducted by a special Site Teamassembled by the DOE Nuclear Energy ResearchAdvisory Committee’s (NERAC) Subcommittee onLong-Term Isotope Research and Production Planning.The Team was composed of Sekazi Mtingwa, Ph.D.,NERAC Site Team Leader, Wilkins Professor of Physics,Morgan State University; Robert Atcher, Ph.D., ChemicalScience and Technology Division, Los Alamos NationalLaboratory; Ronald Finn, Ph.D., Chief, Cyclotron/Radiochemistry, Medical Imaging Department,Memorial Sloan-Kettering Cancer Center.

The purpose of the site visit was to conduct an in-depthreview of BNL’s present and future capabilities to meeta substantial portion of the national need for a variety ofradioisotopes for medical, research, and commercialapplications.

To facilitate the visit, the NERAC Site Team electronicallysubmitted a list of questions prior to the site visit toLeonard Mausner, Ph.D., Director of BNL’s RadionuclideResearch, Radioisotope Production, and BLIPOperations. Those questions and Mausner’s responsesare attached.

Mission

The primary mission of BNL’s Radioisotope Productionand Research Program is to prepare certain commerciallyunavailable radioisotopes to distribute to the nuclearmedicine community and industry, and to performresearch to develop new radioisotopes desired by nuclearmedicine investigators. In conjunction with this mission,the group also performs service irradiations, sells by-products and explores opportunities for new productsand radioisotope applications as needed. 1


BLIP

The only isotope production facility currently operatingat BNL under the auspices of the Department of Energy’sIsotope Programs (IP) is the Brookhaven LINAC IsotopeProducer (BLIP). Until recently, BLIP has used the excess,amounting to 78%, of the proton pulses produced by the200 MeV LINAC, whose primary mission was theproduction of protons for injection into the Booster andsubsequently into the Alternating Gradient Synchrotron(AGS) for high energy physics experiments. However,the AGS will soon operate as a heavy ion Booster for

injection into the new Relativistic Heavy Ion Collider(RHIC), whose goal is to create a quark-gluon plasma - aform of hot, dense matter that has not existed since theBig Bang. With a start-up scheduled for later in 1999, itis anticipated that the RHIC accelerator complex willoperate in proton mode for up to 21 weeks in both FY2000 and FY 2001, and there may be an additional 2-4weeks per year of proton operations each year supportedby DOE Defense Programs. It is during such periodsthat BLIP should be able to produce radioisotopes.Beyond FY 2001, there will be 6-12 weeks per year ofproton beams for RHIC, and BNL is requesting between15 and 30 weeks per year of AGS proton experiments,concurrent with RHIC operations. Thus, after the firsttwo years of RHIC’s operations, it is difficult to predictthe number of weeks that the accelerator complex willoperate in proton mode. In the past, the BLIP staff hasbeen actively involved in the scheduling meetings wherebeam time was allocated by the AGS management, andthe plan is to continue that input during periods whenthe AGS will accelerate protons instead of ions.

The radioisotopes produced and distributed by BLIPsince FY 97, along with typical applications, are asfollows:

Be-7 Berylliosis studies

Cu-67 Radioimmunotherapy

Ge-68 Parent in the generator system for producing thepositron-emitting Ga-68; required in calibratingPET tomographs, potential antibody label

Mg-28 Magnesium tracer

Sr-82 Parent in the generator system for producing thepositron-emitting Rb-82, a potassium analog

Zn-65 Zn tracer

To date, the primary shipments for FY 99 have been Ge-68 and Sr-82.

HFBR

Last operated as a 30 MW reactor, the High Flux BeamReactor (HFBR) also has been used for the production ofradioisotopes. Unfortunately, the reactor has been instandby mode since December 1996 due to a leak intothe soil of tritiated water from the reactor’s spent fuelstorage pool. Presently, it is unclear if and when thereactor will resume operations. However, once restarted,DOE’s Basic Energy Sciences Advisory Committee hasrecommended that its power be boosted to 60 MW.

The reactor generally operates much of the year inroughly 6-week cycles - 30 days of operation followedby a 12-day shutdown for fuel change and maintenance.The HFBR has/could have the capability of producingthe following radioisotopes: Sc-47, Sn-117m, Cu-64, Sm-

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153, Re-186, Gd-153, Ho-166, Lu-177, Au-198, and Au-199, with all but the last two being recommended by theDOE Expert Panel.

Typical applications of these isotopes are as follows:

Sc-47 Cancer therapy with radiolabeledmonoclonal antibodies

Sn-117m Treatment without marrow toxicity of paindue to metastatic bone cancer

Cu-64 Diagnosis of cancers by PET imaging

Sm-153 Treatment of pain due to metastatic bonecancer

Re-186 Bone cancer therapy; treatment ofrheumatoid arthritis

Gd-153 Source isotope

Ho-166 Cancer therapy and treatment ofrheumatoid arthritis

Lu-177 Cancer therapy with radiolabeledmonoclonal antibodies

Au-198 Treatment of severe arthritis in knee joints

Au-199 Cancer therapy with radiolabeledmonoclonal antibodies.

Other Facilities

Presently, six of seven hot cells are being utilized. Duringrecent upgrades, nine radiochemistry labs were totallyrenovated, two more hot cells were added, and existinghot cells received shielding enhancements. [SeeQuestions 1 and 9.]

Brief History

In general, the DOE-supported Radionuclide andRadiopharmaceutical Research Program in the MedicalDepartment at BNL has a distinguished history. Over80% of all clinical imaging procedures carried outworldwide at the present time (approximately 12 millionin the U.S. per year) utilize radionuclides and/orradiopharmaceuticals developed at BNL. Examplesinclude the technetium-99m generator and varioustechnetium labeled radiopharmaceuticals, blood celllabeling kits, thallium-201, iodine-123, xenon-127,copper-67, ruthenium-97, and a number of otherradionuclides. Today, more than 85% of the nuclearmedicine procedures done annually in the U.S. utilizetechnetium-99m.

BLIP

In 1950, the Brookhaven Graphite Research Reactor wasestablished and produced a variety of radioisotopes forresearch and development. Subsequently, in 1972, BLIPwas commissioned to open new paths in radioisotope

R&D, and for the first time, it became possible to producelarge quantities of a variety of radioisotopes for medicine,research, and commercial applications. As a result ofrecent upgrades, the maximum LINAC beam intensitywas increased from 65 to 145 mA and provision wasmade for a variable proton energy option for BLIP.

HFBR

Since it began operating in 1965, HFBR has providedneutron beams for a variety of neutron scatteringexperiments in physics, materials science, biology, andchemical crystal structure. Moreover, it has the capabilityof irradiating samples for the production ofradioisotopes. It operated from 1965 to 1982 at 40 MWpower level. In 1982 the power level was increased to60 MW, in order to improve research capacity. After asafety assessment in 1989 the power level was decreasedto 30 MW. An increase in the power level back to 60MW has been recommended by the Basic Energy ScienceAdvisory Committee if restart is allowed.



Brookhaven’s Radioisotope Production and ResearchProgram is located at a DOE laboratory and is operatedunder the auspices of the Office of Nuclear Energy,Science & Technology. However, parts of the financialsupport for the program’s activities come from othersources, such as DOE’s Office of Science. As for the pricesof isotopes distributed by the program, DOE’s Office ofIsotope Programs sets the prices, not BNL. [For moredetails, see Questions 12 and 13.]

3. Relationship to Academic Programs and Training

The site team was concerned that there have been nopostdoctoral associates or graduate students trained bythe Radioisotope Production and Research Program overthe past three years. While part of the reason may haveto do with funding limitations and the need for extensiveradiation safety training, there is general agreement thatthe future of the field is being jeopardized by the lownumbers of new personnel being trained in theexperimental methods of radiochemistry.


Throughput

The Radioisotope Production and Research Programkeeps a careful log of all inquiries by potential customersinterested in purchasing radioisotopes. This is doneregardless of whether the inquiries come into the maindistribution office or are made to individual membersof the program. Whenever possible, orders are filled;however, typical reasons for not filling orders are asfollows:

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Appendix C

• BLIP not operating

• Not practical at BLIP

• New isotope, large development required

• Cannot meet minimum order

• HFBR-produced and hence currently unavailable.

Customers

Currently, only the accelerator-produced (BLIP) isotopesenumerated above are being produced at BNL. Thecustomer base is composed of entities, both private andpublic, who have a need for radioisotopes for medical,research, or commercial applications.

Research & Development (R&D)

The BLIP is a world class radionuclide research andproduction facility that has continued to serve as a uniquenational resource for the production of many isotopeswhich are generally unavailable elsewhere. It hassupported research at BNL on diagnostic and therapeuticradiopharmaceuticals and remained a source fordistribution of many difficult-to-produce isotopes toindustry and other research investigators.

A number of research projects have resulted intosuccessful technology transfer. Examples include (1) Anew 99mTc-RBC Kit presently being marketed byMallinckrodt Inc., under an exclusive AUI license; (2)FDA-approved isotopes (127Xe, 82Sr, and others) routinelydistributed to industry for resale; (3) Use of BNL-developed technology for commercial production of99Mo/ 99mTc generators, kits, and radiopharmaceuticals,201Tl, 123I, 67Cu, and 127Xe, etc. Efforts are in progress totransfer two other technologies: 117mSn-DTPA for bonepain palliation therapy, and new semi-rigid chelatingagents for producing stable radioimmunoconjugates forimaging and therapy.


Continued Operation

Currently, the physical facilities at BLIP and relatedresearch areas are in varied condition. A problem withthe steering magnet that introduces beam into BLIPresulted in a hole being burned in the side of theequipment. As a result, there needs to be a substantialrepair in a high radiation region of BLIP in order tocontinue operations. Due to the upgrades outlinedabove, the support facilities are in good condition. In FY97, an upgrade was completed at a cost of $5.82 M thatshould enable BLIP to improve its production anddistribution capabilities. Parts of the upgrade involvedincreasing the available beam from 65 mA to 145 mA,providing a variable proton energy option for BLIP,adding two rooms to the BLIP work area, and addingtwo new hot cells to the Target Processing Laboratory

(TPL). All laboratory renovations and hot cellconstruction are nearly complete and are scheduled tobe finished before the end of this fiscal year. Moreover,the BLIP beamline repair is scheduled to be completedin September 1999. [For more details, see Questions 1and 9.]

As for HFBR, its future is uncertain and the currentactivity revolves around cleaning up the tritiumcontamination and insuring that the systems wouldoperate without problems should they berecommissioned. A decision on restart is expected fromDOE at the end of the calendar year 1999.

Expanded Operations or Service�Underway

With the completion of the recent upgrades and theaddition of two new hot cells to the TPL, BLIP and relatedfacilities are positioned to increase their isotopeproduction, distribution, and research activities.However, the BNL staff stated that, aside from theobvious need for LINAC operating funds to extend therunning period of BLIP, the biggest single bottleneck toexpanded operations is the lack of sufficient personnel.Another problem perceived by the staff is the heftyamount of reporting and documentation that is requiredfor submission to DOE headquarters. Finally, given thecommissioning of RHIC, another major concern for BLIPis the uncertain availability of proton beams in theLINAC.


To insure a reliable year-round supply of radioisotopesfor medical, research, and commercial applications, BNLhas proposed acquiring and installing a 20-70 MeVcyclotron with a beam current in the range 750-1,000 mA.The proposal involves constructing three beam lines: onefor isotope production, one for PET studies, and one fortarget and isotope R&D. A building to house the facilityalso is included in the proposal. Early estimates of thetotal capital cost are in the range $17-25 M.



The BNL management has a history of stronglysupporting its radioisotope production, distribution, andR&D activities. Moreover, supporting BLIP has beendesignated as an official - although secondary - missionof the Collider Accelerator Department, whichsometimes provides support to BLIP without charge. [Formore details, see Questions 5 and 6.]

Marketing

Users of radioisotopes know of the limited sources fromwhich to obtain both accelerator and reactor-producedisotopes. With BNL housing each of the two types ofisotope-producing facilities (BLIP and HFBR),

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prospective purchasers make inquiries to the BNLIsotope Distribution Office or directly to the staff. Asmentioned previously, all such inquiries are tracked fromthe initial time of contact to the final distribution, or non-distribution, of the requested isotopes. The numbers andamounts of shipments made per year and the reasonsfor inquiries not leading to shipments are carefullylogged into the Distribution Office’s records. [For moreinformation, see Questions 10-16.]

Waste Management

Waste management at BNL is currently under tightscrutiny by environmental authorities to insure that it isbeing conducted in accordance with existing governmentregulations. There are a number of concerns that arepresently being addressed, with perhaps the mostpublicized concern having to do with the leak into thesoil of tritiated water from HFBR’s spent fuel storagepool. Another concern is the tritium-contaminated soilsouth of BLIP. Measures to correct this BLIP problem andothers are discussed in Questions 2 and 8.

7. Summary Comments

Brookhaven has been one of the longer-standingradioisotope producers for the Department of Energy;however, it currently is experiencing more limitedperiods of operation, exacerbated by the HFBR shutdownand the parasitic operation of BLIP impacted by thecurrent high energy physics research scheduled forRHIC. Under the present configuration, the minimal staffof the Medical Department’s Radioisotope DistributionProgram has restricted input in production schedules.Therefore, the staff is represented in the table oforganization in several roles with a major emphasis onresearch in the areas of therapeutic radioisotopedevelopment, radiolabeled monoclonal antibodies andpeptides, and pain ablation chelated radionuclides. Thecampus atmosphere includes the unique laboratoryfacilities, such as BLIP, HFBR, the Brookhaven MedicalResearch Reactor (BMRR), two cyclotrons, and high-levelradiation processing cells. A note of caution wasinterjected to the site visitors in that HFBR is presentlyshutdown and the prognosis for restart by DOE is notavailable. Also, BLIP is operated parasitically with theBNL High Energy Physics Program, and the direction ofthat program’s Relativistic Heavy Ion Collider researchinterjects some uncertainty as to the need for protons inthe future.

The DOE IP has attempted to form a Virtual IsotopeCenter through coordination of the operating schedulesof accelerators at LANL and TRIUMF with BNL, suchthat a “year-round” availability of specific radionuclidescould be forthcoming. The primary shipments from BLIPare Ge-68 and Sr-82. IP lists BNL and LANL as theirprimary suppliers of accelerator-produced isotopes withmarketing management at Germantown, Maryland. The

Department of Energy sets all pricing, and the currentisotope production activity is focussed on the twonuclides mentioned above. The time available whenBLIP is not in operation for radionuclide production isspent in repairs and upgrades of the BLIP/LINACfacilities, such as the recently completed beam upgradeof available current and research and developmentefforts relevant to the nuclear medicine field.

It was extremely difficult to anticipate the futuredevelopments and capacities of the program due to theindecision on HFBR and the outcome of the high energyphysics research program with RHIC. It is thereforedifficult to determine the status of the operations atBrookhaven for the current year. The facilities forradionuclide production are present; however, they stillrequire some renovations and overhauling. The presentstaff is primarily focussed on research and developmentactivities. Should the decision be made to operate BLIPfor a more significant portion of the year and/or shouldthe HFBR start-up be authorized, the needs of the facilityto expand/maintain operations would include addingtechnician production staff. The internal programmaticsupport within Brookhaven National Laboratory hasbeen strong due to its public relations role, which thisoperation has generated. There is a renewed directionon the site for the environmentally safe handling ofradionuclides and wastes generated. This is an importantconsideration for the public at large, but it is also asignificant burden on the research staff in terms of timeand effort for completion and documentation. It alsopresents a potential problem for the isotope productionactivity at BNL since environmental concerns haveinterrupted operations in the past.

The BNL production staff appreciates the problems withthe parasitic operation necessitated, and therefore, itshared with us the option of installation of a dedicatedcyclotron of nominal 70 MeV proton energy, to undertakethe production program. Space for siting the instrument,the continued use of existing hot cell processing facilities,and health physics support were addressedappropriately.

If a reliable source of accelerator-produced radioisotopesis to be assured for future medical, research, andcommercial applications, the establishment of such adedicated facility should be given full consideration byDOE. However, it is not clear that the need for such afacility is warranted given the construction of the IPFfacility at LANL, the impending start of operations atInternational Isotopes, Inc., in Denton, Texas, and thesuccess to date of the Virtual Isotope Center.

1 Excerpted from www.medical.bnl.gov/iso.htm

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Appendix C

Brookhaven National Laboratory(BNL)


Capability, status, and operation of DOE isotopeproduction infrastructure

1. What is the physical condition of your isotopeprocessing facilities and equipment?

In general our facilities are in excellent condition!This represents a big change from five years ago andis the result of several large renovation efforts. In1994 the lighting throughout the laboratory area wasreplaced using BNL special maintenance funds.From 1995-1997 the Biomedical Isotope ResourceCenter project (DOE Office of Energy Researchfunds) along with Accelerator Improvement Projectfunds (DOE OER) spent about $8.7M to upgradethe LINAC, the Brookhaven Linac Isotope Producer(BLIP) and selected areas of our Target ProcessingLaboratory (TPL). This resulted in an increase ofthe maximum LINAC beam intensity from 65 to 145mA, provided a variable proton energy option forBLIP, added two rooms to BLIP working area,upgraded the BLIP beam line vacuum, control,cooling and waste systems, added two new hot cellsto the TPL and upgraded the hot cell ventilationsystem. This was followed by the Building 801Renovation Project ($6.7M from DOE OER) 1996-1999. This ongoing work is making majorimprovements to the laboratory infrastructure items,such as HVAC, asbestos removal, and bringingwaste piping up to code. In addition nineradiochemistry labs were totally renovated, twomore hot cells added and existing hot cells gotshielding enhancements. A BNL funded projectstarting soon will upgrade our aqueous radwastestorage tanks. Note that the DOE Office of IsotopePrograms provided none of this funding. Duringyour visit you will have ample time to see all thesefacilities.

2. What capital investments are needed to assurenear term operability?

The most important short term investment isoperating funds for the LINAC to extend therunning period of BLIP beyond that of the limitedand declining proton physics program (see question#4 below). Depending on the status of the rest ofthe accelerator complex these costs range from$25,000 - 98,000 per week. It will also be possible tooperate intermittently for short periods with thecharge by the hour, ranging from $250/hr (with a$900 set up fee) to $450/hr (with a $5000 set up fee).Funding permitting, this option would allow us to

stretch our production for short lived isotopesbeyond the normal period of accelerator use forproton physics. Nevertheless, within five years it isnot clear that there will be enough proton operatingweeks, in a contiguous block, for BLIP to remainviable. Therefore we are investigating the purchaseand installation of a cyclotron, tunable from 20-70MeV and with at least 750µA of beam intensity. Thepreliminary concept is for three beam lines; one forregular isotope production, one to support theChemistry Department PET program, and one fortarget development and isotope research to beshared by both the Medical and ChemistryDepartments. The capital and operating costs wouldalso be shared. Very early estimates of the totalcapital cost are approximately $17-20M. Existinglaboratory facilities would continue to be utilized.This machine and its mission do not completelyfulfill the NBTF goals as defined earlier. However,at a much lower cost it would allow a year roundsupply of about 90% of the isotopes included in theNBTF list.

There are also several facility environmental issuesrequiring capital investments. These are describedin more detail below in question #8. Prime amongthese is the tritium contaminated soil south of BLIP.In FY 98 DOE Office of Isotope Programs providedapproximately $76,000 to upgrade the BLIPdownspouts and cap our shield berm to partlyaddress the soil problem. In FY1999-2000 a $600,000project has been proposed to inject silica grout intothe activated zone of soil under BLIP, forming aviscous barrier layer. The Engineering EvaluationCost Analysis (EECA) has been submitted for reviewby all the cognizant environmental authorities (EPA,New York State, Suffolk County etc.).

3. Are the additional resources practical, quickly andeasily integrated into existing infrastructure, andsustainable by local financial and personnelresources?

Additional operating weeks of the Linac will notcause infrastructure burdens. However, isotopeproduction of greater than approximately 6 monthsper year would require additional personnel to keepup with maintenance, waste disposal etc, whileperforming isotope irradiations and processing. TheBLIP tritium remediation work is to be funded byDOE Office of Environmental Management,Superfund, and BNL general plant funds, and canbe scheduled for installation during acceleratordowntime. The new cyclotron project is not likelyto be complete until 2004, unless the DOE Office ofIsotope Programs and Office of Biological andEnvironmental Research can get Congressional fasttrack approval.

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4. What is the availability of your primary nuclearfacility over the next five years?

Our primary facility is the BLIP, with the High FluxBeam Reactor (HFBR) a secondary facility. The BLIPutilizes extra pulses from the 200 MeV Linac. TheLinac prime mission is to supply protons forsubsequent acceleration in the Booster andAlternating Gradient Synchrotron (AGS) for highenergy physics research. The high operating cost ofthe large Linac has limited BLIP to secondary orparasitic running with the high energy physicsprogram. Parasitic operation is very efficientbecause only incremental accelerator costs arecharged to the isotope program, while the highenergy and beam current allow simultaneousproduction of many isotopes. The principalimpediment to better isotope availability from BNLis the declining operational funding of the protonphysics program at the AGS. From a high of 34weeks in 1983 BLIP operations have slowly declinedto an average of 18 weeks over the last several years.A major program change at BNL in FY 2000 mayreduce this inadequate level even further in thefuture. In FY 2000 the Relativistic Heavy IonCollider (RHIC) becomes operational and theaccelerator program emphasis will shift from highenergy proton physics to heavy ion nuclear physics.Indeed the AGS proton physics program willcontinue only as an incremental parasitic operationwith RHIC. It is expected that there will be 16 weeksof such proton running in FY 2000, perhaps followedby about 5 weeks of polarized proton experimentsat RHIC for a total of ~21 weeks for BLIP. Althoughthe overall mission emphasis on protons in lateryears is expected to decline, an increase in protonoperations in some years may occur if RHIC mountsa major proton experiment (colliding proton andgold beams for example). We have no quantitativeprediction at this time however. Senior BNLmanagement and the chairman of the ColliderAccelerator Department will be present during yourvisit and may be able to address this question foryou.

The HFBR has been in standby mode sinceDecember 1996 due to a leak into the soil of tritiumcontaining water from the spent fuel storage pool.Its restart will be decided by the Secretary of Energyfollowing the completion and public comment onan Environmental Impact Statement. This isexpected by the end of 1999. The HFBR couldcommence operations within 18 months of a positivedetermination. If the HFBR restarts we will use it

for the production of such isotopes as Sc-47, Sn-117m, Re-186, and Sm-153.

5. What understanding exists at the site about thepriority of isotope production to serve isotopecustomers?

This program’s visibility and the attention we getfrom upper management is considerably better thanmight be expected given our small staff and fundinglevel. In fact, supporting BLIP operations is anofficial mission of the Collider AcceleratorDepartment, albeit a secondary one. Technicalassistance from the Accelerator Department isgenerally not hard to get and is sometimes gratis.We have also received assistance from theDirectorate on several occasions in cutting throughred tape and mobilizing non accelerator resources,such as waste disposal and environmentalmanagement. As mentioned above, seniormanagement and Accelerator Departmentpersonnel will be available to discuss this issue withyou.

6. How much influence do you as site manager havein planning the use of multi-purpose facilities?

In general the needs of the Isotope Program do notsignificantly influence the macro-scheduling andlong term planning of the accelerator complex.However, through the 27 years of BLIP’s existenceand many technical and programmatic changes atthe Linac and AGS, the Accelerator Department hasmaintained the compatibility of our operations withthe physics programs, sometimes at additionaldevelopment cost. For example, it is projected thatprobably in the Spring of 2000 there will be apolarized proton experiment at RHIC. Thepolarized beam intensity is several orders ofmagnitude too low for isotope production, but apulsed switching magnet will be installed to allowsimultaneous high intensity BLIP running. TheIsotope Program will not be charged for this device.

For short term scheduling and planning we do havedirect input. Each week there is an acceleratorscheduling meeting at which BLIP is alwaysrepresented and recognized. Our short termscheduling needs are usually met, sometimes evenwhen they conflict with physics. For example,repairing the BLIP beam line due to a vacuum leakrequires that the entire accelerator complex be shutdown. We generally get this access as soon as safetyreviews allow, despite the disruption to the manyAGS users.

C-6

Appendix C

7. What cost containment measures are beingpursued?

In an attempt to reduce the BNL overhead rate inthe last year many overhead items are now directcharged. For the isotope effort the major items sofar have been the space charge, waste disposalcharge, and instrumentation calibration service. Inorder to contain the impact of these new fees wehave given up space and consolidated ouroperations, retired some older radiation detectors,and revised some isotope processes to reduce oreliminate the creation of mixed waste. Also, toreduce radwaste shipping charges we have procuredtwo special use casks for our more radioactive wasteforms. We are also in the midst of an effort to builda neutralization and solidification system for ourhot cell liquid waste. This will reduce overallvolumes needed to be stored and shipped.


In the wake of the above mentioned leak of tritiumcontaining water from the HFBR fuel pool, the DOEand the new BNL management have instituted wideranging reforms. At this time all applicable town,county, state and Federal (DOE, EPA, DOT, OSHAetc.) regulations are being rigorously implementedand enforced. The major items that we need toaddress which involve substantial labor and/orequipment include:

a) Category III Nuclear Facility exemption to allowproduction of Xe-127. The radioiodines predictedto be coproduced with Xe-127 put BLIP and the TPLabove the radioactive inventory threshold to becomea Category III Nuclear Facility. The financial,personnel, regulatory, and liability burdens fromsuch a classification are unsustainable for thisprogram. Indeed the BNL Director’s Office has toldus that they do not want another such facility onsite.Therefore, we have been working for the last yearon obtaining an exemption based on a more realisticrelease scenario. At this point we have developed amethodology to justify an exemption that has beenaccepted by the BNL Radiological Control Divisionand the DOE Area Group, but there are still manydetails to address.

b) remove, cleanup or isolate activated soil beneathBLIP for compliance with the ComprehensiveEnvironmental Response, Compensation andLiability Act (CERCLA); the various actionstaken and planned are described above in #2.

c) install quantitative airborne radioactiveemission monitoring in order to bring BLIP, theTarget Processing Laboratory (TPL), and all

radiochemistry labs into compliance with40CFR61- Emissions;

d) upgrade TPL access security and install shieldingfor hot cell HEPA filter bank to bring the TPLinto compliance with 10CFR835 - RadiologicalControl;

e) establish mechanisms and controls to bring allour facilities and operations into compliancewith ISO14001 Environmental ManagementStandards;

f) perform engineering and safety analysis of leadtransport casks for onsite movement of BLIPtargets to document equivalence with DOTstandards or procure new certified casks;

g) implement new DOE Office of Isotope ProgramsQA Plan directives for compliance with DOEOrder 5700.6C-Quality Assurance.

9. What unused or underused capacity, e.g. facilities,personnel, could be mobilized to support a growthin isotope demand?

We presently utilize 6 of our 7 hot cells. With twomore new ones entering into service shortly we willhave 3 underutilized hot cells available. There arealso three very large, heavy duty hot cells in a roomadjacent to ours, designed for metallurgical analysisof reactor core samples. This program isexperiencing funding difficulties, so it is possiblethat these hot cells may become available for isotopeprocessing in the future. There are also someunderutilized target slots in BLIP, primarily in theenergy range of 180-120 MeV. The high energy slots(200 MeV) and especially those receiving energiesunder 120 MeV are used constantly. Our majorlimitations in supporting growth in isotope demandare processing personnel and beam time.

10. Summarize customer inquiries received duringthe past two years.

Table 1 summarizes the isotope shipments for thisperiod and Table 2 summarizes the customerinquiries that did not culminate in a sale, along withthe reason. For example, some requested isotopesare presently producible but are not available yearround. Some inquiries request isotopes that are notpractical or possible to make at BLIP. Some requestsare for isotopes that could be made at BLIP butwould require extensive and expensivedevelopment effort. We also get requests forisotopes on the current distribution list but forminute quantities that do not justify the substantialcost of the production run. Finally, some inquiriesare for information only, with no short term need atall.

C-7


11. How do you rate customer satisfaction for yoursite? For the overall program?

We feel that customers are satisfied with the qualityand timely delivery of our products. In FY 1998 wereceived no complaints, and only one in FY1999.However, there is great dissatisfaction with theoverall availability of our isotopes, due to verylimited operating periods. We also sense generalfrustration with the overall DOE program as beingunresponsive to the needs of the researchcommunity. The Office of Isotope Programs doesput its major emphasis on larger volume routineisotope distribution, such as Sr-82 and Ge-68.

12&13. Kindly detail how you set the price of a mCi ofa radioisotope? Illustrate with several examples.

The DOE Office of Isotope Programs sets isotopeprices, not BNL. They no longer use a full costrecovery strategy, but rather price to market.Nevertheless, each production site does preparedetailed cost studies annually, both as a pricingguide and for budget development. The entiremethodology we use, “Activity Based Costing”, wasmandated by DOE Office of Isotope Programs. Theactivities are: Target Fabrication, Irradiation, HotCell/Lab Maintenance, Chemical Processing, WasteManagement, Quality Assurance, ESH andRegulatory Compliance, Production Packaging,Customer Sales & Service, and ProgramManagement. The exact definitions of each werealso provided by DOE. Each activity typicallyincludes labor, materials and supplies. Some of theactivities also include machine or glass shop costs,plant maintenance costs, computer support, andhealth physics support. No research or facilitydevelopment costs are included in isotopeproduction costs. Also, unused capacity is notcharged to production activities but put in anunassigned category.

Each isotope requires each of the above activities,but to differing extent. We therefore have allocationformulas to apportion the costs. For example, weapportion the irradiation charge to a product bycreating a cost per “slot hour”. This is calculated bydividing the total annual cost of operating andmaintaining the BLIP by the total anticipatednumber of operating hours and by the availablenumber of target slots (12 typical). In FY 1999 thisworked out to $10.67 per slot hour. The number ofslots occupied by the target multiplied by the hoursthat target is to be irradiated is the irradiation costfor the product. Unassigned target slots are notcharged to the product.

Hot cell costs are allocated by dividing the totaloperating and maintenance costs of the hot cell suiteby the number of hot cells available in order toobtain an individual hot cell annual cost. This isthen multiplied by the fraction of the hot cell spacededicated to a particular isotope and divided by theanticipated number of runs per year to obtain a perrun hot cell cost. Similar strategies are used for allthe other activities.

14&15. What process, mechanism, and organizationalstructure do you have for the timely distributionof your product? For customer service?

The initial contact by telephone, FAX or email forany user is with the Medical Department IsotopeProduction Office, which is staffed by anadministrative secretary. Those radioisotopes witha half life less than one month, e.g. Cu-67, Sr-82, arenot inventoried but are shipped as soon as produced.For these situations the irradiation and processingdates are prescheduled by the Program Manager,generally 3-4 months in advance. All known usersare informed of the schedule by the groupadministrative secretary. Any other inquirers to theIsotope Production Office concerning these isotopesare given the schedule. Shipping, license, technicalspecification data and ordering information are alsoimparted. All required paperwork is sent to theIsotope Production Office. We then prepare thenecessary internal documents for each shipment.Back up administrative staff from within theMedical Department is arranged as required so thatwe can always respond to customer inquiries orquestions within 24 hours. Technical questionsbeyond the customer liaison staff member ’sexpertise are referred to the Program Manager or inhis absence the Staff Radiochemist or Hot CellProcessing Supervisor. The internal isotope orderform is sent to the Hot Cell Processing Supervisor,who is responsible for preparing the bottle ofradioactive liquid in a shipping pig. The pig istransferred to members of the Isotope and SpecialMaterials Group (housed in the same building butnot a part of the Medical Department), who preparethe final shipping package, the requireddocumentation and arrange for pickup (we usuallyuse Federal Express).

We try to maintain longer lived isotopes, e.g. Ge-68,Be-7, Zn-65, in inventory. Therefore, we fill ordersfor these isotopes as they come in throughout theyear. The mechanism for customer contact is thesame as for short lived isotopes. Typically, shipmentis within 4 days of our receiving the requiredpaperwork.

C-8

Appendix C

16. Will you sign contracts that guarantee delivery atthe contracted time of delivery and where thecontract has penalty clauses for non-timelydelivery of specified product?

No. This is not feasible due to the lack of controlover many of the required production resources,such as the accelerator and waste disposal schedules.Also, BNL research facilities are constantly beingmodified to experimental needs. This usuallyreduces overall reliability. However, the DOE Officeof Isotope Programs can and does establish suchcontracts. There are several such contracts presentlyin place to deliver Sr-82 and Ge-68. Please note thatin order to fulfill these contracts it requires the effortsof accelerators at BNL (BLIP), LANL (IPF), TRIUMFin Vancouver Canada, the National AcceleratorCenter in South Africa and the Institute of NuclearResearch in Troitsk, Russia. No one or even twoinstitutions can pull it off. Table 3 summarizes thelatest multi accelerator production matrix for Sr-82.This type of international effort is not feasible forshorter lived radioisotopes.

Table 1. Production of Radionuclides

Be-7

Cu-67

Ge-68

Mg-28

Sc-47

Sn-117m

Sr-82

Zn-65

RadionuclideNo. of

ShipmentsAmount(mCi)

No. ofShipments

Amount(mCi)

FY 97

Includes transfer to LANL to fulfill DOE contractTo date

* +

FY98 FY 99+

No. ofShipments

Amount(mCi)

4

24

13

1

8

0

4

0

15

466

262

.04

38

0

3950

0

2

13

16

0

0

3

4

0

*

*

*

*

3

68

1236

0

0

145

3150

0

3

7

12

0

0

0

4

1

4

89

266

0

0

0

4673

50

17. What should the long term role of government bein providing medical, commercial and researchisotopes?

In our opinion the mission of government inproviding isotopes and isotope related technologyand products should concentrate on supporting andencouraging research. Government (in this casemostly DOE) should provide healthy, stable fundingfor R&D into new isotopes and isotope applications,and providing such isotopes to researchers. Isotopeswhose production is routine should largely be acommercial function. Government can step in if thecommercial sector cannot or will not (for examplefor “orphan” isotopes), or if commercial productioncapacity is inadequate to meet need. We suggestthat the costs of operating and maintaining the verylarge infrastructure necessary for isotope productionshould be a government responsibility with coresupport, with research users bearing incremental,out of pocket production costs for labor, supplies,packaging, waste disposal etc. This is analogous tothe model already practiced by DOE and NSF forphysics and chemistry research at large acceleratoror reactor facilities. Researchers at such facilitiesare responsible for building and operating theirexperimental equipment, but do not pay for beam.

C-9


Table 2. Inquiries Not resulting in Sale

Ag-105

Ag-110

Ar-39

As-72

Au-195

Au-198

Au-199

B-11

Be-10

Be-7

Ca-47

Ca-44

Ca-48

Ce-144

Co-55

Co-57

Co-58

Co-60

Cu-64

Cu-67

Fe-52

Fe-55

Fe-59

Ga-66

Gd-153

Ge-68

I-123

I-124

I-125

In-113m

Kr-85

Mg-28

1

1

2

1

4

1

1

1

1

7

2

1

1

1

1

2

2

1

8

33

2

1

1

1

1

19

1

1

1

1

1

7

c

b

b

d

c

b

b

b

b

d(6),e

b

b

b

c

d

b

b

b

D(6), a(2)

a(18), d(15)

e

b

b

d

b

d(18), a

d

b

b

b

b

e(4), d(2), b

Isotope Inquiries Reason*

= BLIP not operating= Not practical at BLIP= New isotope, large development required= Information request only= Can't meet minimum order

a b c d e

Mn-53

Mn-54

Ni-56

O-16-18

P-32

Pb-203

Pb-212

Pt-193m

Pt-195m

Ra-226

Ru-106

Sb-124

Sc-47

Si-32

Sm-153

Sr-82

Sr-89

Sr-90

Tc-94m

Tc-95m

Tc-96

Tc-97

U-235

V-49

W-188

Xe-127

Y-86

Y-87

Y-90

Zn-65

Zr-95

1

1

2

1

1

2

1

2

1

1

1

1

1

1

1

4

1

2

1

6

3

2

1

2

1

2

1

1

1

2

1

b

b

d, c

b

b

c

b

c

c

b

b

b

d

d

b

d

b

b

d

d(4), e(2)

e(2), d

b

b

b

b

c

c

c

b

d

b

Isotope Inquiries Reason*

C-10

Appendix C

Table 3. Sr-82 Production Matrix

1/12/99

2/9/99

2/24/99 Nycomed

3/10/99 Nycomed

3/17/99 Nycomed

3/24/99 Nycomed

3/9/99

4/6/99

5/4/99

6/1/99

6/29/99

7/27/99

8/24/99

9/21/99

10/19/99

11/16/99

12/14/99

1/11/00

2/8/00

3/7/00

4/4/00

5/2/00

5/30/00

Nycomed 6/29/00

B,T

B,I,T

B,I,N,T

I,N,T

I,N,T

I,N,T

I,N

I,N

I,N

I,N

N,T

N,T

N,T

I,N,T

I,N

I,N,L,?

I,N,L?,T

I,N,T

I,N

I,N

B,N,I

B,N,I

B,N,I

B,N,I

516

516

516

600

1700

1700

1700

400

516

200

1700

1000

900

1150

1000

1200

1200

1200

1200

500

500

500

650

650

1200

500

500

500

500

1200

1600

1100

1600

1600

1100

1600

1600

1600

400

1700

1700

Squibb/NycomedDelivery Date

AcceleratorsOperating

BNL(mCi)

LANL(mCi)

INR(mCi)

NAC(mCi)

TRIUMF(mCi)

(4/21/99 rev)

C-11


Oak Ridge National Laboratory(ORNL) Site Visit


1. Introduction

On May 12, 1999, a site visit to Oak Ridge NationalLaboratory (ORNL) was conducted. The team wascomposed of Sekazi Mtingwa, Ph.D., Site Team Leader,Morgan State University; Richard Reba, M.D., RobertAtcher, Ph.D., Los Alamos National Laboratory; andRalph Bennett, Ph.D., Idaho National Engineering andEnvironmental Laboratory.

The purpose of the site visit was to conduct an in-depthreview of ORNL’s present and future capabilities to meeta substantial portion of the national need for a variety ofradioisotopes for medical, research, and commercialapplications.

To facilitate the visit, the NERAC Site Team electronicallysubmitted a list of questions prior to the site visit to JerryKlein, Ph.D., Manager of ORNL’s Isotope Production andDistribution Program. Those questions and answers areattached.

Mission

The primary mission of ORNL’s Isotope Production &Distribution Program is to produce and distribute tovendors a variety of stable and radioactive isotopes formedical, research, and commercial applications. To fulfillits mission, the program utilizes four main facilities: aset of thirty electromagnetic separators called Calutrons(CALifornia University Cyclotrons), the High FluxIsotope Reactor (HFIR), the Radioisotope DevelopmentLaboratory (RDL) also called the Building 3047 Hot CellFacility, and the Radiochemical EngineeringDevelopment Center (REDC) for the production ofcalifornium-252 and other transplutonium isotopes.


Calutrons

The Calutrons are located in what is called the IsotopeEnrichment Facility (IEF). The Calutrons consist of 30high-current mass spectrometers housed in individualtanks. However, the first eight tanks, the second eighttanks, the third eight tanks, and the final six tanks operatetogether and are referred to as segments. Although theCalutrons are presently in standby mode, when operatingthey are capable of enriching some 225 stable isotopesfrom approximately 50 multi-isotopic elements. Theprocess of electromagnetic separation used by theCalutrons is applicable to many elements and all isotopesof a multi-isotopic element are enriched simultaneously.The facility is well suited to produce modest quantities

of isotopes at high enrichments. In addition to enrichingstable isotopes, IEF also provides a myriad of otherservices for customers, such as using chemical and highvacuum processing techniques to convert inventorymaterials to custom-order forms (such as metals andoxides) and shapes for direct application by customers.

HFIR

The High Flux Isotope Reactor is an 85 MW reactor, withone of its primary missions being to produce californium-252 and other transplutonium radioisotopes for medical,research, and commercial applications. Reaching thehighest thermal-neutron flux (2.3 x 1015 neutrons/cm2 -sec) in the world, the reactor is well-suited to provideirradiation of a variety of target materials. In addition,HFIR provides fast-neutron irradiation-damage studiesand neutrons for neutron scattering experiments to revealthe structure and dynamics of a variety of substances ofinterest to solid-state physicists, chemists, biologists, andothers. Some 200-400 researchers use the facilityannually.

Some of the medical radioisotopes produced anddistributed by HFIR, along with typical applications, areas follows:

Tungsten-188 Decays to rhenium-188 fortreatment of cancer and rheumatoidarthritis

Yttrium-90 To radiolabel various molecules ascancer therapeutic agents

Copper-67 Cancer therapy and to labelantibodies for cancer therapy

Iridium-192 Cancer therapy with sealed sources

Dysprosium-166 Decays to Holmium-166which is used in cancer therapy

Holmium-166 Cancer therapy and to treatrheumatoid arthritis

Lutetium-177 Cancer therapy and to labelantibodies for cancer therapy

Rhenium-186 Bone cancer therapeutic agent and toradiolabel various molecules ascancer therapeutic agents; also usedto treat rheumatoid arthritis

Tin-117m Treatment without marrow toxicityof pain due to metastatic bone cancer

In the above isotopes, rhenium-188, yttrium-90, copper-67, holmium-166, lutetium-177, rhenium-186, and tin-117m are all recommended for production by the DOEExpert Panel Report. 1

D-1

Appendix D

Radioisotope Development Laboratory

The Radioisotope Development Laboratory (RDL) in theChemical Technology Division at ORNL is a hot cellfacility located in Building 3047. It houses four b-g hotcells and one a hot cell. In addition, the RDL utilizes avariety of radiochemical analytical tools, including agamma spectroscopy system, a beta liquid scintillationcounter, an a spectrometer system, and a new ionchromatography system.

Radiochemical Engineering Development Center

Working closely with nearby HFIR, the RadiochemicalEngineering Development Center (REDC) in theChemical Technology Division at ORNL is theproduction, storage, and distribution center fortransplutonium elements, such as californium-252, in theUnited States. It provides selected radioisotopes andrelated technical services to customers involved inmedical, research, and commercial applications ofradioisotopes. In addition, the REDC houses theCalifornium User Facility (CUF) for Neutron Science.californium-252 is an intense neutron source, and thuscan substitute for a neutron-emitting reactor when a lowneutron flux is adequate for any application. At the CUF,researchers can irradiate their samples with californium-252 neutrons in uncontaminated hot cells.

Brief History

Calutrons

The Calutrons were constructed in the 1940s for theenrichment of uranium-235 and later converted for theseparation of stable and actinide isotopes. Presently, theyare in standby mode, apparently scheduled to bepermanently shutdown. More modern and possibly cost-effective techniques, such as utilizing plasmas for isotopeseparation, are being considered by the Department ofEnergy. At present, ORNL has in its inventory up to $300M of stable isotopes left over from the days of Calutronoperations. However, several isotopes, such as Ru-96and Hg-202, are either in short or zero supply.

HFIR

The status of the transuranium production program wascritically reviewed by the U.S. Atomic EnergyCommission (AEC) Division of Research at a meetingon January 17, 1958. At that time the AEC decided toembark on a program designed to meet the anticipatedneeds for transuranium isotopes by undertaking certainirradiations in existing reactors. By late 1958 it becameapparent that acceleration of this program was desirable.Following a meeting in Washington, D.C., on November24, 1958, the AEC recommended that a high-flux reactorbe designed, built, and operated at ORNL, withconstruction to start in FY 1961.

As a result of this decision ORNL submitted a proposalto the AEC in March 1959. Authorization to proceed withthe design of a high-flux reactor was received in July1959. The preliminary conceptual design of the reactorwas based on the “flux trap” principle, in which thereactor core consists of an annular region of fuelsurrounding an unfueled moderating region or “island.”Such a configuration permits fast neutrons leaking fromthe fuel to be moderated in the island and thus producesa region of very high thermal-neutron flux at the centerof the island. This reservoir of thermalized neutrons is“trapped” within the reactor, making it available forisotope production. The large flux of neutrons in thereflector outside the fuel of such a reactor may be tappedby extending empty “beam” tubes into the reflector, thusallowing neutrons to be beamed into experiments outsidethe reactor shielding. Finally, a variety of holes in thereflector may be provided in which to irradiate materialsfor later retrieval.

In June 1961, preliminary construction activity wasstarted at the site. In early 1965, with constructioncomplete, final hydraulic and mechanical testing began.Criticality was achieved on August 25, 1965. The low-power testing program was completed in January 1966,and operation cycles at 20, 50, 75, 90, and 100 MW began.

From the time it attained its design power of 100 MW inSeptember 1966, a little over 5 years from the beginningof its construction, until it was temporarily shut downin late 1986, the HFIR achieved a record of operation timeunsurpassed by any other reactor in the United States.By December 1973, it had completed its 100th fuel cycle,approximately 23 days each.

Notable accomplishments resulting from HFIR operationinclude the production of californium-252, which is usedfor reactor startup sources, scanners for measuring thefissile content of fuel rods, neutron activation analysis,and fissile isotope safeguards measuring systems. Inaddition, californium-252 is used as a medical isotope totreat several types of cancer. Also, neutron activationanalysis at HFIR has been used by the semiconductorindustry, environmental remediation operations, and theFood and Drug Administration.

Radioisotope Development Laboratory

The Radioisotope Development Laboratory was built in1962 for research and development involving beta andgamma-emitting radioisotopes. Subsequently, thenecessity of working with alpha-emitting radioisotopesled to the construction of a water-shielded alpha facilityfor studying and performing research on transuranicelements.

D-2


Radiochemical Engineering Development Center

The REDC and neighboring HFIR began operations in1966 to produce transplutonium elements for use inresearch. Since then, the REDC has been the main centerof production for transplutonium elements in the UnitedStates.

Target rods containing principally curium oxide areremotely fabricated at the REDC, irradiated in the HFIR,and then processed at the REDC for the separation andpurification of the heavy actinide elements. All elementsfrom plutonium through fermium are separated andpurified. Portions of the americium and curium arerefabricated into targets for additional irradiations. Theberkelium, californium, einsteinium and fermium aredistributed to researchers.



ORNL’s Isotope Production & Distribution Program isoperated under the auspices of DOE’s Office of NuclearEnergy, Science & Technology. However, parts of thefinancial support for the program’s activities come fromother sources, such as DOE’s Office of Science and itsOffice of Defense Programs. As for the prices of isotopesdistributed by the program, DOE’s Office of IsotopePrograms (IP) sets the prices, not ORNL. For more detailssee Questions 12 & 13, attached.


Although ORNL’s Isotope Production & DistributionProgram recently hosted a postdoctoral researchassociate from the University of Tennessee and twograduate students who received their Master’s degreesfrom Rice University, the site team was concerned thatinsufficient academic training opportunities exist withinthe program. While part of the reason may have to dowith the need for extensive radiation safety training andparticularly funding limitations, there is generalagreement that the future of the field is being jeopardizedby the low numbers of new personnel being trained inthe experimental methods of radiochemistry.


Since the Calutrons are in standby mode, no stableisotopes currently are being enriched. However,inventory still includes some $300 M of stable isotopesleft over from prior Calutron operations. The continuedshutdown of the Calutrons and any interruption in theRussian supply from Sverdlovsk could lead to a shortageof targets for radioisotope production at both reactorsand accelerators.

The only facility presently available for isotopeproduction at ORNL is the High Flux Isotope Reactor.

Throughput

ORNL’s Isotope Production and Research Program keepsa careful log of all inquiries by potential customersinterested in purchasing isotopes. This is done regardlessof whether the inquiries come into the main distributionoffice or are made to individual members of the program.Radioisotope orders may not be filled if the order is notlarge enough to be practical to the customer. However,stable isotope orders always are filled, no matter whatthe size. Shipments of all isotopes are coordinatedthrough the Lockheed Martin Energy ResearchCorporation’s shipping department.

Customers

The customer base is composed of entities, both privateand public, that have a need for stable or radioactiveisotopes for medical, research, or commercialapplications.

Research & Development (R&D)

Presently, no R&D activities are associated with theCalutrons. As for HFIR, it was designed to producetransplutonium isotopes, including curium-244,berkelium-249, californium-252, einsteinium-253, andfermium-257. Even though only small quantities areproduced annually, they have been used to study thechemical and physical properties of transcuriumisotopes, as well as to provide target materials for theproduction of still heavier isotopes in accelerators. Othermedical isotopes produced at HFIR are listed above.

Cf-252 has been used extensively for medical, defense,and industrials applications, including the treatment ofcervical and uterine cancers, neutron radiography ofaircraft for the Air Force, and as the industry standardfor a neutron source in the start-up or restart of nuclearreactors. As for cancer therapy, over 2000 patients havebeen treated with Cf-252 neutron brachytherapy. Forcervical and uterine cancer, the overall results areimpressive with a 75% 5-year survival rate for otherwisefatal cases of those cancers.

Limited funds have been used to develop radiochemicalseparation and purification procedures for radioisotopesproduced at HFIR. The program at ORNL has beenlimited in its ability to expand operations by limitedfunds. For example, Th-229 supplies needed forproduction of Ac-225 are available in stores of U-233 onsite. Limited funds have been made available forseparating the Th-229 from the U-233, although this hassomewhat limited the amount of Ac-225 that can beproduced for existing customers. In addition, customerswho need Ra-224 generators also have not been serveddue to the lack of funds to establish operations.

D-3

Appendix D


Continued Operation

A number of improvements to the Calutron facility havebeen implemented in recent years. The staff believes that,with the improvements and spare parts currentlyavailable, the Calutrons could continue to operate forsome time to come. As for HFIR, it is in good operatingcondition.


For the Calutrons, current or just completed upgradesinclude a new roof, emergency generator, a 13.8 kVswitch gear, and a 50 megawatt transformer. [For moredetails, see Question 1, attached] However, there are noplans to expand the operations, or operate at all, at thistime.

At HFIR, the recent addition of 42 new Peripheral TargetPositions have dramatically increased its isotopeproduction capabilities.


The staff needed to operate the Calutrons includes 5facility and compliance, 4 chemistry, 4 isotopedistribution, and 3 IRML staff, for a total of 16 FTEs.Standby costs are $3.6M per year, with the option ofoperating one segment estimated to require $5.2M, andtwo segments estimated at $6.2M per year (see detail inSection VI). Sales of existing stocks are currently about$2.4M per year. A Commerce Business Daily (CBD)announcement for expressions of interest in privatizationof the Calutrons was released in May, and responses aredue in June. DOE has initiated a study by an outsideconsultant to investigate possible replacementtechnologies for enriching stable isotopes. Also, DOEhas signed an agreement with Theragenics, Inc., for theirexclusive use of the existing Plasma Separation Processequipment. Their intent is to use this equipment toproduce enriched Pd-102 with subsequent HFIRirradiation to supply Pd-103 for use as brachytherapysources.

Major upgrades are planned for HFIR during the year2000, including a beryllium reflector change. Theupgrades should increase the availability from thecurrent 64% to 65-70% while maintaining the reliabilityat the current 100%. The joint venture with Theragenics,Inc., to produce palladium-103 should lead to theestablishment of 16 new removable hydraulic targetpositions. Although the HFIR upgrades will lead to a 6-8 month interruption in isotope production, they shouldinsure the soundness of the facility for isotope productionfor the next 25-30 years.

6. General Issues


The ORNL management has a history of stronglysupporting its radioisotope production and distributionactivities. However, the Site Team has concerns aboutsupport for R&D on new research isotopes, since thereis not much discretionary funding awarded to thisactivity at ORNL. While there are some opportunitiesfor Laboratory Directed R&D (LDRD) support, thereneeds to be R&D support from external sources.

Marketing

Users of radioisotopes know that ORNL is one of thelimited sources from which to obtain both stable isotopesand reactor-produced radioactive isotopes. Therefore,prospective purchasers make inquiries to the ORNLIsotope Distribution Office or directly to the staff. Asmentioned previously, all such inquiries are tracked fromthe initial time of contact to the final distribution, or non-distribution, of the requested isotopes. It frequently takesabout one month to fill a customer order for radioisotopesdue to the unique studies that often are needed toformulate a response. However, an initial reply to thecustomer ’s inquiry is made within several days.Moreover, off-the-shelf stable isotopes are shipped to thecustomer within several days.

Waste Management

Waste management at ORNL is conducted in accordancewith existing government regulations. However, costsfor waste management are not a major component inORNL’s radioisotope pricing, since the hot cell facilitycharge for Building 3047 includes a waste collectionsystem that reduces waste costs charged specifically toradioisotope products.

7. Summary Comments

ORNL has two major facilities for producing isotopes:the Calutrons, which are capable of enriching most stableisotopes of Z equal to about 12 and higher; and the HighFlux Isotope Reactor, which is designed to produceradioactive transplutonium isotopes. In lieu ofpermanently shutting down the Calutrons, the ORNLstaff estimates that it could operate on a part-time basisfor about $4 M per year. Full-time operation of onesegment of the Calutrons would cost approximately $5.2M. This would include the recommissioning of oneCalutron segment, or eight isotope enrichmentspectrometers. An additional segment could berecommissioned for an extra $1 M. While they enrichstable isotopes, other options of enriching the isotopes,such as the plasma separation technique, could undergomore research and development. As for HFIR, theupgrades to be performed in the year 2000 will increasethe thermal core flux to 2.2 to perhaps 3.5 x 1015 neutrons/cm2 -sec. Finally, the hot cell facility requires about $1.5M per year to operate and $0.5 M per year for 3 years toupgrade.

D-4


ORNL currently is selling about $2.4 M of isotopesannually. There is some indication of a future shortageof stable isotopes that could be used as reactor oraccelerator targets for the production of other isotopes.To date, these isotopes have been available from foreignsources. The long-term availability and reliability ofthese sources is unclear. Current stable isotope inventoryat ORNL stands at a net worth of about $300M. It maybe wise to investigate whether the physical security ofthose isotopes needs improvement. However, with theinternal organizational controls and the location of theinventory within the Y-12 Exclusion Area, ORNL believesthat the physical security of the stable isotope inventoryis more than adequate.

The current focus of ORNL’s Isotope Production andDistribution Program has been on providing commercialneeds with little attention paid to research isotopes. Nodevelopment for the production of new research isotopeshas been performed other than, on occasion, to providea cost-estimate to DOE Headquarters. The ORNL facilityis a deteriorating infrastructure in maintaining adevelopment expertise in isotope production, chemistry,and source fabrication and recovery. The Site Team isconcerned about the present and especially future lackof trained personnel in this field. In most instances, staffis only one deep and many of those staff are close toretirement.

A prominent complaint of the ORNL staff is that sufficientresources often are not available to allow ORNL torespond adequately to customer inquiries, especiallythose that require development activities. They also feelthat too much reporting and documentation is requiredby DOE Headquarters. They estimate that one man-yearof effort is required to comply with DOE Headquartersreporting requirements.

The status of stable isotope enrichment in the UnitedStates is at a crossroads. The Calutrons could berecommissioned, even at partial capacity, while otherenrichment techniques are being studied, or theCalutrons could be shutdown permanently while a newalternative is explored. Since the inventory of certainstable isotopes has become exhausted, vendors have topurchase them from Russia. It is important to note that,even with current inventory, Russian prices are cheaper.Thus, DOE has to come to a decision soon as to the futureof stable isotope enrichment in the United States.

1 Expert Panel: Forecast Future Demand for MedicalIsotopes, Appendix D, March 1999. http:/www.NE.doe.gov/nerac/isotopedemand.pdf

D-5

Appendix D

Oak Ridge National Laboratory(ORNL)

Question and Answers

How well does DOE’s existing five-site productioninfrastructure serve the current need for medical,commercial and research isotopes?

1. What is the physical condition of your isotopeprocessing facilities and equipment?

Isotope production facilities located at ORNLinclude the electromagnetic separators (calutrons),the High Flux Isotope Reactor (HFIR), the Building3047 Hot Cell Facility, and the RadiochemicalEngineering Development Center (REDC) for theproduction of Californium-252 and othertransplutonium isotopes.

The calutrons are presently scheduled forabandonment, but are currently in good operatingcondition for a fifty year old facility. Many of theCalutron support systems have been replaced inrecent years including: mechanical vacuum pumps,oil diffusion pumps, Z-Oil circulating pumps,demineralized water pumps, Z-Oil reclaimingsystem, vacuum oil reclaiming system, Z-Oil headtank, cooling tower, and demineralized water heatexchangers. Completed within the last year orcurrently in progress are: new roof, emergencygenerator, 13.8 kV switch gear, 50 mega-watttransformer and refurbishment of the IsotopeResearch Materials Laboratory which includes newceiling and windows. A more than adequate supplyof spare parts has been maintained, but recentdecisions by DOE/HQ/NE have resulted in the lossof key operating personnel.

The HFIR is in good operating condition. The HFIRwill be temporarily out of operation for about 6months in the year 2000 for a beryllium reflectorchange and other modifications which will increasethe radioisotope production capabilities and providethe foundation for operation for at least another 30year period. The recent installation of 42 newPeripheral Target Positions (PTP) have dramaticallyincreased the production capabilities of the HFIRand medical and other radioisotopes - Tungsten-188/Rhenium-188 being a prime example.Theragenics Inc., as part of a recently announcedventure to produce Pd-103 in Oak Ridge, has statedtheir intention of installing two new HydraulicTubes (HT) in the HFIR. These tubes, when notbeing used for palladium irradiations, will add anadditional 16 removable target positions. The HFIRdoes requires close attention by management with

regards to scheduling and maintenance in order toachieve reliable operation. This has not alwaysoccurred in the past, but during FY 1999 HFIR hasachieved an availability of 64% and a predictability/reliability performance indicator of 1.

The Building 3047 Hot Cell Facility (4 beta/gammacells, 1 alpha cell) is required for the processing, andpackaging for the majority of the radioisotopesproduced at ORNL. The facility requires and willcontinue to require periodic upgrades to maintainits operability. Currently modifications/upgradesare underway on two of the building’s 5 hot cells(Cell D and the alpha cell). Cell C and possibly CellA will need to be upgraded within the next year.

The REDC is in very good operating condition. It isjointly funded by DOE/DP and DOE/SC. DOE/NE only contribution relates to the production ofCf-252.

2. What capital investments are needed to assure thenear term operability of your facilities?

Based on recent decisions from DOE/HQ continuedproduction of stable isotopes will depend upon thefuture investment in an alternative facility for theirproduction. The type of facility, necessary capitalinvestment, and realized production output haveyet to be determined. No capital investments arerequired to assure near term operability of thecurrent Calutron facility.

$1 million would purchase and install three or foursmall hot cells which would be perfect for manyHFIR produced research radioisotopes, especiallyfor the beta-emitting and alpha-emitting isotopes,and would have the distinct advantage ofminimizing cross contamination.


The technical rational for acquiring an alternativemethod for the production of stable isotopes that isflexible (capable of separating a wide range ofisotopes), is capable of producing milligramquantities of isotopes annually (as opposed tomicrogram quantities), and can be acquired andoperated at a reasonable cost remains to bedetermined. The infrastructure, both facilities andpersonnel, currently exist at ORNL, but are erodingdue to a lack of support from the national program.There is no mechanism for providing local financialand personnel resources.

D-6


Additional small hot cells for the production of awide variety of medical radioisotopes are readilyobtainable and can easily be incorporated into theexisting infrastructure.

4. What is the availability of your primary nuclearfacility (accelerator or reactor) over the next fiveyears, e.g., operational outages and programchanges?

The calutrons are currently in a cold shut downmode with no intention of restarting.

The HFIR will be implementing a major plannedupgrade program in the year 2000. This willpreclude the production of reactor producedradioisotopes for a 6-8 month period in that year.However, the major upgrades to the HFIR willinsure that this resource will be able to operate andfulfill an important role in radioisotope productionfor at least another 25-30 years.

5. What understanding exists at your site about thepriority of isotope production to serve isotopecustomers?

Although it is the stated intention of ORNLmanagement to serve the many and varied isotopecustomers, the HFIR is operated by DOE/SC andas such its first priority is meeting the needs of thehigh-energy research community it serves. For thecalutrons, the emphasis appears to be, not on isotopeproduction, but on cost recovery.

6. How much influence do you as site manager havein planning the use of multi-purpose facilities?

As ORNL Isotope Program site manager, I have littleinfluence in the use of the multi-purpose facilities.For the HFIR, schedules and proposed maintenanceitems are communicated to the Isotope Office, butwe have little control over these items. In a fewspecific areas, such as use of some of the HFIR targetpositions, the Isotope Program has considerablymore influence. Our design, planning, andinstallation of the new PTP units is an excellentexample of the influence that the Isotope Programcan have and how we can work effectively withmulti-purpose facilities.


In the recent past the stable isotope inventory, theIsotope Distribution Office, and the Isotope ResearchMaterials Laboratory were consolidated under oneroof at the Calutron facility to achieve a moreefficient utilization of personnel and to minimize

overhead and administrative costs. In order tocontain further costs, the calutrons have been placedin cold shutdown and a number of staff terminatedor reassigned to other positions. A number ofresearch projects have been eliminated or scaledback.


A number of licensing items have been consideredrecently. Over the last few years, these haveincluded licensing of Mo-99/Tc-99m and W-188/Re-188 concentrators, exclusive rights to pursue In-111technology, and the transfer of Plasma SeparationTechnology to a private firm, the privatization ofiridium targets (for the production of Ir-192). Stableisotope production, sales and distribution arecurrently being evaluated for privatization.


ORNL currently has unused or underused capacityin terms of facilities, but not in terms of personnel.The existing calutrons could support a very largeincrease in the production of stable isotopes if animmediate decision would be made to reverse therecent decisions to shutdown the calutron facility.Personnel are being lost, but for the immediatefuture the facility remains in an operable condition.The HFIR and Building 3047 hot cells have aconsiderable amount of remaining capacity. Anumber of other facilities, including additional hotcells, have been shutdown, but could be resurrectedif the need required.

10. Summarize customer inquiries received duringthe past two years. What per cent was filled,referred to other facilities, rejected?

A variety of requests for quotation are receivedduring the fiscal year ranging form off-the-shelfinventory stock to customized fabrications andconversions. For the fiscal years 1997 and 1998, thenumber of quotations processed were 829 and 734respectively. For the first six months of fiscal year1999, there have been 376 quotations processed.These numbers do not include informal phonequotations that are received daily. Of the formallydocumented quotations, approximately 30% resultin orders. Referrals to other DOE facilities areseldom necessary since the Web site and publishedcatalog give the site location and contact point foreach product offered. ORNL is currently the onlysite offering stable and reactor produced isotopesamong the DOE facilities.

D-7

Appendix D

11. How do you rate customer satisfaction for yoursite? For the overall program?

No formal mechanism exists for rating customersatisfaction for ORNL’s service within the IsotopeProgram. ORNL has no way of knowing thecustomer satisfaction rating for the overall program.Anecdotal feedback would indicate that mostcustomers would like lower costs, increasedavailability, and guaranteed reliability. The qualityof ORNL’s products has generally been consideredof high quality.

12. Kindly detail how you set the price of a mCi of aradioisotope? The detail should show if the costis fully loaded or incremental, and should includelabor, materials and parts, facility rental andamortization costs, listing of all the actualoverhead charges, waste disposal (a major cost),and all other costs that are tagged to the cost ofproducing, marketing, selling, and distributing ofthe product (e.g., customer service, distribution,ordering).

DOE/IPDP sets radioisotope prices based in parton ORNL price recommendations which are basedon an analysis of expected costs incurred to producethe subject radioisotope at the required productionlevel plus an allocation of other necessary businessexpenses of the program (Isotope Sales Office/DOEAdded Factor). The structure for these studies isbased on the established DOE/NE IPDP Budget andReporting Codes for radioisotope production costreporting. Projected costs are categorized as:

Each category is estimated using the current ratesfor direct labor, site services, and material purchases.Applicable ORNL overhead is shown separately foreach cost item.

Target Fabrication/Purchase: The specific cost forpurchase of feed material (target) or site fabricationof the required target to produce specified quantityof radioisotope product is included in the productestimate.

Irradiate Targets: ORNL radioisotopes are irradiatedin ORNL’s High Flux Isotope Reactor (HFIR). Basedon the position and number of cycles, irradiationcosts are estimated using current pricing list for useof HFIR services.

Target Fabrication/Purchase

Target Irradiation

Hot Cell Operations

Processing

Waste Management

Quality Assurance

ES&H Regulatory Compliance

Production Packaging

Program Management

ST0101010

ST0101020

ST0101030

ST0101040

ST0101050

ST0101060

ST0101070

ST0101080

ST0101090

Budget andReporting CodeCategory

Hot Cell Operations: The ORNL IPDP is responsiblefor the facility operation and maintenance costs forHot Cell Building 3047 which is used for theprocessing of radioisotopes. In order to allocate thecost of this facility to the radioisotope productsproduced, the annual operating/maintenance costsis forecast and divided by the expected availablehot cell hours yielding a “hot cell rate”. Theprojected cost per hot cell hour is then used forproduct price studies to estimate the portion of hotcell operations costs to be assigned to the product.Currently, ORNL does not include amortization forany “unassigned” operating/maintenance costs orfacility upgrades for Building 3047 in radioisotopeprice studies.

Processing: The estimated effort needed to process/analyze irradiated material and place into shippingcontainer based on customer request is included inthis category.

Waste Management: Costs for waste disposaldirectly related to the production of the specifiedradioisotope are included in this category.Generally, waste management costs are not a majorcomponent in ORNL radioisotope price studies dueto the fact that the hot cell facility charge for Building3047 includes a waste collection system whichreduces waste costs charged specifically toradioisotope products.

Quality Assurance: The estimated effort from QApersonnel to meet quality standards is included inthis category.

ES&H Regulatory Compliance & Safety: Theestimated effort from Health Physics personnelnecessary to meet ES&H regulations in included inthis category.

Production Packaging: The estimated effort for“custom” packaging per customer request (prior toplacing into shipping container) is included in thiscategory. Routine placing of completed product into

D-8


shipping container is normally included above asprocessing effort. Final labeling, packaging andshipping costs are included below in the addedfactor for packing and shipping.

Program Management: The estimated effortrequired by the project manager to coordinate andsupervise activities throughout the productionprocess is included in this category.

Total of Cost of Production: Total of all direct chargedcategories which will be recorded as cost of goodsmanufactured in the accounting system.

Added Factor for Isotope Sales Office: In order torecover the indirect cost of the Isotope Sales Office,a predetermined percentage of total production cost(currently 6.5%) is included in the price study.

Added Factor for DOE Cost Recovery: In order torecover other DOE indirect costs, a predeterminedpercentage of total production cost (currently 3.0%)is included in the price study.

Addition for Final Packaging and Shipping: In orderto recover the cost of final labeling, packaging andshipping, an addition based on the number ofshipping containers is included in the price.

13. Where applicable to your facility, please illustratethe above question for the followingradioisotopes: In-11, P-32, I-123, I-125, and severalresearch radioisotopes.

Answer combined with the response to Question12.

14. What process, mechanism, and organizationalstructure do you have for the timely distributionof your product?

ORNL is a multi-faceted research organization. Assuch, few employees are dedicated solely to theproduction and distribution of isotopes. However,the Isotope Distribution Office does maintain fourfull-time employees to handle all customerquotations, customer contracts, shippingdocumentation, and customer invoices. In addition,for EM-Stable isotopes, there are personnel assignedin the loading facility, the chemistry laboratory, andin the special conversions and fabrication areas.These employees are generally cross trained forother assumable duties should some personnel be

not available. The EM-Stable isotope productionand the entire isotope distribution functions are ISO9000 certified. For radioisotope production, theprogram does sponsor the building 3047 hot-cells.Production of the different isotopes, however,crosses divisional lines. Shipments of all isotopesproducts are coordinated through the LockheedMartin Energy Research Corporation’s shippingdepartment.


With the ISO 9000 certification, a formal customerstructure and resolution procedure exists. Thisprocedure is used by the Isotope Distribution Officefor both stable and radioactive isotopes.

16. Will you sign contracts that guarantee delivery atthe contracted time of delivery and where thecontract has penalty clauses for non-timelydelivery of the specified product?

As a DOE facility, I do not believe that we areallowed to sign contracts that contain penaltyclauses for the non-timely delivery of product. Thisoption, if possible, can only be negotiated with theconcurrence of DOE.

17. What should be the long-term role of governmentin providing medical, commercial and researchisotopes?

The long-term role of government (U.S. DOE)should be related to the providing of the necessaryinfrastructure and support necessary to producethose isotopes (stable and radio) that are requiredby the medical, commercial, and researchcommunities. For commercial isotopes this roleshould be limited to the infrastructure that is eitherimpossible or very difficult for industry to provide(i.e. reactors). Other support should only beprovided on a full cost recovery basis. For medicalisotopes, institutional decisions will need to be madeas to whether this support should be full costrecovery (even if the decision means the medicalapplication may be too expensive to provide) or ifthe support should be subsidized (as should be forresearch isotopes). The Isotope Program cannot beoperated in a true business sense, since theprogram’s requirements and constraints aredifferent than that of a private entity.

D-9

Appendix E

Los Alamos National Laboratory(LANL) Site Visit


1. Introduction

A site visit was conducted at Los Alamos NationalLaboratory (LANL) on May 17, 1999. Site visitors wereDr. Ralph Bennett, Idaho National Engineering andEnvironmental Laboratory, Dr. Henry Kramer,consultant, and Dr. Richard Reba, University of Chicago.Mr. Gene Peterson acted as host for the visit.

Mission

The mission of LANL with regard to isotope productionis primarily as a source of accelerator-producedradioisotopes for medical research and commercial uses,with a variety of additional roles based on uniquecapabilities. The mission has primarily been derivedfrom the longstanding capabilities of the high energylinear accelerator at the Los Alamos Neutron ScienceCenter, as well as staff strengths in accelerator and targetdesign, radiochemistry, and more recently, the life andphysical sciences.

Facilities

The Los Alamos Neutron Science Center (LANSCE), isthe cornerstone of isotope production at LANL. This800 MeV, 1 mA linear accelerator has been operating for25 years. It is capable of delivering beams of H+, H-, andpolarized H- ions. For many years, isotope productionhas been based on direct interactions with high-energyprotons as well as a spallation reaction capability withup to 9 target stations. It is notable that the first sectionof the accelerator drives the beam to 100 MeV. The abilityto divert a portion of the beam at this point affords theconstruction of an Isotope Production Facility (IPF) whichis discussed below under Expanded Operations—Underway.

The TA-48 Hot Cell Facility is located at the MainRadiochemistry Site, about four miles from LANSCE.Within the facility is Building RC-1, which houses theprimary hot cell facility for processing of acceleratortargets. The facility consists of two banks of six hot cells,connected at one end by a large multipurpose“dispensary” cell into which materials are received orremoved from the facility. Most of the cells are dedicatedto various radioisotope production campaigns, withsome capacity still available. There are about eight fulltime staff dedicated to radioisotope production. Whileother staff and technicians are located in the facility, theywould need training to be available to supportproduction. A number of the products are preparedunder current good manufacturing practice (cGMP)protocols required by FDA regulation of the products

and the facility. Supporting the facility are severalradiochemistry laboratories, a machine shop, twoanalytical chemistry laboratories, a well-equippedcounting room, and staff offices. The hot cell facility hasrecently received upgrades to its air handling system,bringing it to state-of-the-art, and a crane.

The Chemistry Metallurgical Research (CMR) building’sWing-9 hot cells are a complementary facility to the TA-48 hot cells. The Wing-9 hot cells are a Category 2 nuclearfacility, available for work that requires such a safetyauthorization basis. The CMR is the site for high enricheduranium (HEU) target fabrication to support 99Moproduction at Sandia, for example. The facility couldalso process reactor-irradiated targets from the AnnularCore Research Reactor (ACRR) facility at Sandia,excluding the 99Mo targets. Currently the isotopeprogram is installing an electromagnetic isotopeseparator in the CMR to be made available for theseparation of radioactive isotopes.

Several important waste treatment and disposal facilitiesexist within LANL. The TA-50 Radioactive Liquid WasteTreatment Plant treats and disposes liquid effluents fromisotope production activities. All such effluents arereceived by TA-50 via an acid waste line that connectsfrom both TA-48 and CMR. The TA-54 Solid RadioactiveWaste Disposal Site is used for storage and permanentdisposal of low-level wastes. All wastes except mixedwastes are handled on site at LANL. It is important tonote that the isotope production activities at LANL havebeen extensively engineered to produce no mixed wastes,making the isotope program self-contained from a wastetreatment and disposal standpoint.


Overall, LANL produces about 160 shipments ofradioisotopes per year. The range of isotopes that canbe produced is found in Table 1. The number of theseisotopes actually produced in any year is about half ofthose in the table, however. The isotopes with the largestdemand are 68Ge and 82Sr, whose revenues give aconsiderable stimulus to the overall program at LANL.None of the radioisotopes supplied have very short half-lives, so the shipping time from the laboratory to theAlbuquerque airport and on to customer sites has notbeen a factor.

The largest barrier to increased production is the lack ofavailability of irradiation time at LANSCE, stemmingprimarily from the limited time that the facility operatesthe beamline during the year. Recently the facility hasoperated only about 5–6 months per year. In an effort toincrease radioisotope supply, LANL coordinates a VirtualIsotope Center (VIC) in collaboration with four otheraccelerator centers (described below under BusinessPractices). LANL’s chief contribution to the VIC is theoperation of its FDA-approved processes in the TA-48

E-1


hot cells, which affords high-quality processing andfinishing of targets irradiated at other facilities in theCenter.

Other products and services at LANL include (1)distribution of actinides, (2) unique electromagneticseparations at CMR, (3) fabrication of HEU Cintichem-style targets to support 99Mo production at Sandia, and(4) recycle of 82Sr generators. In recent years, actinidedistribution amounts to sales of $240K per year, with thechief product being 241Am. To provide electromagneticseparation of radioactive isotopes, a 1 m radius separatoris being installed in a cell at CMR, and is capable ofseparating about 1 milligram per day. The primarymotivation for the investment is the separation of Sr andP isotopes to improve product quality, and to improvespecific activity of reactor-produced isotopes. Anotheruse of this unique capability is planned to be separationof several fission product isotopes from the 99Mooperations at Sandia. The limited capacity of theseparator is actually well-matched to the requiredthroughput of very small radioactive samples rather thanlarge quantities of non-radioactive elements. Also inconjunction with Sandia is the fabrication of HEU targetsfor demonstration of the 99Mo process. This involves theapplication of a thin layer of HEU inside a tubularCintichem-style target. Recent funding for this activityhas been about $800K per year, with plans for doublingthis amount to support active production operations atSandia. Recent decisions by DOE have redirected thisactivity, however, and the plans are to discontinue thiswork. A new service developed recently at TA-48 is therecycle of 82Sr from Cardiogen (82Sr/82Rb) generators thatare routinely received in the facility from the generatorcustomers. The service developed on the initiative ofthe hot cell staff, who recognized the value of therecycling and suggested it to the pharmaceuticalmanufacturer, who had independently developed thesame idea. The recovery process is the subject of a jointpatent between the manufacturer and LANL.

Table 1. Radioisotopes Historically Producedby LANSCE Irradiation

26Al105Ag72As73As74As7Be207Bi109Cd77Br67Cu146Gd148Gd68Ge172Hf194Hg163Ho172Lu173Lu52Mn22Na83Rb

Not identified

Not identified

Not identified

Not identified

Not identified

Not identified

Not identified

Not identified

Not identified

3

Not identified

Not identified

3

Not identified

Not identified

Not identified

Not identified

Not identified

Not identified

Not identified

Not identified

RadioisotopeExpert Panel

Category

720,000 y

41 d

1.1 d

80 d

18 d

53 d

32 y

1.3 y

2.4 d

2.6 d

48 d

75 y

270 d

1.9 y

520 y

33 y

6.7 d

1.4 y

5.6 d

2.6 y

83 d

Half-life

86Rb44Sc46Sc72Se75Se32Si145Sm82Sr179Ta95mTc44Ti48V49V127Xe88Y65Zn88Zr

Not identified

Not identified

Not identified

Not identified

Not identified

Not identified

Not identified

Not identified

Not identified

Not identified

Not identified

Not identified

Not identified

2

Not identified

Not identified

Not identified

19 d

2.4 d

84 d

8.4 d

120 d

104 y

340 d

26 d

1.8 y

61 d

44 y

16 d

330 d

36 d

110 d

240 d

83 d

E-2

Appendix E



Funding in recent years by the IP for activities at LANLhave averaged between $4–5M per year. A projectedbreakdown is found in Table 2. The TA-48 hot cells arethe only base funded facility. Activities at CMR arefunded only on an incremental basis by IP since thefacility is base funded by Defense Programs (DP). Also,there is a three-way sharing of operations costs atLANSCE, with isotope production being a very minorcontributor in relation to the funds provided by DP andthe Office of Science Programs (SC) in DOE. LANSCEoperations require about $35M per year overall, of whichisotope production contributes only a very small amountto cover facility charges and some incremental costs—the major contributor to LANSCE operations is DP, owingprimarily to the very steady needs of the StockpileStewardship programs.

and three graduate students conducting research in thisarea at LANL, with occasional recruitment of summerinterns. There are also several postdoctoral fellows onthe staff with funding from the Office of Biological andEnvironmental Research (OBER). Unfortunately, theintense scrutiny on security practices at LANL in recentmonths has given rise to some concern about whetherthese levels of participation can continue, since it isexpected that expansion of these programs will lead tostrong interest in participation by foreign nationals.


Throughput

In a typical year LANL will supply approximately 15 to20 individual isotopes. Four of these isotopes (82Sr, 68Ge,22Na and 241Am) provide the majority of the revenue,while the other 10 to 15 products are of interest to variousresearch constituencies. As an example, in FY 1998 LANLprovided 20 isotopes and generated $2.0 M from theirsale.

Customers

Overall, LANL serves about 100 customers with 160shipments of radioisotopes per year. Of these customers,about 70 are for research needs, and about 30 arecommercial needs.

Pricing Policies

Pricing policies have been established and are reviewedyearly with IPDP staff. The new MOU for LANSCEmanagement will consider the future allocation of costsfor the IPF, and will have a considerable impact on thebasis for cost recovery of isotopes. The currentproduction of isotopes in the LANSCE beam dump isnot burdened with any beamline operations costs, sincethe beam entering the dump is considered to be a by-product of operations. On the other hand, the futureproduction of isotopes in the IPF is considered to use adirect fraction of the beamline, since its extraction reducesthe beamline directly.

Product Development

The staff has recognized several dozen new researchisotopes. They feel that the most immediate emergingneed is for 127Xe, as well as several isotopes of Pt and As.As a general rule, one can expect the development oftargetry and processing for a new research isotope torequire an effort of about six months.


Continued Operation

The stated goal of the LANSCE facility is to achieve eightmonths operation in each calendar year over the nextfive years. Much of the future outlook for radioisotopeproduction at LANSCE depends upon the completion

Table 2. FY-1999/2000 Funding Levelsfor LANL

Ta-48 Operations and Upgrades

LANSCE Irradiations

Process Development and ProgramManagement

CMR 99Mo Target Fabrication

Total

$2.20M

$0.8M

$0.75M

$0.80M

$4.55M

As stated above, there is a considerable influence of DPand SC on the management and funding of operationsat LANSCE and influence of DP at CMR. In addition tonormal operations at LANSCE, there is regularinteraction between these programs and isotopeproduction when accessing resources (especially duringoutages, when maintenance and upgrades need to beperformed). To formalize these interactions as well asagreements that need to be reached on the construction,operation and equitable allocation of operational costsfor the new Isotope Production Facility (IPF), aMemorandum of Understanding (MOU) between DP/SC/NE has been drafted and is expected to be finalizedthis summer.


Isotope production activities at LANL enjoy a relativelyclose relationship with the School of Pharmacy at theUniversity of New Mexico. Three members of the LANLstaff are adjunct professors in Pharmacy. Also, LANLhas close relations with several of the universities withinthe University of California, the management andoperations contractor for LANL, including UC SantaBarbara and UC Davis. There are typically between one

E-3


of the IPF, which is described in the next section. Withregard to the existing target irradiation station, it iscurrently operational but needs to have additional H+

users to share the cost of beam delivery. Recently, thelargest user of H+ ions was the Accelerator Productionof Tritium (APT) program. APT offset much of theoperational costs during the last three years, but hasrecently been set aside as the major option for tritiumproduction by the DOE. The next major user of H+ ionsis likely to be the Accelerator Transmutation of Waste(ATW) program, although it is currently a much smallerprogram than APT and their plans are not yet formalized.Also, the existing target stations do not favor theproduction of short-lived isotopes, with the minimumirradiation time being seven days per target. This hasbeen better addressed in the design of the IPF.


A major new expansion of operations at LANSCE isunderway with the design and construction of theIsotope Production Facility (IPF). The IPF is a 100 MeV,250 mA irradiation facility that extracts 30 pulses persecond from the main beamline with a kicker magnet.The extraction point is just after the first stageacceleration of the main beamline to 100 MeV. The IPFhas a set of target irradiation stations and associatedequipment for unloading and preparing targets forshipment to TA-48. The total cost of the IPF is projectedto be $15.5M, to be funded by IP. The facility is nearing50% design completion, and is expected to be online inFY-2001. There are felt to be no serious design orconstruction issues, although the available space in theexisting beamline for the kicker magnet is quite limited.

When completed, the 100 MeV IPF will be capable ofproducing about 85% of the individual isotopes currentlyproduced in the 800 MeV beam dump facility today.However, with the better match of energy for targetreactions with a 100 MeV beam, the throughput of thoseisotopes is expected to increase by as much as 50%.


The most immediate interest in expanded services is theproposed use of one or more electromagnetic isotopeseparators within TA-48. Two mass spectrometers areavailable, both of which are base funded by NNprograms and which have considerable excessavailability. Both would be appropriate only for non-radioactive separations, unlike the unit being installedin the CMR. The small unit has a 1 m radius, and iscapable of separating approximately 1 milligram per day.A larger unit, currently occupied by a physicsexperiment, has a 1.5 m radius and similar separationcapacity. Base funding of the small building they areboth located within requires only about $160K per year;the cost of separation campaigns would requireadditional funding. It was noted that after the initial

setup, the machines may run largely unattended. A largecampaign for separating Nd isotopes to supply aEuropean stockpile of reference material (not associatedwith isotope production) is planned, which will occupythe smaller machine for several months.

Several other ideas for expansion of services were alsoidentified. First, there has been some interest in theacquisition of a lower energy accelerator to be dedicatedto the production of research isotopes, but plans are notfirm. This concept was first developed as part of the LosAlamos response to the call for National BiomedicalTracer Facility (NBTF) proposals. Second, with excesscapacity in the TA-48 hot cells and the CMR hot cells,there is some potential for teaming with reactorirradiation facilities and having targets sent to LANL forprocessing. Again, there are no firm commitments orplans, although discussions with Sandia are ongoing.Finally, there continues to be occasional interest in variouspartnership or commercialization agreements primarilyfocused on either the separation of light isotopes in thediffusion columns at LANL, or possibly in thedevelopment of accelerator technology and/orapplications.



LANL management support for isotope production isvery strong and is based on an appreciation of the valueof having both isotope production and basic and appliedresearch requiring isotopes at the laboratory. A majorOutstanding Accomplishment Award by the laboratorymanagement recognized the efforts to establish theVirtual Isotope Center last year, for example. Also,isotope production has been able to receive General PlantProjects funds on the order of $1M per year on a fairlyregular basis, although this is not guaranteed from yearto year. There are occasional awards of LDRD funds toprojects developing radioisotope applications, althoughonly a portion of the $100–300K funding per projectbenefits isotope production directly. An effort to definea major $1M support for radiochemistry fromdiscretionary LANL funds is underway, and is expectedto begin next fiscal year.

Marketing

LANL operates a modest marketing and salesorganization responsible for the 160 orders shipped eachyear. The organization has two full time staff. While nothighly computer automated, their operations are quiteadequate to meet their needs. There is a considerableeffort by the staff to solicit customer feedback andcomments. There is also a plan in place, endorsed byDOE IP, to consolidate the sales and marketing functionsfor accelerator-isotopes at LANL. Transfer of thesefunctions from Brookhaven National Laboratory (BNL)

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Appendix E

to LANL and communications to customers will beimplemented by FY-2000. Also LANL will provide thesefunctions for Sandia National Laboratory when theybegin production operations using the ACRR.

Business Practices

The most important development of recent years inLANL’s business practices is the formation of the VirtualIsotope Center (VIC). In concept, the VIC is acollaboration of a number of major accelerator facilitiesworldwide to collectively produce and processradioisotopes. In practice, radioisotopes that have beenproduced by the VIC are those needed by researchers inlarger quantities and very steady supply—typically forclinical studies or early commercialization efforts.

Interest in the VIC began in the mid-1990s. With ashortage in the supply of 82Sr looming in 1998, planswere finalized in 1997 and collaborative effortssuccessfully overcame the shortage. Today, the VICincludes the 800 MeV LANSCE at LANL, the 500 MeVmain cyclotron at the Tri-University Meson Facility(TRIUMF) in Canada, the 400 MeV linear accelerator atthe Institute for Nuclear Research (INR) in Russia, the200 MeV accelerator at BNL in the U.S., and the 200 MeV

cyclotron at the National Accelerator Center (NAC) inSouth Africa, as well as smaller accelerators and a varietyof hot cells at these facilities. These institutions operatewith a Memorandum of Agreement to coordinate theirirradiation schedules as well as to choose locations forprocessing campaigns based on the availability offacilities and/or their regulatory approvals andcapabilities. The VIC also encountered and solved anumber of startup problems dealing with transportation,customs and regulatory issues.

The initial 82Sr campaign culminated in 1998 with themanufacture of the first CardioGen® generators in theU.S. from Russian-irradiated Rb targets processed atLANL. At this time there are about a half-dozen currentand planned campaigns for other radioisotopes, withmost involving irradiation in Canada, South Africa orRussia followed by processing at LANL or BNL.

Waste Management

With the re-engineering of processes to eliminate thegeneration of mixed hazardous wastes, and theavailability of the facilities to treat and dispose of liquidand solid wastes, the waste management operations atLANL are self-contained and unlikely to be affected byany interruptions or problems at other laboratories.

E-5


Los Alamos National Laboratory(LANL)


1. How well does the Department’s existing five siteproduction infrastructure serve the current needfor commercial and research isotopes?

The Los Alamos National Laboratory is one of foursites that produce and distribute stable andradioactive isotopes for the Department of Energy’sOffice of Isotope Programs in the Office of NuclearEnergy, Science, and Technology. At Los Alamos avariety of products and services are available. Theseinclude accelerator-produced isotopes utilizing theLos Alamos Neutron Science Center and the TA-48main Radiochemistry Site hot cell facilities; chemicalprocessing of reactor-irradiated targets utilizing theCMR wing 9 hot cell facilities; the isotopic separationof stable and radioactive elements usingelectromagnetic isotope separation techniques; andthe distribution of inventories of americium-241 andother actinides. Products and services availablefrom the Los Alamos Isotope Program fill animportant niche in the overall worldwide marketfor isotopes, because they are typically not availableelsewhere, or if they are available, they are notavailable in sufficient quantity to satisfy marketdemands. Also many of the products are in theearliest stages of research or development, and thusthe user community cannot afford to pay the fullproduction costs.


The Los Alamos Isotope Program currently uses thefollowing facilities.

The Los Alamos Neutron Science Center is thecornerstone of Los Alamos isotope production.Currently, targets are irradiated at the beam stop atLANSCE in a 25 year old irradiation facility. A newconstruction project funded by NE is building a newbeam line and target irradiation facility that will bededicated to isotope production. When this facilityis operational in FY 2001, the isotope program willhave access to 250 amps of 100 MeV protons fortarget irradiation. It is envisioned that the H+ beamwill be available for isotope production any timethe facility is operating in the H- mode (for neutronscattering). Also because the beam is only beingaccelerated to 100 MeV we could consider operationof the front end of the facility in a dedicated modefor isotope production if the isotope availability needrequired the operation.

The TA-48 Hot Cell facility at the MainRadiochemistry Site, Building RC-1 is the primaryhot cell facility for accelerator isotope production.It consists of two banks of 6 chemical processingcells connected at one end by a large multipurpose“dispensary” cell, where all materials are receivedinto and which all materials leave from the facility.Supporting facilities including severalradiochemistry laboratories, a machine shop, twoanalytical laboratories, an extensive counting roomfacility, and offices for personnel surrounds the hotcell facility.

The CMR wing-9 hot cell facility is a complementaryhot cell facility to the TA-48 hot cells. The wing-9hot cells are located in a category 2 nuclear facility,and are available for work that requires a nuclearfacility safety authorization basis. Currently theisotope program is installing an electromagneticisotope separator in this facility for the separationof radioactive samples. The facility is also availablefor the chemical processing of reactor irradiatedtargets and will be used in conjunction with theACRR reactor at Sandia to expand the IsotopeProgram portfolio of reactor products.

The TA-50 Radioactive Liquid Waste TreatmentPlant is used to treat and dispose of liquid effluentsfrom isotope production activities. All such effluentsare received by TA-50 from an acid waste line thatconnect both TA-48 and CMR to the facility.

The TA-54 Solid Radioactive Waste Disposal Site isuse for the storage and permanent disposal of low-level high activity waste and low-level low activitywastes. All wastes, except mixed wastes are handledon-site. Currently the isotope production activitiesgenerate no mixed waste, so the isotope program istotally self-contained at the Los Alamos site and isnot dependent on off-site facilities for operations.

In general these facilities are in good condition, andadequate for the isotope production and distributionfunction. However, funding for upgrades andpreventative maintenance are in short supply, so theprevious statement may not continue to be true in afive year time horizon.

3. What capital investments are needed to insure thenear term operability of the facilities?

DOE is currently funding the major capitalinvestment required to continue isotope productionat Los Alamos, the 100 MeV Isotope ProductionFacility at LANSCE. The TA-48 hot cell facility hasrecently undergone several upgrades funded byinstitutional funds, including a new state-of-the-artair handling system and a crane upgrade. Other

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Appendix E

upgrades required include an upgrade of the facilityelectrical systems and the facility hydraulic systems.The CMR hot cell facility is in the midst of significantupgrades funded by Defense Programs.

4. If additional resources are needed, are theypractical, e.g., technically rational, easilyintegrated into existing infrastructure, quicklyimplemented and supportable? Will any portionbe sustainable over time by local financial andpersonnel resources.

The near term resources required are practical giventhe extensive infrastructure for isotope productionthat is currently in place. They are technicallyfeasible at reasonable cost, and can be accomplishedquickly if the resources are available. We have beenvery successful in the past at gaining institutionalfunds for infrastructure upgrades, but as with allthings, these funds are becoming scarce and moredifficult to justify.

One area that could be profitably developed withadditional resources over and above the investmentsthat the DOE Isotope Program is already making atLos Alamos is in the area of stable isotopeenrichment. DOE is already investing in thedevelopment of a radioactive sample isotopeseparator based on technology developed at LosAlamos for national security programs. Existingisotope separators at Los Alamos already have thecapability to separate milligram quantities of stableisotopes that could be used for research purposes.With modernization (computer control and otherimprovements) and with sufficient operating fundsthe Los Alamos electromagnetic isotope separatorscould fill an important need for research quantitiesof important stable isotope products. Thispossibility is currently being evaluated by the DOEIsotope Program.

5. What is the availability of the primary nuclearfacility (accelerator or reactor) over the next fiveyears?

LANSCE management’s stated goal is eight monthsof operation in each calendar year over the next fiveyears. Defense Programs support baselineoperations of the facility. As mentioned previously,the new isotope production facility can run anytimethat the facility is operating for other purposes. Withrespect to the existing target irradiation station, itcan be operated currently, but requires additionalH+ users to minimize the cost of beam delivery. Thelast large H+ user was the Accelerator Productionof Tritium program. Operations over the past threeyears have been covered out of APT budgets. Thenext user will probably be the AcceleratorTransmutation of Waste program, but their plans are

not yet formalized. Therefore there is currently nohigh-energy H+ beam scheduled through FY 2000.However, LANSCE management is interested inmaintaining the high-energy H+ beam deliverycapability and is working with the Isotope Programto attempt to find ways to deliver beam at areasonable cost to the Isotope Program.


Currently, the Isotope Program enjoys the bestrelationship with LANSCE management that hasexisted since the inception of the program. We areactively involved by LANSCE management in allplanning activities, we are members of the LANSCEProgram Planning Group (LPPG), and we are avoting member of the LANSCE FacilityManagement Steering Council. The current formaldocumentation that governs the relationshipbetween LANSCE and the Isotope Program is theLaboratory’s landlord-tenant agreement. With allof that, the relationship is still more collegial thanformal. However, this collegiality has actuallyworked well in serving our customers needs. Itunfortunately has not led to improvements inavailability of short-lived research isotopes becauseof operational difficulties with the existing targetirradiation facility. We are, however, taking stepsto change that with the new target irradiation facility.The new facility will lead to the ready availabilityof research isotopes for at least the baseline eightmonths per year. We currently have aMemorandum of Understanding (MOU) that willbe the framework for future operations andrelationship. This will become the foundation forour priority at the facility.


As mentioned above the Los Alamos Site Manageris actively involved in program planning withLANSCE Management and other users. Hisinfluence is no more or no less than any other user.However, it is also true that the Isotope Program isnot as large a customer as Defense Programs, andthe larger customers do tend to have more influencewhen there are programmatic conflicts. As anotherexample the Los Alamos Site Manager has a greatdeal of influence at the TA-48 hot cell facility becausehe is resident in the organization that is responsiblefor the facility. He has less influence at the CMRbuilding because a different line organization is thelandlord of the facility. However, he gains influenceby having excellent relations with the people whoare residents of the facility and responsible for theoperations.

E-7



Cost containment is a high priority for the LosAlamos Isotope Program. Numerous examplesexist. For example, the program has been at theforefront of the Laboratory’s waste minimizationactivities. In 1996 there was a moratorium ongeneration of mixed waste at the Laboratory thatdid not impact a single delivery of isotope products,because the program had already eliminated all EPAlisted hazardous materials from the chemicalprocesses. Also the fact that we do not generatemixed waste saves the program money becausemixed waste is very expensive to dispose. Theprogram is the first at the Laboratory to havedeveloped a successful “Green is Clean” program.We essentially segregate our waste at generation intosuspect contaminated and suspect non-contaminated. We verify the fact that the wasteboxes are not contaminated by counting them in asensitive radiation detector developed for this use,and then they are sent to the county landfill, insteadof TA-54. We have eliminated approximately 80%of our low-level low-activity waste by this approach.With disposal costs increasing to over $200 per boxin FY 2000, this saves the program a significantamount of money. Other examples of costcontainment in the areas of packaging andtransportation and chemical processing can also bediscussed during the site visit.


All current isotope production and distributionactivities are properly permitted and licensed. Theseinclude all environmental, safety, and transportationactivities. The only outstanding “licensing” issuefor the program is the licensing of the newtransportation container that we are going to beusing. The existing shield that we use to transporttargets from LANSCE to TA-48 is not DOTapproved, and cannot be because it is a one-of-a-kind container. We deal with this by closing theroads when we transport targets. The Laboratorydoes this routinely for many packages that they musttransport from site to site for which there are notsuitable containers. The DOE is currently reviewingthe new container that we are planning to purchasefrom Croft Inc., and we expect the DOE to issue aCertificate for this container before it is required forthe new facility.


The under used capacity available at Los Alamos isall in the area of hot cells. Both the TA-48 hot cells

and the CMR hot cells are both underused at thepresent time. In the CMR we only pay for what weuse so it does not impact cost to the Isotope Program.Since the Isotope Program is the only user of theTA-48 hot cells, the program covers all of the “opendoor” costs for this facility. We actively market thiscapability to other projects, but because of the natureof the Isotope Program work (e.g., FDA regulationof products), rarely is the new work compatible withthe existing Isotope Program work.

11. Summarize customer inquiries received duringthe past two years. What per cent were filled,referred to other facilities, rejected? Explainunfilled requests.

A list of written inquiries is attached to thisdocument. The majority of written inquiries comeas a result of the DOE catalog or the informationavailable on the DOE and Los Alamos IsotopeProgram home pages. We respond directly to eachwritten inquiry. In most instances we can fill theorders when they concern existing products. ForCu-67 inquiries we refer customer to Brookhaven,since we have not produced it since 1996. Normallyunfilled requests are for products that can’t be madewith our accelerator. In those cases we direct thecustomer to the appropriate DOE production site,or help them identify other non-DOE sources ofmaterial. We also receive telephone inquiries thatare kept in a telephone log. We respond to andfollow up on each telephone inquiry until it resultsin a sale or we are told that the customer is no longerinterested. All other aspects of telephone inquiriesare handled in a fashion similar to written inquiries.

12. How does each site manager rate customersatisfaction for his site? For the overall program.

Customer service is rated by individual interactionswith customers, both by telephone contacts on aroutine basis and with customer visits whenappropriate. We also find the various professionalmeetings and trade shows where DOE exhibits tobe important for customer interactions. The LosAlamos Site Manager has at least two personalinteractions per year with each major customer. Wealso keep a complete customer complaint/compliment file. It details each complaint orcompliment and is tracked until resolution. Theresolution is documented in the complaint file.

13. Kindly detail how you set prices of a mCi of anisotope? The detail should show if the cost is fullyloaded or incremental, and should include labor,materials and parts, facility rental andamortization costs, listing of the actual overheadcharges, waste disposal (a major cost), and all othercosts that are tagged to the cost of producing,

E-8

Appendix E

marketing selling, and distributing a product (e.g.,customer service, distribution, ordering).

The final decision on pricing is made by the DOE.Each summer each site does a cost-price study. It isdeveloped using activity-based costing. A workbreakdown structure is used by each site to estimateand collect cost by activities. Each activity isresource loaded based on the estimated work scopefor the year. The resource loading determines thenumber of FTE hours (staff, tech, other) that arerequired per task, and fully loaded FTE rates areused to determine the estimated activity cost. Afterthe activity costs are developed, the costs areallocated to each isotope that will be manufacturedas defined by the estimated work scope. Some costsare allocated directly, as in the example of chemicalprocessing costs. Other costs, such as hot celloperations and waste management costs, areallocated on the basis of campaigns (batches) thatare required to meet the production commitmentsin the estimated work scope. Other costs, such assales, marketing, distribution, are estimated as well,and allocated to the products in the portfolio. Theamount to be produced is estimated, and this is thenused to develop the unit cost to produce the isotope.We also estimate the amount that will be sold fromeach campaign (batch) so that we can estimate theunit cost of goods sold. We provide this informationto DOE who then determines prices.


Los Alamos does not produce any of the productslisted above. Also most of our research isotopes areactually by-product and are thus priced to themarketplace. We do not do cost-price studies onby-products. There are numerous examples of cost-price studies for isotopes that are produced at LosAlamos (the so-called “driver” isotopes), and wewill be happy to share this business sensitiveinformation with the committee during the site visit.

15. What process, mechanism, and organizationalstructure do you have for the timely distributionof produced products?

The production, sales, and distribution functions areall managed as an organizational unit and are tightlycoupled. The sales and distribution people are inroutine contact with the production people by beingphysically collocated. There is a stand up meetingevery Monday morning in the hot cell facility todetermine the deliveries scheduled for the week, theproduction schedule for the week, and any problemsthat are anticipated with the deliveries. All activitiesare boarded at the hot cell facility and tracked during

the week by the hot cell team leader. Of course,when Los Alamos becomes responsible for the salesand marketing of Brookhaven and Sandia products,then new mechanisms will have to be put in place.We have already developed procedures forproviding these services for the accelerator productsfrom Brookhaven and we can discuss them duringthe site visit.

16. What process, mechanism, and organizationalstructure do you have in place for customerservice?

Our sales office is the point of contact for customerservice. It is staffed with 2 full time sales andcustomer service representatives, so that there is fullcoverage during business hours. We can afford thisredundancy because of sales/customer servicepersonnel are also our radioactive material shippers.Thus, we have control of our own shipments anddo not have to depend on another Laboratoryorganization for timely deliveries. Our sales/customer service representatives deal with all issuesassociated with customer service and satisfaction.With regard to technical support, our customerservice people route the customer to our technicalstaff who are very active in providing technicalsupport to our customers. As stated previously wetrack customer satisfaction through our complaint/compliment process. All of our customers arecomplimentary about the service and relationshipsthey have with our customer service specialists. Iwould encourage the committee to contact some ofthe customers on our customer list to gauge theirlevel of satisfaction.


Yes we will sign contracts that guarantee deliveryat a contracted time, but DOE Isotope Programpolicy prohibits us from accepting penalty clausesin these contracts.


Clearly, the Government’s long-term role inproviding isotopes for research and commercialapplications has been the topic of many studies bylearned committees, by study groups with particularbiases, and by private enterprises with extensivemarket knowledge and experience. All of thesevarious studies agree that there is a role for theGovernment to play, but there is little agreement asto what that role should be. There is also littleagreement about how future markets will develop.

E-9


If you are a proponent of an existing reactor oraccelerator or a future facility that is trying to appearas a multi-user facility, the Government should befunding that facility to produce isotopes. Theconcept of whether it makes technical or economicsense is usually lost on the proponents. On the otherend of the spectrum are the various usercommunities that stand to benefit from the isotopesthat are produced. Usually these communities haverequirements that can be readily defined, but thecourse to make the isotopes available is usually lessclear, especially when the question of where theresources will come from is considered. The userswant the isotopes at a reasonable cost, which isusually difficult if the producer is required to recovercosts (the private sector or the revolving fund thatwas established by Public Law 101-101). On theother hand the producer can’t understand why theresearch grant that is funding the research cannotfund the cost of the isotope. If there is one area ofagreement among users and producers, whether weare speaking about commercial products or researchisotopes, it is that this dilemma must be solved bythe Government. If this is true we have a beginningto the understanding of what the Government roleshould be.

The solution to availability of research isotopes hasto be the responsibility of Government, since noother entity has motivation to insure adequateisotope availability at a reasonable cost. Theproblem that Government faces is that therequirements of various research constituenciescannot be met within the constraints placed by theresources available. Thus prioritization is essential.This prioritization can be rancorous within any oneresearch constituency, and can be impossible whenthe Government attempts to balance the needs ofmultiple research constituencies. The clear solutionis to obtain more resources for the Governmentprogram, and progress in accomplishing this isevident. However, it is slow and not always assured.The DOE is working diligently on this problem, andwe should recognize those efforts. Two activities atLos Alamos are examples. The construction of thenew 100 MeV IPF at LANSCE is an obvious attemptby DOE to increase the availability of researchisotopes. When it is completed DOE and LosAlamos expect that it will operate 8 months per year,and that short-lived research isotopes can beavailable for 12 months per year, if Los Alamos andBrookhaven schedules can be coordinated. Thesecond activity that is exemplary is DOE’s

encouragement and support of the “Virtual IsotopeCenter” concept. Currently, the Virtual Centerincludes target irradiation at the TRIUMF facilityin Canada, the INR facility in Troitsk Russia, andthe NAC facility in South Africa followed byshipment to Los Alamos and processing in LosAlamos facilities. This concept has demonstratedour ability to insure the 12 month availability ofintermediate and long half-life materials. It has alsohelped us to support clinical trials of Cu-67 by acombination of TRIUMF and Los Alamos facilitiesbut the logistics are much more difficult.

The Government’s role in the availability ofcommercial isotopes should also be clear. Normally,DOE recovers costs from isotopes that weredeveloped in DOE laboratories, have foundapplication in a commercial products, and there isno current private sector interest in the production.DOE has a responsibility to continue to make theseisotopes available to support the commercialproducts until private sector interest develops.Examples of accelerator isotopes that are in thiscategory are Sr-82 and Ge-68. They generatesignificant revenue for DOE, offset costs of operatingfacilities at Los Alamos and Brookhaven, and couldbecome the interest of a private sector entity. If thiswere to happen then the amount of appropriationrequired for isotope production activities at thesesite would increase. It is an interesting dilemma.DOE has an active program in privatization ofproducts that are interesting to the private sector,and it has been very successful. However, if theprivate sector produces Sr-82 and Ge-68 then DOEhas achieved the privatization goal, but theconsequence would be that more money would berequired from the appropriation to fund isotopeproduction, and less money would be available forisotope research. This is a dilemma for which thereis not a clear solution.

In summary, there is a clear role for the Governmentto play in the availability of research isotopes andthe development of isotopes for which productiontechnologies do not currently exist. There is also arole for the Government to play in the availabilityof commercial “niche” isotopes that were developedby DOE or others, but for which no private sectorproducer exists. How the DOE balances the needsto minimize appropriations with the requirementto privatize isotope production technology ofinterest to the private sector is not evident at thistime.

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Appendix F

Sandia National Laboratories (SNL)Site Visit


1. Introduction

A site visit was conducted at Sandia NationalLaboratories (SNL) on may 18, 1999. Site visitorsincluded Dr. Ralph Bennett, Idaho National Engineeringand Environmental Laboratory, Dr. Robert Atcher, LosAlamos National Laboratory, and Dr. Henry Kramer,consultant. Dr. Richard Coats acted as host for the sitevisit.

Mission

The mission of SNL with regard to isotope productionhas been focused on providing a backup supply of 99Mofor commercial medical use. The mission formally beganon September 11, 1996 with a Record of Decision (ROD)by the Department of Energy (DOE) to, “develop thecapability to produce 99Mo as a means of establishing abackup source until a more reliable commercial sourceis available.” Initial funding of this work began in 1994.

The mission to provide a backup supply is accomplishedby delivering 99Mo to the major manufacturers of 99Mo/99mTc generators. This requires the irradiation of highenriched uranium (HEU) targets in the Annular CoreResearch Reactor (ACRR) and separation of valuablefission products from wastes in the Hot Cell Facility(HCF). These facilities and the upgrades beingundertaken to prepare them are described next.

Facilities

The ACRR is an open pool reactor which has beenupgraded to 4 MW steady state operation and outfittedwith a flooded central region available for Cintichem-type targets. The new configuration has been tested anda new Safety Analysis Report has been prepared and isexpected to be approved this fiscal year. There are avariety of options for loading Cintichem-type targets intothe central region, with the primary options being either19 or 37 target elements. With sufficient loading, theACRR is capable of producing the entire U.S. demandfor 99Mo, currently known to require about 3000 6-dayCi per week. The core also has many grid positionsavailable within and outside of the fueled region for otherirradiations. The total neutron flux in the central regionis 1.0 x 1014 n/cm2-sec at 4 MW core power, with a thermalcomponent of 0.6 x 1014 n/cm2-sec. The Cintichem-typetargets will be fabricated with high enriched uranium

(HEU) in the Chemistry Metallurgical Research (CMR)facility at Los Alamos National Laboratory (LANL).

The HCF is a large hot cell that has been upgraded witha number of clean process boxes that are laid out toaccommodate the 99Mo process flow. The HCF is andwill remain a Category 2 nuclear facility capable ofhandling many kCi of activity. The upgraded HCF willaccommodate the processing of up to 6–12 fission targetsper day. Most facility modifications will be completedby the end of this fiscal year. A new Safety AnalysisReport has been prepared and is expected to be approvedthis year. The Operational Readiness Review and muchof the hot cell equipment, however, has been deferredbeyond this fiscal year (this is discussed in Section 2below). All of the facilities are located a few miles fromthe Albuquerque airport which enhances their ability todeliver products.


The primary product is envisioned to be finished sodiummolybdate for distribution to major radiopharmaceuticalmanufacturers of 99Mo/99mTc generators. Ademonstration of the capability was held in late 1996 withthe irradiation and processing of four targets in the HCFprior to its upgrade. The demonstration resulted in thesuccessful loading and test of several generators by amajor radiopharmaceutical manufacturer.

Given the primary mission for a backup supply, thepotential exists to separate and supply relatedcommercial or research fission product isotopes as anadd-on to the 99Mo operations. The principal commercialfission product isotopes are 131I and 133Xe. A more limitedpotential exists to supply 89Sr and 153Sm: While theseradioisotopes are in commercial demand, theirseparation from fission products would require anelectromagnetic separation to obtain the desiredradioisotopes on a routine basis. It has not beenevaluated whether these could be produced at or belowtheir market prices.

The principal research fission product isotope is 90Y,which is already available from the commercializedprocess at Pacific Northwest National Laboratory(PNNL). It was noted that a variety of fission productsnot identified as important in the Expert Panel Reportare produced. Quantities of all the above are listed inTable 1. Of course, these supplies are available only whenthe backup supply actually operates.

F-1


A number of non-fission radioisotopes could also beproduced from steady state irradiations in the ACRR.Targetry would be based on the standard techniques ofneutron activation reactions, since the reactor producesfluxes typical of a moderate-size research reactor.



In order to dedicate the ACRR and HCF facilities to thebackup mission, a Management Agreement wasexecuted between Defense Programs (DP) and NuclearEnergy (NE) on June 23, 1997. The ManagementAgreement decidedly prioritized the use of these facilitiesto the medical isotope mission and set forth theunderstanding that NE would assume mostresponsibilities and base funding indefinitely. TheAgreement has no discussion of what happens in theevent that no backup supply is developed.

The funding outlook for the program at SNL has changedrecently. Prior planning for FY-2000 (shown in Table 2)included completion of the backup supply, and provideda total of $9.87M for the program. This plan was revisedby DOE to reflect a halt in the preparations to develop abackup supply. The current FY-2000 budget now focuseson ACRR facility operations and provides funding of$3.5M including $2.8M ACRR base funding foroperations, $0.3M to bring the HCF into a standdowncondition, and $0.4M for program management andexploration of research isotope products based on theACRR. The Senate appropriation for FY-2000 includesan additional $2.5 million for this program. At this time,the House has not passed the appropriations bill for theDOE.

Table 1. Selected Activities Present After a24 Hour Cooling Period in a Typical ACRRFission Target Irradiated for 7 Days at 20 kW

99Mo90Sr/90Y131I133Xe89Sr153Sm140Ba/140La141Ce144Ce147Nd95Zr/95Nb103Ru/103mRh105Rh91Y

1

1

2

Not Identified

2

2

Not Identified

Not Identified

Not Identified

Not Identified

Not Identified

Not Identified

Not Identified

Not Identified

66 h

29 y/2.7 d

8.0 d

5.2 d

51 d

1.9 d

13 d/1.7 d

33 d

285 d

11 d

64 d/35 d

39 d/56 m

36 h

59 d

670

0.4

200

600

70

20

320/260

140

15

130

78/7

60/54

110

76

RadioisotopeExpert Panel

Category Half-LifeActivity

(Ci)

Table 2. Prior Funding Plan for FY-2000

ACRR Operations

HCF Operations

ACRR Modifications

HCF Completion

HCF Operational Readiness Review

FDA Validation

LANL Target Production Line and Production

Program/Project Management and Research

Isotope Programs Support

Total

$2.87M

$2.58M

$0.28M

$0.51M

$0.30M

$0.67M

$1.64M

$0.90M

$0.12M

$9.87M

Approximately $40-50M has been spent to date on themission at SNL, with the prior FY-1999/2000 budgetsplanned to be the amount needed to bring the backupsupply online. Since the current FY-1999/2000 budgetswill not complete the supply, many alternatives havebeen proposed and are presented below in the discussionof Continued Operations.

Other DOE Programs

Despite the clear priority for medical production in theManagement Agreement, DP will have priority in theuse of the ACRR in pulsed operation to support nationalneeds in stockpile stewardship. Recent amendments tothe Management Agreement provide for a period of timefor pulse operations for the DP test program in FY-2000,for example. The use of the ACRR by DP involvesreconfiguring the central core cavity from a flooded zonewith Cintichem-style targets, to a dry zone forexperiments. The reconfiguration requires from severalweeks to approximately two months. Subsequentreconfigurations should require approximately twoweeks. The optimal configuration for 99Mo is obviouslyto have the central cavity flooded and loaded with asmany HEU fission targets as possible. This precludespulsed operation, however. The optimal (in fact,required) configuration for pulsed testing is to have thecentral cavity dry and available for experiment packages.This does not preclude steady state operation in the sameday, however, since the control mechanisms can beswitched from pulsed to steady state in a few hours. Thisdoes severely limit the available target positions for 99Moproduction since it precludes the use of the central cavityvolume. The only positions available would be on theperiphery of the core where the flux is lower by a factorof two to three, but still feasible for limited production.

DOE Nonproliferation and National Security (NN)Programs is funding some limited studies of the potentialfor fission product 99Mo based on low enriched uranium(LEU) targets. This is support of the Department of Stateinitiatives to reduce the dependence of developingnations on HEU and thereby alleviate proliferationconcerns.

F-2

Appendix F


Sandia’s isotope production activity has someinvolvement with the University of New Mexico’sDepartment of Nuclear Engineering. There is occasionalparticipation on studies by summer interns and graduatestudents from the department. The level of LaboratoryDirected Research and Development (LDRD) at SNLspent on isotope production is quite small, however, with$50K spent recently on a study of 125I production capacityby standard techniques. Sandia has had some contactwith the School of Pharmacy, but has not involved anystudents to date. A fairly substantial amount of SNLfunding (approximately $2M) was made available priorto the ROD to decontaminate hot cell spaces in supportof isotope mission development.


Throughput

SNL is not currently producing radioisotopes.

Customers

SNL does not have any firm customer contracts forradioisotope deliveries.

Pricing Policies

Pricing policies have not been developed.

Product Development

The primary interest in product development (aside fromfission products) is for 125I production through standardmethods with an enriched 124Xe target loop in a low flux

region. There has been other interest expressed by SNLin irradiating semiconductor devices, producing lowspecific activity 192Ir, and possibly offering radiographyservices with the ACRR.


Continued Operation

As stated above, redirection of the SNL isotopeproduction activities was given by NE early in FY-1999.With the approaching completion of the two Maplereactors in Canada, the redirection stipulated that therewas to be no further HCF development. Accordingly,funding to complete the HCF was reduced in FY-1999and eliminated in FY-2000, and thereafter. The fundingavailable for the HCF in FY-2000 is only to bring thefacility to a standdown condition, although the facilityhas made considerable progress toward a 99Mo capability.The consequence of not completing the upgrade nowwould be to increase the cost of completing it at a latertime, if needed, since resources and momentum will bedirected elsewhere at the laboratories. A further issuewith operations is the need to purchase fuel for the ACRRwithin several years after startup of full production.While SNL has the option to purchase a higherperformance ZrH fuel than the BeO fuel needed forpulsed operation, the product pricing will need to yieldthe funds for its purchase and modification of the safetybasis.

The prospects for continued operation need to considerthe various production options and their costs. Theoptions are presented against the 99Mo backup or steadyproduction scenarios, which are presented in Table 3.

Table 3. Options for 99Mo Supply at SNL

Funds toestablish thecapabilityc

Funds foryearlyoperations

Several qualification runs per year, without any sales to U.S. manufacturers.Production of 10-25% of U.S. demand during an emergency of 1-2 months.Assumes FY-2000 funding is assured without delay. Invalid if funding lapse occurs.

a b c

$0.7M

$7.5M

Establishcapability only

a

Emergencyproduction

onlybSubsidized

supplyBreakeven

supplyFull U.S.supply

$8.2M

$8.1M

$8.6M

$8.6M

$10.4M

$12.3M

$12.7M

$17.0M

F-3


Several headings in Table 3 require further explanation.The term, “Funds to establish capability,” means the one-time expenditures on facility modifications, equipment,qualification runs, documentation and staff developmentin order to establish a capability with the statedthroughput. These funds are based on the assumptionthat there is no gap in funding after FY-1999, and thatthese amounts are available in FY-2000 to complete thecapability. “Funds for yearly operation” includes all basefunding to maintain operations at ACRR and HCF, aswell as at supporting operations at Los Alamos.“Subsidized supply” means that annual federal funding(up to these amounts) is required regardless of whetherany privatization goes forward and is able to offset thesefunds. “Breakeven supply” means that privatization isextremely successful and captures 40% of the U.S. marketshare at current prices, allowing the supply to recoupthe full amount of yearly operations shown. “Full U.S.supply” means that the supply has a throughput equalto 100% of the U.S. market, although this is not intendedto suggest that the market could actually be captured.

If the SNL facility is to be used for isotope productionother than 99Mo, the current plan is to ship the irradiatedtargets to LANL for processing in their hot cells. Thereare discussions underway on what isotopes should beproduced if the 99Mo production activity is notdeveloped.


Some discussion was held regarding the possibility ofonly establishing the capability to send “green solution”(i.e., first-cut separated 99Mo) to Nordion for purificationand finishing. It was estimated that the funds requiredto establish this capability would be $0.6M. This optionmay not effectively backup the U.S. supply, for example,in the event of a site-wide strike in Canada.



The Sandia management continues its strong support forcompleting the project, even in a limited capacity.

Marketing

The medical isotope initiative at SNL has no establishedmarketing or sales organization. LANL will providethese functions for SNL when they begin productionoperations using the ACRR. Distribution is proposed tobe handled by the existing shipping and transportationorganization for radioactive sources and wastes atSandia.

Business Practices

There has been a strong interest on the part of the Officeof Management and Budget in the potential forprivatization of significant portions of the backup supply.Most recently, the Conference Report for Energy andWater Development for fiscal year 1999 requested a planfrom NE for privatization of its 99Mo production. Thereport from NE was completed in January 1999, andspecified that a source evaluation board (SEB) would beformed and be responsible for several cycles of requestsand proposals, resulting in an award of privatized effortsby September 30, 1999.

The efforts to execute the privatization plan were notsuccessful. At the Expression of Interest stage, a total ofeight responses were received. A subsequent request wasissued for concept papers which could guide the finalRequest for Proposal (RFP) provisions. Only oneresponse was received, and it was consideredunresponsive because it would not guarantee thatgovernment funding would not be required to completethe backup capability before they began operations. Thisset of events has effectively stopped the privatizationprocess.

Waste Management

The proposed waste management plan envisionsneutralization and grouting of the fission product wastes.This would adequately prepare them to meet the wasteacceptance criteria for shipment to the Nevada Test Site.It is important to note that the current facility has nospace to accomplish this process, however. The currentplan is limited to storing barrels of waste in a vault nextto the hot cells. The shipment of waste requires theconstruction of an additional building to handle theoutgoing shipments.

F-4

Appendix F

Sandia National Laboratories (SNL)


How well does the Department’s existing five-siteproduction infrastructure serve the current needfor commercial and research isotopes?


The SNL Annular Core Research Reactor (ACRR)was recently modified to give an accessible largevolume internal flux trap for target irradiation.Likewise, modifications to the SNL Hot Cell Facility(HCF) to give the ability to extract 99Mo or otherselect fission products (131I, 133Xe, 153Sm, —) from afission product stream are near completion.However some equipment essential to processingand waste management remain to be procured andinstalled. Facility functional check-out remains tobe accomplished.

2. What capital investments are needed to assure thenear term operability of the facilities?

With the exception of an improvement to the ACRRpool cooling system for improved performance andreliability, the no significant capital investmentneeds for the ACRR are foreseen.

An investment of approximately $2 M is requiredto achieve full HCF capacity for both near and out-year scenarios.


Capital investments discussed in #2 are practical andwere included in initial planning. Hence, they arealready integrated into existing infrastructure. Someportion may implemented and sustained throughother funding sources.

Although no plan has been formalized, it isanticipated that trained adjunct staff willcomplement a small core of dedicated staff. Theadjunct staff, normally working in other areas, willbe called upon as need arises to meet changes indemand. Agreements will be in place to establishpriorities and to permit rapid implementation ofthose staff.

4. What is the availability of the primary nuclearfacility (accelerator or reactor) over the next fiveyears, e.g., HFIR outage, LANSCE programchanges?

With the exception of some near term tests, no majoroutages or program changes are anticipated overthe next five years.


It is understood that the priority for the ACRR andHCF at SNL is isotope production and research.DOE/IP funds both facilities.


Baseline funding for the ACRR and HCF operationis provided by DOE/IP and hence, the productionsite manager has considerable influence in useplanning.


Assuming that this question applies to productioncosts, The question is premature for current SNLactivities.


NRC licensing is appropriate for transportationcasks. Validation as a supplier requires FDAapproval in some cases.


Considerable resources could be mobilized tosupport a growth in isotope demand. The ACRR andHCF capacity is much greater than current demand.

10. Summarize customer inquiries received duringthe past two years. What per cent was filled,referred to other facilities, rejected? Explainunfilled requests.

The question is premature for current SNL activities.



F-5


12. Kindly detail how you set the price of a mCi of aradioisotope? The detail should show if the costis fully loaded or incremental, and should includelabor, materials and parts, facility rental andamortization costs, listing of all the actualoverhead charges, waste disposal (a major costs),and all other costs that are tagged to the cost ofproducing, marketing, selling, and distributing ofthe product (e.g. customer service, distribution,ordering).

The question is premature for current SNL activities.Price setting is under study.


The question is premature for current SNL activities.Price setting is under study.

14. What process, mechanism, and organizationalstructure do you have for the timely distributionof the produced product?





Although the policy has not yet been established, itis anticipated that some such guarantee will beprovided to the customer.


F-6

Appendix G

Pacific Northwest NationalLaboratory (PNNL) Site Visit

Site Visited July 23, 1999

1. Introduction

On July 23rd, 1999 representatives of the subcommitteeon Long-Term Isotope Research and Production Plan ofthe Nuclear Energy Research Advisory Committee(NERAC) participated in a site visit of the radioisotopeproduction facilities of Pacific Northwest NationalLaboratory (PNNL) in Richland, Washington. TheNERAC representatives included Drs. Robert Atcher(LANL), Ralph Bennett (INEEL), Henry Kramer(consultant) and Thomas Ruth (TRIUMF), chair. Dr.Thomas Tenforde served as host for PNNL. The agendafor the visit along with the participants is attached.

Prior to the site visit a series of questions that had beenprepared by the Subcommittee for all site visits wasprovided to the PNNL team to address. The answers tothese questions were provided in report PNNL-12249,which has been excerpted and attached to this site visitreport. Supplemental material related to the isotopeproduction program at PNNL was provided in reportPNNL-12228.1 The site visit team was also provided withthe Scoping Plan submitted to NERAC on the case forrestarting the Fast Flux Test Reactor (FFTF).2

At the site visit Dr. Walter Apley presented a briefoverview of the FFTF Scoping Plan. Dr. Tenforde made apresentation covering much of the material provided inthe above reports. Topics of discussion included:

• Radioisotopes program at Hanford

• FFTF capabilities

• FFTF medical isotope production

• Operational costs and isotope revenues, and

• Staffing and facilities.

Mission

The FFTF Scoping Plan outlines the plans for restartingthe Fast Flux Test Facility at 100 megawatts with fourmajor missions:

• Medical and industrial isotope production

• Plutonium-238 production

• Non-proliferation programs

• Materials testing

As indicated below the medical isotope productionprogram is projected to become a major source ofrevenues when fully implemented.

Facilities

It is important to note that the FFTF has not operatedsince 1992, and is not operating at the present. In May1999 a Scoping Plan was requested by DOE for itsdecision-making regarding restart. This Scoping Plan wassubmitted to DOE in August, 1999. The timetablepresented in this document calls for operation to resumein 2004.

The FFTF reactor facilities are described in PNNL-12228and PNNL12245. The reactor is a liquid sodium coolednuclear reactor. It was originally designed to operate at400 MW for testing to support fast reactor development.The planned restart would reduce the operating powerto 100 MW. This would reduce fuel consumption andextend the life of the reactor.

Irradiation Facilities

The irradiation facilities include one gaseous isotopeproduction location in the core, 3 to 5 proposed rapidradioisotope retrieval locations in the core and 3 to 12irradiation vehicles for long-term radioisotopeproduction in the core. In addition, there are otherlocations both in the core and outside the core for otherpurposes such as 60Co and 238Pu production.

The target assemblies in the core are exposed to the liquidsodium metal coolant and thus need to be cleaned beforetransferring to the chemistry processing facilities. Theturn-around for removing a target bundle from thereactor and getting it to the lab for processing isapproximately 24 hours. Thus the shortest half-liferadioisotope that can reasonably be expected to beproduced at the FFTF would be approximately 2.5 days.

Neutron Fluxes

The FFTF has a fast reactor neutron energy flux profile(spectrum) range with a peak energy of the neutrons at300500 keV. The average fluxes at a power level of 100MW are in the range of 1014 to 1015 neutrons/cm2/second.This is a much higher average energy than found inthermal reactors operating in the U.S. The fast spectrum

1 “Isotope Production at the Hanford Site in Richland,Washington,” PNNL-12228, Pacific Northwest NationalLaboratory, Richland Washington, June 1999> (Availableon the Web at http://www.pnl.gov/isotopes.)

2 “Program Scoping Plan for the Fast Flux Test Facility:A Nuclear Science and Irradiation Services User Facility,”PNNL-12245, Pacific Northwest National Laboratory,Richland Washington, July 1999.

G-1


allows significant production via (n,p) and (n,n’) reactionchannels. In order to thermalize the flux for (n,g)reactions, special energy moderating elements would berequired.

None of the other reactors in the world that have medicalradioisotope production capability has a similar neutronenergy flux profile. To produce radioisotopes of a purityneeded for medical applications, it appears that the FFTFwould sometimes be required to irradiate enriched stableisotope targets to reduce the production of unwantedradioisotopes that are concurrently produced during theirradiation primarily because of the FFTF’s fast neutronflux profile.

Laboratories

The radiochemical processing facilities are locatedapproximately 8 miles from the reactor facility. TheRadiochemical Processing Laboratories include 143,700ft2 of which general chemistry laboratories occupy 44,500ft2. There are two areas that contain heavily shieldedfacilities for receiving the irradiated targets and the initialprocessing. There is other lab space that can be renovatedto perform radioisotope processing suitable for medicalproducts. Such renovations are estimated to cost $16M.The Scoping Plan anticipates getting the bulk of thefinancial support from outside users.

The other lab spaces include reagent preparation,analytical counting rooms and final product testing.

Personnel

The personnel requirements were also discussed. Thestaff would have to be increased for the full steady-stateisotope production program from the present 12 FTEs to74 FTEs. The bulk of these would be in target fabricationand testing (34) and in radiochemical processing (21).The remainder would be involved in target handling atthe reactor, product packaging and shipping and incustomer services, marketing and sales. There is anexpectation that a commercial partner(s) would providesome percentage of these positions.


The FFTF has the capability of producing a wide rangeof radioisotopes in large quantities, a number of whichare higher quality than can be produced with thermalreactors. However, the isotope production team hasidentified ten candidate isotopes to focus on for theirbusiness plan. Table 1 lists these isotopes and thecorresponding category from the Expert Panel. 3

Since the FFTF would not be operational for five years,the supply of these isotopes would not be enhanced untilthat time. The proposed production of these isotopes atFFTF includes a significant percentage (up to 10%) ofthe total projected U.S. market at the time of re-start.



Research into technologies for preparing a-emittingradioisotopes has been supported by DOE Office ofNuclear Energy. The presentations did not specificallyaddress the supply of research isotopes other than these.However, both at the site visit and following the site visitassurances were made that the production of researchquantities of radioisotopes could be accommodated.Following the site visit Mr. Bruce Klos responded to thehypothetical question of what would be required toproduce a generic radioisotope that had not beenproduced in the FFTF previously. The lead-time wouldvary depending on the state of knowledge of the targetmaterial and required processing. For small targets thatare compatible with other ongoing irradiation programsand for which behavior at the operating temperature isexpected to be acceptable, the lead-time could be lessthan two weeks. For new, one-of-a-kind target assemblies(e.g., a significantly changed driver fuel assembly), thelead-time for design, fabrication, review and approvalwould be approximately 6 months. For the case of a largenumber of core assemblies containing a new target withstrong reactivity properties and marginal stability, thetime required to qualify the targets for full-scaleirradiation could be as much as several years.

Other DOE Programs

If the FFTF were to re-start the other programs envisionedfor the facility would interact with a number of DOEprograms and other government agencies. For example

3 “Expert Panel: Forecast future Demand for MedicalIsotopes,” Arlington, VA, September 25-26, 1998.(Available of the Web at http://www.ne.doe.gov/nerac/isotpedemand.pdf)

Table 1. Radioisotopes proposed forproduction at the FFTF Identified inthe Expert Panel Report.

131I186Re103Pd117mSn125I32P153Gd89Sr67Cu188W

1

1

2

2

2

2

3

3

3

3

RadioisotopesExpert Panel

Category

G-2

Appendix G

Material Testing would be sponsored by the Office ofScience in DOE, and the Office of Nuclear Energy throughthe Transmutation Research and Nuclear EnergyResearch Initiatives. The plutonium-238 productionwould be sponsored by the Office of Nuclear Energy andthe National Aeronautics and Space Administration. TheNon-Proliferation Technical Programs would besponsored by the DOE-Materials Disposition and theOffice of Nuclear Energy as well as internationalorganizations such as the International Atomic EnergyAgency.


During the last few years 12 undergraduates have spentperiods ranging from 3 to 24 months on various researchprojects. These students were associated with a numberof different colleges and universities. There has been onegraduate student at the doctoral level in NuclearEngineering. The support for the students came fromvarious sources including the DOE, the AssociatedWestern University scholarship funds and Laboratory-Directed Research and Development funds.

Several research projects that relate to the medical isotopeprogram were cited. They are carried out withresearchers from the colleges and universities in theNorthwest as well as a couple of Institutes in Russia.These projects range from dosimetry calculations tolabeling techniques for various heavy metal alpha-emitters. Support for the various projects comes fromDOE, the National Cancer Institute and a privatecorporation. The total funding level is about $300K/year.


Until FY-1998 the primary medical isotope produced andsold by PNNL was 90Y, recovered from stocks of 90Sr.However that technology and a large stock of 90Sr hasbeen transferred to New England Nuclear in Billerica,MA where this isotope is now produced and soldcommercially.

During the last 3 years the primary effort has been in thearea of developing separation and purificationtechniques for 229Th, 225Ac, 223Ra and 213Bi, also obtainedfrom parent stocks.


The business plan for recovery and re-start of FFTF andoperational costs of the facility was presented. Thisinformation was in the provided documents. The restarteffort would require approximately 5 years to complete.During that time modifications to the target handlingcapability and the lab space would be undertaken. Thecost for these modifications has been estimated to be$30M. Of this $23M (FY99 dollars) is principally formodifications to the FFTF for rapid sample changing.

These costs are included in the estimated $229M for therestart of the FFTF, with annual operating costs estimatedto be $55M. The current budget for standby operationalstatus is $40M per year.

Throughput

The projected production quantities and schedule aredetailed in the attached questions and answers.

Customers

The Scoping Plan included letters of support for the FFTFfrom a variety of sources including commercial suppliersof radioisotopes, professional societies, regionalacademic centers and special interest groups. Nocommitments to purchase radioisotopes or services havebeen made at this point in the process.

Pricing Policies

Direct discussions between the DOE and the PNNLProject Manager are used to arrive at the sale price forisotopes based on an activity-based costing and isotopepricing policy. It was assumed that there would be nomajor change to market conditions five years out andthat the entry of a new major isotope supplier would notchange the market.

Product Development

Most of the proposed products listed in Table 1 have notbeen prepared in the estimated quantities at the FFTFbefore (an exception being 153Gd that was produced andsold in large quantities). The Radioisotope processingteam plans to utilize the start-up period to prepare thetargets and chemical processes.



The production of medically useful radioisotopes is oneof the four major functions presented in the ProgramScoping Plan. This aspect of the program would accountfor 27% of the projected revenues during the initial fiveyears of operation, growing to 56% of the gross revenuesduring the period beyond 2010. However, it was not clearwhat priority this aspect had within the entire PNNLprogram, given that the other programs will all be DOEsponsored.

Marketing & Business Practices

A whole new infrastructure will have to be rebuilt sincemost of these activities ceased following the transfer ofthe 90Y project to NEN.

Waste Management

According to the background documents “various wastestreams from the proposed activities are and wouldcontinue to be managed in accordance with the

G-3


applicable Federal and State regulations. In addition, aWaste Management and Minimization Plan will be preparedwith the states of Oregon and Washington to ensure thatany FFTF waste issues do not negatively impact Hanfordsite cleanup.” 4

7. Summary Comments

Use of enriched stable isotope targets requires thefollowing two key issues to be addressed: 1) cost ofprocuring the enriched material and 2) the availabilityof the required isotopes.

Enriched stable isotopes are costly. The cost analysis ofthe business plan incorporated the cost of target materialsinto the total cost of target preparation, and did not showa line item that represents the costs of enriched stableisotopes. For realistic operating cost the business planmust include the costs for the enriched stable isotopesper large target for each of the proposed radioisotopes.

The U.S. Department of Energy has a limited inventoryof enriched stable isotopes and no longer produces them.Russia is currently the major supplier of some enrichedstable isotopes. Thus the supply for the enriched stableisotopes, in a form that can be irradiated in the FFTF,must be determined. If an assured supplier is notpresently available then a U.S. government supportedprogram would have to be implemented and maintainedto ensure a supply for the FFTF with enriched stableisotopes.

The irradiation environment at 100 MW and 400 MWoperation is approximately 725o and 900o F, respectively,for the large target assemblies that are directly cooled bycirculating liquid sodium. Higher steady-statetemperatures of 1500o F or above may be reached in smallmetal target materials placed in capsules within rapidradioisotope retrieval systems that are not directly cooledby the liquid sodium. This high temperature maysignificantly limit the chemical forms (e.g. oxides, metals)of the irradiated target to eliminate target degassing(release of a gas in the sealed irradiation capsule willresult in an internal pressure build-up). Exposure of the

small targets to such high temperature for significanttime periods will most likely alter the chemical structureof the target, making it a challenge to chemists attemptingto put the irradiated target into a medically usefulchemical form. Some of the points of clarificationincluded that a 20 to 30 day down period between the100 day operating cycles is required. Most of theproduction yield measurements have been made on verysmall quantities of irradiated targets that have not beenprocessed to a completed product. Some key chemicalexperiments need to be performed utilizing the proposedsmall FFTF targets exposed to 1500° F for periods of 10to 25 days. These experiments would be designed todemonstrate what type of research program (if any) isneeded to develop post irradiation cost-effectivequantitative chemical processes for the production ofmedically useful radioisotopes in an appropriate usefulchemical form. For large target assemblies in which morethan 40 types of radioisotopes were produced during the10 years that FFTF was operational, it was demonstratedthat thermal effects of prolonged exposure to 900o F onthe physical form and chemical stability of the targetmaterials did not cause problems with post-irradiationchemical processing of the product isotopes.

The site visit team is not in a position to ascertain theviability of the business plan that was compiled todemonstrate the economics of restarting the FFTF witha major mission of supplying radioisotopes for thebiomedical community. Nevertheless it should bepointed out that the product line proposed by the PNNLteam includes radioisotopes that are presentlycommercially available. The projected revenues are basedon the assumption of breaking into the existing marketwith a significant share of the existing and projectedgrowth in the demand for these products. The supply ofresearch radioisotopes was not a major consideration inthe business plan. The FFTF is more ideally suited toproducing large quantities using large volume targetsrather the production of small quantities on an irregularschedule. Thus, the ability of FFTF to meet research needsin a cost-effective manner is significantly in question.

4 Ibid., PNNL-12245, pp. 4-7.

G-4

Appendix G

Pacific Northwest NationalLaboratory (PNNL)


How well does the Department’s existing five-siteproduction infrastructure serve the need forcommercial and research isotopes?


The primary isotope production facilities at theHanford Site are the Radiochemical ProcessingLaboratory (RPL) (Building 325 in the 300 Area ofthe Hanford Site) and the Fast Flux Test Facility(FFTF) reactor (in the 400 Area of the Hanford Site).In addition, there are several other laboratoryfacilities that are suitable for various aspects of targetpreparation and radiochemical processing ofisotopes. These facilities are discussed briefly in thisdocument, with reference to a PNNL report foradditional details. 1

RPL

The RPL is a 143,700 ft2 building that containslaboratories and specialized facilities designed forwork with nonradioactive materials, microgram-to-kilogram quantities of fissionable materials, and upto megacurie quantities of other radionuclides. Thetotal space occupied by general chemistrylaboratories is 44,300 ft2, of which 6,950 ft2 (15.6%)is presently unoccupied. All of the occupied, andnearly all of the unoccupied laboratories arefunctional and fully equipped with standardutilities. Several of the laboratories, especially thoseused for radioanalytical work, have been renovatedduring the past few years. The upgrading andmodernization of equipment within the chemistrylaboratories has been given a high priority duringthe past two years.

During a recent space utilization survey of the RPL,an assessment was made of the number of fumehoods and shielded glove boxes (including small hotcells) that are available for additional programmaticwork. Of the 79 functional fume hoods and 23shielded glove boxes, 50 and 15, respectively, areavailable for additional work.

A special feature of the RPL is the existence of twoheavily shielded facilities located in annexes on theEast and West sides of the building. These shielded

facilities are the High-Level Radiochemistry Facility(HLRF) and the Shielded Analytical Laboratory(SAL). These two hot cell complexes, which areheavily utilized at the present time, providecapabilities for conducting bench-scale to pilot-scalework with a wide variety of highly radioactivematerials. Capabilities include those required toconduct radiochemical separation and purificationprocedures, irradiated fuel or target sectioning andprocessing, metallography, physical propertiestesting of activated metals, thermal processing(including waste vitrification), and radioanalyticaland preparatory chemistry operations.

The HLRF contains three large, interconnected hotcells designated as A-Cell, B-Cell, and C-Cell. Thethree cells are each 15 ft high and 7 ft deep; the A-Cell is 15 ft wide and the B-Cell and C-Cell are each6 ft wide. In-cell operations are performed usingmedium-duty electromechanical manipulators, andthe work is viewed through leaded-glass, oil-filledwindows. The hot cells are equipped with televisioncameras, VCRs, overhead bridges, hoists, andstandard utilities. They have shielded servicepenetrations at the front wall for insertion of specialinstrumentation.

The SAL contains six interconnecting hot cells, eachof which is 5.5 ft wide, 5.5 ft deep, and 9.5 ft high.Each hot cell is equipped with a pair of medium-duty manipulators. Turntables built into the rearwalls of the hot cells provide rapid transfers ofradioactive samples into and out of the cells. TheSAL hot cells are equipped to perform a wide varietyof analytical chemistry operations with highlyradioactive samples.

Additional information on the RPL, and itslaboratory facilities that could be devoted to newisotope production missions in the future, iscontained in Section 2.5.1 of Reference 1.

FFTF

The FFTF’s original mission was to support liquid-metal reactor technology development and reactorsafety by providing fuels and materials irradiationservices. Although the U.S. liquid-metal reactorprogram ended at about the same time that the FFTFcommenced operation in 1982, the reactor continuedoperation for 10 years as a national research facilityto test advanced nuclear fuels and materials, nuclearpower plant operating procedures, and active andpassive reactor safety technologies. The facility wasalso used to produce more than 40 differentradioisotopes for use in research, medicine, andindustry. In addition, FFTF generated tritium forthe U.S. fusion research program and supportedcooperative, international nuclear research activities.

1 “Isotope Production at the Hanford Site in Richland,Washington,” PNNL-12228, Pacific Northwest NationalLaboratory, Richland Washington, June 1999. (Availableon the Web at http://www.pnl.gov/isotopes.)

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The reactor was shut down in December 1993, andsince that time has been in a standby operationalcondition, pending a decision by DOE on its futureuse. In May 1999, the Secretary of Energyannounced that a special 90-day study led by theDirector of the Pacific Northwest NationalLaboratory, Dr. William Madia, would be conductedto establish whether the FFTF should be consideredfor future missions related to national andinternational nuclear technology needs. The nuclearscience and irradiation services provided by FFTFwill focus on a core federal role of meeting multiple21st Century needs, including:

1. Providing a large and reliable supply ofradioisotopes for research, medical, andindustrial applications

2. Promoting safer nuclear technology throughreactor safety testing and the development ofproliferation resistant nuclear fuels

3. Producing power sources for deep-spaceexploration through the production ofplutonium for radioisotope thermoelectricgenerators, and for research on compact spacereactor technology

4. Sustaining the nuclear option for powerproduction through testing of fuels, components,and reactor instrumentation

5. Conducting advanced research and providingservices related to the testing of materials forfusion reactors, hardening and testing ofmaterials such as semiconductors, and researchon transmutation of nuclear waste materials.

These future missions, and the business plan forFFTF’s proposed future operations, are described ina document that will be submitted to NERAC onJuly 20, 1999 for review before submission to theSecretary of Energy on August 2, 1999. Thisdocument is referred to in this report as the ScopingPlan.1

The FFTF consists of the reactor, which is capable ofsteady-state operation at a rated power level of400 MW, and several support buildings andequipment arranged around the central reactorcontainment building. Heat is removed from thereactor by liquid sodium that is circulated throughthree primary loops, which include the pumps,piping, and intermediate heat exchangers. Duringa total loss of power, the FFTF is designed to shutdown automatically and the reactor will continueto be cooled by natural circulation of the sodium.

An emergency power source consisting of batterieswill provide essential plant monitoring capabilitiesin the event of a shutdown. The reactor also hassafety features that can maintain cooling if a leakoccurs in the liquid sodium heat transport system.

Other major systems located in the FFTF reactorcontainment building are:

• The Closed Loop Ex-Vessel Handling Machinethat is used to install fuel and target assembliesin the reactor and to remove them at the end ofthe irradiation cycle

• The Interim Examination and Maintenance(IEM) Cell, in which an irradiated assembly iswashed and dried to remove residual sodiumbefore disassembly; the target pins are thenremoved from irradiated assemblies withmanipulators and placed in containers forremoval from the IEM cell

• A Bottom-Loading Transfer Cask, which is usedto transfer the pin container from the reactorcontainment building to a cask loading stationin the Reactor Service Building.

Detailed descriptions and photographs of the FFTFcontainment building and the special facilitiesdescribed above are contained in Section 2.5.2 ofReference 1.

Other Available Facilities

In planning for a proposed future FFTF isotopeproduction mission, several facilities at the HanfordSite have been examined as possible locations fortarget preparation and the processing of isotopeproducts. In all cases, these facilities have desirablephysical features and equipment that could makethem useful if an expansion of facilities is requiredlater to meet a growth in the demand for FFTFisotope products. Three candidate facilities are:

1. Building 306E. Located in the 300 Area of theHanford Site, this facility has been used in thepast to fabricate a variety of reactor components,fuel assemblies, and radioisotope targetassemblies. Some of the target fabricationequipment and non-destructive examinationequipment still exist in the building and areavailable for use.

2. Postirradiation Testing Laboratory. Located inthe 300 Area at the Hanford Site, this facilitycontains 13 hot cells and support laboratoriesfor the physical and metallurgical examinationof irradiated fuels, fission products, andirradiated structural materials.Decontamination of the hot cell facilities has

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Appendix G

been underway for two years, and is expectedto be completed within the next two years. Onlya small amount of programmatic work iscurrently being conducted, and a study on thelong-range utilization of thisfacility is underway, including use bycommercial companies under lease agreements.This alternative may be attractive forestablishing long-term business relationshipswith companies interested in the preparationand processing of targets irradiated at FFTF.

3. Maintenance and Storage Facility. Located inthe 400 Area of the Hanford Site about 500 ftnorth of FFTF, this facility is a multi-purposeservice center that supports the specializedmaintenance and storage requirements of theFFTF. A special feature of this facility is a largeshielded enclosure that contains twoshielded decontamination rooms that can beused for both remote and hands-on cleaning ofequipment and tools. This facility, including theshielded enclosures, was not fully utilizedduring the ten years offull-scale FFTF operation, and consideration hasbeen given to its possible use for the fabricationand disassembly of FFTF targets.

Additional details on each of these facilities arecontained in Section 2.5.3 of Reference 1.

2&3. What capital investments are needed toensure the near-term operability of the facilities?If additional resources are needed, are theypractical (e.g., technically rational, easilyintegrated into existing infrastructure, quicklyimplemented and supportable)? Will any portionbe sustainable over time by local financial andpersonnel resources?

As part of the planning activities for a future FFTFnuclear science and irradiation services mission, anestimate has been prepared of the costs associatedwith restarting the reactor for steady-stateoperations at a 100-MW power level. This estimate,expressed in FY 1999 dollars, is $229M. The capitalexpenditures are distributed over a four-year periodfrom 2001 – 2004, and include funds for(1) recovering systems that were shut down beforethe standby decision in late 1993, (2) equipment andinstrumentation upgrades, (3) fabrication of rapidradioisotope retrieval (R3) vehicles for removal ofshort-lived isotope targets while the reactor is atpower, (4) modification of hot cells and supportlaboratories for target processing operations, and (5)staff increases and training. Once restarted, theestimated annual cost of FFTF operations is $55M.A more detailed description of the schedule and

costs for FFTF restart is provided in the Scoping Plan.

A business model has been developed as part of theScoping Plan that incorporates plans for recoveringapproximately $100M of the restart costs over theprojected 35-year operating life of the reactor. Thisbusiness model was developed using the guidelinesprovided in DOE Order 2110.1A, “Pricing ofDepartment Materials and Services and DOEImplementing Guidance on Federal AdministrativeCharges.” The model is comparable to thosecurrently in use at other DOE reactor facilities, andhas been reviewed and accepted by the DOE ChiefFinancial Officer in meetings held during June 1999.The FFTF business model provides adequateresources to ensure both the near-term and sustainedfuture operability of the reactor.

In this business model, the funding in FY 1999dollars required during the reactor restart phaseincludes both the $229M discussed above and $55Min operating funds to maintain the FFTF’s standbymode of operation during the period 2000-2001.During the projected 35-year operating lifetime ofthe reactor (2004-2038), a “value recovery charge”of ~4% will be applied to all private-sectorirradiation services. The funds recovered throughthis charge will be placed in an investment fund thatis expected to grow at an annual rate estimated tobe ~5% above inflation, and thereby generate~$100M to offset a portion of the restart costs.

The staffing infrastructure to support both thereactor operations and radiochemical processing ofirradiated targets are in place and adaptable to rapidgrowth of the nuclear science and irradiationservices components of the FFTF mission. Asdescribed in detail in the two referenced reports, theoperations staff at the FFTF will increase from thecurrent level of 260 full-time equivalent (FTE) to 410FTE at the time of restart. This increase willaccommodate the full set of operational servicesrequired for target insertion, irradiation, andretrieval in the isotope production program. Targetpreparation is expected to be carried out by asubcontractor working in facilities at the HanfordSite.

Radiochemical processing of the isotope targets willbe carried out by members of the PNNLRadiochemical Processing Group (RPG), whichconsists of 75 technical and administrative staff thatoccupy the RPL. Section 2.4.1 of Reference 1. Theisotope production team within the RPG currentlyhas 12 staff members, of which 5 performradiochemical processing operations. It is expectedthat the number of scientists and techniciansperforming radiochemical operations will increase

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to 21 FTE at the time FFTF commences fulloperation. This expansion will be achieved byreassignment of radiochemists and technicalsupport staff within the RPG, and by new hires. Inaddition to the staff involved in radiochemicalprocessing operations, it is expected that the numberof staff involved in packaging and shipping willincrease from 0.5 FTE to 7.5 FTE, and that themarketing, sales and administrative staff willincrease from 1.5 FTE to 5.5 FTE.

Although the Scoping Plan does not explicitly includeprivatization of the reactor operations or the isotopeproduction mission, discussions have been initiatedwith private-sector companies that may have aninterest in commercializing various components ofthese operations (e.g., the marketing, sales, anddistribution of isotope products). These discussionsare expected to continue over the coming five-yearperiod (i.e., during the preparation of the FFTFEnvironmental Impact Statement and the reactorrestart activities), with a reasonable probability ofsuccess in establishing partnership agreementsbetween DOE and commercial organizations.

4. What is the availability of the primary nuclearfacility (accelerator or reactor) over the next fiveyears (e.g., HFIR outage, LANSCE programchanges)?

If the current plans to initiate preparation of anEnvironmental Impact Statement in October, 1999are met, then it is expected that FFTF will berestarted by July 2004. Details of the restart scheduleare given in the Scoping Plan. In addition, all of thetarget preparation and processing facilities such asthe RPL are expected to remain available for workin support of the FFTF isotope production mission.


Because many of the isotopes produced at theHanford Site are shipped to customers at medicalcenters for the treatment of critically ill cancerpatients, the isotope production program receives avery high priority. For example, the staff performingthe radioanalytical work and on-site transportationservices in support of the isotopes program give thiswork the highest priority among their multipletasks. A complete radionuclide analysis andInductively Coupled Plasma (ICP) analysis of thechemical purity of the isotopes sent to customersare performed within 24 hours of the completion ofisotope production. These data are then sentimmediately to the customer for review before useof the isotope.

Another example of the high priority given to themedical isotopes program occurred five years agowhen the RPL was shut down temporarily for safetyupgrades. By direct order of the Manager of theDOE Richland Operations Office, Mr. John Wagoner,the production of yttrium-90 for medical customerswas allowed to continue uninterrupted during theentire shutdown period, which lasted about oneyear.


The Manager of the Hanford RadioisotopesProgram, Dr. Thomas Tenforde, also serves as thelead scientist for the isotope production team withinthe RPG. The organizational structure and primaryareas of research are described in Section 2.4.1 ofReference 1. In his capacity as head of the isotopeproduction team within the RPG, the manager ofthe Hanford Radioisotopes Program has linemanagement responsibilities for the staff andfacilities involved in the radiochemical processingof isotopes for commercial, medical, and researchapplications. These staff, together with a matrixedteam of nuclear physicists, engineers, radiochemists,and nuclear safety specialists from PNNL and otherHanford contractor organizations, have functionedsince 1997 as a support group for planning theproposed future FFTF isotope production mission.An important part of this planning has been theidentification of laboratory facilities that will begiven a high priority for future use in support of theFFTF isotope production mission.


Cost-containment efforts in the isotopes program arecentered around the use of activity-based costingprocedures for all isotope products. Following thecosting procedures adopted by the DOE Office ofIsotope Programs (NE-70), an annual cost/priceanalysis is performed on each isotope product usinga four-level Work Breakdown Structure. Examplesof this type of cost analysis are given in Section 2.6.1of Reference 1.

In all aspects of isotope production, efforts are madeto streamline the radiochemical laboratoryprocedures and to use the most economical servicesavailable from various contractor organizations atthe Hanford Site. For example, ICP analyses of thechemical purity of isotope products are performedat the 222S Building under a subcontract with theFluor Daniel Hanford Company, which is a lessexpensive option (by nearly a factor of 2) thanperforming these analyses in the RPL operated byPNNL.

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8. What licensing issues need to be addressed?

If a decision is made to restart the FFTF, it will besubject to all DOE requirements for the operation ofa nuclear facility, as described under DOE Order425.1A (“Startup and Restart of Nuclear Facilities,”1995). Licensing of the FFTF under the regulationsfor commercial reactors will not be a regulatoryrequirement. However, it is expected that DOE willrequest the Nuclear Regulatory Commission toconduct a detailed technical review of the safetyaspects of operating the facility, similar to theprocedure that was followed prior to initial startupof the reactor in the early 1980s. In addition, theInternational Atomic Energy Agency (IAEA) maybe requested to verify the inventory andcharacteristics of nuclear materials at the FFTF. TheIAEA has declared its willingness to help facilitateFFTF’s use by the international nuclear sciencecommunity.

It is the goal of the Hanford Radioisotopes Programto transfer technology for the production andapplications of medical isotopes to the private sectorthrough appropriate licensing agreements. A recentexample is the licensing agreement signed by NENLife Science Products, Inc., on October 12, 1998, touse PNNL’s patented process for extracting yttrium-90 from a strontium-90 generator in a highly purifiedform. Under this license agreement, themanagement contractor organization for PNNL ––the Battelle Memorial Institute –– receives an initialfee of $75K and subsequent royalties based on apercentage of the net sales value of yttrium-90 soldby NEN. The estimated value of this agreement forBattelle is approximately $500K over a five-yearlicense period. This licensing agreement was partof a broader commercialization effort in which NENtook over from PNNL all aspects of the production,marketing, sales, and distribution of yttrium-90(described in more detail in Section 2.2.2 ofReference 1.

Based on the success of the yttrium-90 privatizationactivity, PNNL is currently involved in efforts tocommercialize other technology that has beendeveloped for the medical application ofradioisotopes. For example, negotiations areunderway with a private company for use ofPNNL’s radioactive composite polymer deliverysystem for treating prostate tumors and other formsof cancer.

In addition to technology licensing agreements,consideration has been given to establishing facilitylease agreements under which commercialcompanies could perform work in DOE facilities atthe Hanford Site. For example, a study is underway

on the feasibility and opportunities for privatizingpart or all of the Postirradiation Testing Laboratorydescribed above in the response to Question A.1.This facility, as well as other laboratories in the 300Area of the Hanford Site, will be considered for useby private-sector companies in future work relatedto the preparation and processing of targets for FFTFisotope production.


As discussed above in the response to Question 1, arecent survey of space utilization in the RPLindicated that ~7000 ft2 of functional laboratoryspace is currently available for radiochemical workin new projects. It is anticipated that reassignmentof laboratory space within the RPL will be made inthe future to accommodate the full set ofrequirements for the radiochemical processing ofmultiple FFTF isotope targets. In addition, as alsodiscussed above in the response to Question 2, thereare extensive support facilities available for isotopetarget preparation and processing in Building 306Eand in the Postirradiation Testing Laboratory at theHanford Site.

With regard to the availability of trained staff whocould be mobilized in support of a growth in isotopedemand, there are currently about five scientists andtechnicians within the 75-member RPG that couldbe utilized in that capacity (in addition to the staffthat are members of the isotope production team).The overall workload and availability for newassignments of radiochemistry staff in the RPG isdriven primarily by funding for work in support ofthe Hanford nuclear waste cleanup mission and theprocessing and disposal of nuclear fuels. As the timeapproaches for restart of the FFTF reactor in mid-2004, an assessment will be made of staffassignments to support the isotope productionmission. It appears likely at this time thatrecruitment and hiring of new staff will be requiredduring the year preceding restart of the FFTF.However, as indicated above in the response toQuestion 2, ongoing discussions with private-sectorcompanies could lead to privatization of variouscomponents of the FFTF isotope productionprogram. The commercialization of variouselements of work involved in the preparation,irradiation, and processing of isotope targets, as wellas the marketing, sales, and distribution of the finalisotope products, could have a significant impacton the staffing requirements that must be met byPNNL and other contractor organizations at theHanford Site involved in the FFTF isotopeproduction mission.

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10. Summarize customer inquiries received duringthe past two years. What percent was filled,referred to other facilities, or rejected? Explainunfilled requests.

During the past two years the primary isotopeproduct supplied by the Hanford Site has beenyttrium-90. Weekly shipments of this medicalisotope have been supplied to more than 40customers who are using yttrium-90 primarily forcancer radioimmunotherapy. As described inSection 2.6.2 of Reference 2, PNNL provided morethan 1200 consecutive on-time shipments of yttrium-90 to DOE customers during the two-year periodpreceding the commercialization of this program.No orders were rejected and there were no unfilledrequests for yttrium-90 over the past two years.

Responses are also made to customer inquiriesregarding isotopes that are not produced at theHanford Site. These inquiries are answered withinone work day by referring the customers to otherDOE Isotope Production Sites or commercialsuppliers.


The level of satisfaction expressed by customers forisotope products supplied by the HanfordRadioisotopes Program has consistently been veryhigh. Our dedication to customer service, asexemplified by the 100% on-time record for morethan 1200 shipments of yttrium-90 over the past twoyears, has earned a number of compliments in letterssent by satisfied customers (summarized in Section2.6.2 of Reference 1. In addition to the timeliness ofisotope shipments, the staff involved in isotopeproduction have received a number of complimentsfor the consistently high quality of isotope productsproduced at the Hanford Site.

With regard to the overall DOE isotope program, itis our perception that customers are satisfied withthe quality of the isotope products that are providedfor medical, industrial, and research applications.However, improvements could be made in theavailability and timely supply of isotopes that arein demand for therapeutic medical applications andresearch (e.g., copper-67 and bismuth-212 for early-stage cancer therapy trials and laboratory animalresearch).


It is our firm belief that the supply of isotopesprovided by DOE for medical, industrial, andresearch applications must be strengthened in thenear future. This opinion is reinforced by theconclusions of a recent DOE Expert Panel Reporton the future need for medical isotopes. Many ofthe radioisotopes currently used for medicaldiagnosis and therapy of cancer and other diseasesare imported from Canada, Europe, and Asia. Thissituation places the control of isotope availability,quality, and pricing in the hands of non-U.S.suppliers. It is our opinion that the needs of theU.S. customers for isotopes and isotope products arenot being adequately served, and that the DOEinfrastructure and facilities devoted to the supplyof these products must be improved. The need forgreater U.S. capabilities to supply isotopes formedicine and research is one of the fundamentalbases for our proposal to restart the FFTF as anational DOE resource.

Additional Questions and Answers

13. How many undergraduate, graduate andpostdoctoral students have been in the PNNLprogram during the past three years? What wasthe source of funding for these students?

Twelve undergraduate students have worked in thePNNL isotopes program for periods ranging from3 to 24 months during the past three years. Thecolleges and universities attended by these studentsinclude Brigham Young University (1 student),Columbia Basin College (1), Gonzaga (2), OregonState University (1), Reed (1), Washington StateUniversity (4), and Vanderbilt (1).

One graduate student, who is working on his PhDin Nuclear Engineering at the University ofMaryland, is performing thesis research on neutroncross-section calculations under the guidance of amember of the PNNL isotopes program.

Sources of support for the undergraduate studentshave included direct DOE project work (2 students),Associated Western University scholarship funds(2), DOE summer internship funds (5), Laboratory-Directed Research and Development (LDRD) projectfunds (3).

The PhD candidate’s funding is obtained from aDOE Nuclear Engineering Fellowship, which beganin January, 1999.

14. What academic institutions are affiliated with theisotope production program? Please describe thisinteraction.

2 “Program Scoping Plan for the Fast Flux Test Facility:A Nuclear Science and Irradiation Services User Facility,”PNNL-12245, Pacific Northwest National Laboratory,Richland Washington, July 1999.

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Appendix G

Members of the PNNL isotopes program areinvolved in several national and internationalscientific collaborations with academic institutions.Eleven examples of university collaborations inresearch related to medical isotopes over the pastthree years are the following:

1) University of Idaho: Synthesis and testingof chelating agents for the alpha emittersradium-223 and actinium-225

2) University of Washington: Covalent linking ofchelated alpha emitters to monoclonalantibodies for cancer therapy; also, collaborativeresearch on the development of an automatedbismuth-213 generator

3) University of California at Los Angeles: Testingof affinity, avidity, and biodistribution ofchelated alpha emitters linked to monoclonalantibodies for cancer therapy

4) Fred Hutchinson Cancer Research Center:Dosimetry and pharmacokinetic modeling ofmonoclonal antibodies labeled with yttrium-90and iodine-131 (used for cancer therapy)

5) Stanford University: Dosimetry of radiolabeledmonoclonal antibodies for cancer therapy

6) Syracuse University: Synthesis and testingof chelating agents for the alpha emittersradium-223 and actinium-225

7) Oregon State University: Research onapplications of small university reactors forproduction of medical radioisotopes

8) Reed College: Research on applications of smalluniversity reactors for production of medicalradioisotopes

9) Washington State University: Development ofa graduate-level radiopharmacy program

10) Klopin Radium Institute (St. Petersburg, Russia):Development of a medical isotopes program

11) Russian Research Institute of ChemicalTechnology (Moscow, Russia): Development ofa medical isotopes program

15. What other peer-reviewed, external funding isreceived by those scientists working in theisotope production program? What researchdoes this support?

The staff members in the PNNL isotopes programhave several sources of external support providedby commercial clients and government agenciesother than the DOE/NE Isotopes Program Office.

Much of the research that does not involve medicalisotopes relates to the characterization andcontainment of radioactive waste materials at DOEsites.

The following are examples of peer-reviewedprojects funded by government sources during thepast three years:

12) DOE Office of Environmental Management(DOE/EM-50): “Caustic Leaching of HanfordTank Sludges” (project led by PNNL staff, withORNL and LANL collaborators); funding levelsof $650K in FY 1997 and $900K in FY 1998.

13) DOE/EM-50 programs: “Technetium FlowStudies and Chromium Speciation” (two projectsinvolving PNNL staff); funding levels of $230Kin FY 1997 and $150K in FY 1998.

14) DOE Office of Science’s EnvironmentalManagement Science Program (DOE/EMSP):“Architectural Design Criteria for MetalSequestering Agents” (project led by PNNL staff,with collaborators from theUniversity of California at Berkeley, Texas TechUniversity, the University of New Mexico, andthe University of Alabama); funding levels of$600K in FY 1997, $600K in FY 1998, and $600Kin FY 1999.

15) DOE/EMSP programs in “AqueousElectrochemical Oxidation Mechanisms andTechnetium Species in Hanford Nuclear Wastes”(two projects led by LANL investigators, withPNNL collaborators); funding levels of $86K inboth FY 1998 and FY 1999.

16) DOE Office of Science (Office of Biological andEnvironmental Research): “Development andTesting of Injectable Radionuclide PolymerComposites for Cancer Therapy” (projectinvolving PNNL staff); funding levels of $42Kin FY 1998 and $58K in FY 1999.

17) Fred Hutchinson Cancer Research Center,National Cancer Institute Grant (Seattle, WA):“Dosimetry Support for Therapy of Leukemiaand Lymphoma with Radiolabeled MonoclonalAntibodies” (collaboration involving PNNLstaff); PNNL funding levels of $22K in FY 1997,$23K in FY 1998, and $24K in FY 1999.

18) NeoRx Corporation, National Cancer InstituteGrant (Seattle, WA): “Internal Dosimetry andAssistance in the Development of RadiolabeledMonoclonal Antibodies” (collaborationinvolving PNNL staff); PNNL funding levels of$51K in FY 1997, $53K in FY 1998, and $26K inFY 1999.

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19) DOE/U.S. Industry Coalition Program: “HighPerformance Sealed Source Phantoms forNuclear Medicine” (project involving PNNLstaff); funding levels of $47K in FY 1997, $64Kin FY 1998, and $37K in FY 1999.

20) DOE/NN Initiatives for ProliferationPrevention: “Medical Isotope Production inRussian Nuclear Facilities” (two projects led byPNNL staff, with collaborators from the KhlopinRadium Institute and theRussian Research Institute of ChemicalTechnology); funding level of $100K in FY 1997.

In addition to peer-reviewed projects funded bygovernment agencies, staff in the PNNL isotopesprogram also receive funding from contracts withprivate companies. The following are examples offunding support from these sources during the pastthree years.

1) British Nuclear Fuels, Ltd., Tank WastePrivatization Work: “Ion Exchange Testing”(project involving PNNL staff); funding level of$100K in FY 1999.

2) Private contractor (confidential): “CompositePipe Coating Using Strontium-90” (projectinvolving PNNL staff); funding level of $250Kin FY 1998.

3) International Isotopes of Idaho, Inc. (Idaho Fall,ID): “Calculation of Reactor-Generated IsotopeProduction Rates” (project involving PNNLstaff); funding levels of $20K in FY 1998 and $10Kin FY 1999.

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Appendix G G-3

Nuclear Energy Research Advisory Committee (NERAC) Subcommittee

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