Radioisotope and radiopharmaceutical production in viet nam

IAEA/RCA REGIONAL WORKSHOP ON PRODUCTION AND SUPPLY OF RADIOISOTOPES Serpong , Indonesia , 6-10 October 2003 RADIOISOTOPE AND RADIOPHARMACEUTICAL PRODUCTION IN VIETNAM LE VAN SO Abstract This is an outline of the radioisotope production programme using a research reactor of 500 kW in Vietnam The production laboratory and facilities including the nuclear reactor with its irradiation positions ans characteristics, hot cells, production lines and equipment for the production of Kits for labelling with 99mTc and for quality control, as well as the production rate are mentioned The methods used for production of 131I, 99mTc, 51Cr, 32P, etc and the procedure for preparation of radiopharmaceuticals are briefly described Status of utilization of domestic radioisotopes and radiopharmaceuticals in Vietnam was also reported INTRODUCTION After the reconstruction of our reactor in late 1983, the production of radioisotopes and labelled compounds for medical use was started In a developing country of very low economic level, the benefit of establishment of a nuclear research center with a research reactor of low power will be recognized by society only when its contributions to social progress become evident This point of view has oriented us to put forward a limited radioisotope production programme to support radioisotope application in medicine, agriculture and industry For this objective the core of our reactor of 500 kW reconstructed from the old 250 kW TRIGA MARK II reactor is equipped with more neutron irradiation channels and with a neutron trap for improving thermal neutron flux In addition, the reactor characteristics are more useful as far as radioisotope production is concerned, i.e of higher excess reactivity, the cadmium ratio in neutron irradiation channels being rather high in the thermal neutron trap and rather low in the fast neutron channels The establishment of a laboratory for routine production of radioisotopes was carefully considered by balancing the investment requirement and the production technology of choice, as well as the radioactive waste treatment problem and radiation protection Dalat Nuclear Research Reactor of nominal power of 500 KW is today the unique one in Vietnam More than 90% of reactor operation time and over 80 % of reactor irradiation capacity have been exploited for radiopharmaceutical production With one main irradiation channel of neutron flux of 2*1013 n/cm2.sec and some irradiation positions of much lower neutron flux we have now routinely produced some important radioisotopes especially for medical purposes The radioisotopes, radiolabelled compounds and radiopharmaceuticals produced in Dalat reactor have regularly been supplied to all nuclear medicine centres in Vietnam The radioactivity of more than 150 Ci of 131I, 99Mo- 99mTc, 32P, 51Cr, 153Sm; 46Sc; 192 Ir was annually produced Radiopharmaceuticals such as 153Sm-EDTMP 131IHippuran and in-vivo Kits for 99mTc labelling were also prepared routinely and regularly; More- than 10 in-vivo Kits including modern radiophannaceuticals such as HMPAO kit were supplied to hospitals in Vietnam RIA Kits such as T3, T Kit for invitro assay were prepared and ready to be supplied Our radioactive isotope products were regularly supplied to hospitals in Vietnam In addition, research in radiochemistry laid the basis for the development of technologies suitable for isotope production in low power research reactors PRODUCTION OF RADIOISOTOPES AND RADIOPHARMACEUTICALS Local production volume and demand: The routine production of radioisotopes in Dalat Nuclear Research Institute has been focussed on the main radionuclides used in nuclear medicine such as: - 32P in injectable orthophosphate solution and 32P applicator for skin disease therapeutics - 131I in Na131I solution - 99mTc generator using Zirconium-(99Mo) Molybdate gel - 51Cr in injectable sodium-chromate and chromium-chloride solution - 153Sm in solution form ready for labelling These types of radioisotopes have regularly been supplied to more than 30 hospitals in Vietnam monthly The 1311 radioisotope labelled radiopharmaceuticals such as 131 I-Hippuran have also been regularly supplied to hospitals Radioisotope production rate is shown in Tab and Fig In order to support the application of 99mTc, 113mIn and 153Sm radioisotopes in clinical diagnosis and therapeutics the preparation of radiopharmaceuticals in KIT forms was carried out The following Kits have regularly been manufactured in our institute: Phytate, Gluconate, Pyrophosphate, Citrate, DMSA, EHIDA, DTPA, HSA macroaggregated and HEDP, The HmPAO, MIHI, MDP kits are presently under clinical trial For therapeutic purposes radiopharmaceuticals labelling with 153Sm and 131I such as l53Sm-EDTMP ,131I-MIBG are also prepared and put through clinical trial Radioimmunoassay kits: The RIA kit production and distribution programme have just now started T3 and T4 kit will be selected locally produced and supplied to users with a share of 10% of domestic market Other RIA and IRMA kits will be supplied to users by dispensing process based on the contract Activity (Ci) 200 150 100 50 1995 1996 1997 1998 1999 2000 Year Figure : Total Radioactivity of radioisotopes produced at NRI,Dalat Table 1: The supply / demand for radioisotopes and diagnostic Kits in Vietnam Supply Demand Limitation & Remarks Ci/month – 15 Ci/month – – – 99m generators (500mCi/each) /month 20 generators (500mCi/each) /month Low neutron flux of our reactor 32 100 mCi/month 100 mCi/month – 20 Kit/ month 20 Kit/ month 20 Kit/ month 30 Kit/ month 20 Kit/ month – 50 Kit/ month 50 Kit/ month 50 Kit/ month 50 Kit/ month 100 Kit/ month 20 Kit/ month 100 Kit/ month Kit/ month Kit/ month 20 Kit/ month 20 Kit/ month 20 Kit/ month 30 Kit/ month Product 131 I- Diagnostic and therapeutic capsule/solution Tc-Generator P- Solution Kits for 99mTc-Labelling - MDP - DTPA - Macro Agregated HSA - PHOSPHON - PHYTATE - HIDA derivatives - Others (HM-PAO, MIBI, MAG-3, ECD) Radioimmunoassay Kits - T4 - T3 - TSH - Others Not enough chemical supply Use of local products in the country : - Numbers of nuclear medicine centre in Vietnam: 31 These centres are located in almost all parts of country, see Fig.3 - - Numbers of gamma cameras (planar and SPECT) : 14 Radiopharmaceuticals used in these centres: Na131I solution, Sodium-(99mTc) pertechnetate, 131I-Hippuran, Sodium-(32P) orthophosphate, invivo Kits (DTPA, DMSA, Phosphon, Glucon, Phytate ,MAHSA ,EHIDA, HMPAO, MIBI, MAG-3 etc.) Locally manufactured products takes 50% of total market To get a higher market share in case of 99mTc generators we will increase the production by loading generations with imported 99Mo solution and in case of invivo kits the production of modern kit such as HMPAO, MIBI, MAG-3 etc must be improved Figure : Location of Nuclear Medicine Centers in Vietnam 3- Production laboratory and facilities Nuclear Reactor description and its operation : The Dalat Reactor includes the reactor tank, shielding and graphite reflector of the former TRIGA MARK II reactor and the core with a control system and neutron irradiation channels designed by the Russian is shown in Fig The reactor characteristics are as follows : Reactor type Nominal thermal power Coolant and moderator Core cooling mechanism Reflector Fuel type Number of control rods Control rod material Neutron measuring channels Vertical irradiation channels Horizontal beam-ports Thermal column Spent fuel storage (temporary) Swimming pool, TRIGA Mark II, modified to Russian type of IVV-9 500 kW, steady state Light water Natural convection Beryllium and Graphite WWR-SM, U-Al alloy, 36% enrichment (2 safety rods, shim rods, regulating rod) B4C for safety and shim rods, Stainless steel for automatic regulating rod (6 CFC, CIC) (neutron trap, wet channel, dry channels) and 40 holes at the rotary rack (1 tangential, radial) 1, inside reactor building, next to the reactor shielding Neutron irradiation positions and its neutron flux (at 500 kW ) • Neutron trap at center of active core with thermal neutron flux of 13 -2 -1 2.1x 10 n.cm sec , cadmium ratio RCd=2.5 • Rotary specimen rack providing 40 wet irradiation positions with thermal 12 -2 -1 neutron flux of 5.0 x 10 n.cm sec , cadmium ration RCd=3.4 13 -2 -1 • Channel for fast neutron irradiation with flux of x 10 n.cm sec • Pneumatic transfer channels at core perimeter with a thermal neutron flux of 11 -2 -1 5.0 x 10 n.cm sec • Thermal column and horizontal beam tubes For radioisotope production the neutron trap and 40 irradiation positions of rotary rack are used for thermal neutron irradiation and a channel for fast neutron irradiation Fuel assembly Irradiation channel Regulating rod Beryllium block Control rod Graphite reflector Neutron trap Irradiation hole Figure Cross-section view of the reactor core From the first start-up of the reactor in March 1984 to the present time, the reactor has proved to be safe and reliable, as it has never suffered from any incident which significantly affected the environment, and annual operation schedules have been rigorously respected (Fig 5) Operation time at 500 kW (hr) STATI STI CS OF OPERATI ON TI M E OF THE DALAT REACTOR 2000 1771 1654 1505 1500 1387 1286 1486 1343 1302 1120 1000 993 1351 1370 1206 1203 1228 1215 1113 1220 966 500 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 Year Figuer 5: Statistics of operation time of the Dalat reactor Radioisotope production laboratory : An area of 200 sq.m is reserved for a rather limited programme of isotope production The facilities available for the isotope 131 production consist of one hot cell with master slave manipulator, one I isotope production line equipped under Technical Cooperation Project No-VIE/0/002 of IAEA (1987) with shielded cells, ball-joint manipulators and five shielded fume 99m hoods for isotope labelling and emitted isotope processing 0ne Tc 99 99 generator production line (using fission Mo solution and (n,γ) Mo contained molybdate gel column) composed of two shielded cells and one multipurpose junior cave were put to use under Technical Cooperation Project No-VIE/6/016 of IAEA in 1990 All these facilities are connected with the existing ventilation system of the reactor 99m Equipment for the production of Kits to be labeled with Tc isotope and for the quality control of radioisotopes and radiopharmaceuticals was also supplied by the IAEA 4- Production methods Irradiation techniques : The targets held in the quartz ampoule were irradiated with thermal neutron either in the neutron trap at the center of the reactor core or in the rotary specimen rack Fast neutron irradiation was carried out in a dry channel inserted between fuel elements of the reactor core Before reactor irradiation the targets were purified to remove traces of impurities Radiochemical processing of activated targets : Iodine-131 : This isotope was produced by thermal neutron bombardment of tellurium-130 nuclide according to the reaction : ß130Te (n,γ ) 131Te >131I 1.2 d The method of dry distillation separation of carrier-free 131 I from irradiated Te02 was used The distillation apparatus was purchased from ISOCOMMERZ 131 (GDR) with finance support of IAEA In Fig , I production process is shown Figure I-131 radioisotope production line at NRI 99m 99 Tc generator : Among the two reactions of choice for production of Mo 235 99 parent isotope, the large investment for use of U(n,fission) Mo reaction let us 99m 98 99 to opt for the Mo(n,γ) Mo reaction to produce Tc generator 99m 99 In order to separate Tc from its parent Mo we first used the MEK extraction method The inherent disadvantages of this method compelled us to start our studies on the preparation of gel type generators in late 1984 in the framework of the IAEA99m coordinated research programme on the “Development of Tc generators using low power research reactor” This represents the state-of-the-art for generator technology and promises opportunities for both developed and developing countries 99 particularly with respect to eliminating the need for fission Mo Two directions of preparation of gel type generators were studied : o Preparation of chromatographic generators using zirconium molybdate (ZrMo) or titanium molybdate (TiMo) column packing materials synthesized from the neutron irradiated molybdenum trioxide and the zirconium chloride and/or titanium chloride, respectively o Preparation of chromatographic generators using TiMo column packing material (preformed TiMo) synthesized from the inactive molybdenum compound and TiCl4 and subsequently neutron activated in the reactor In both modes of preparation we have carried out studies on three different options of generators : - The chromatographic generator using 0.9% NaCl solution as eluant - The chromatographic generator using organic solvent as eluant (SolidSolvent-extraction) 99m - The chromatographic generator using dilute saline as eluant and Tc concentration column Figure : Tc-99m generator production line at Dalat NRI 113 113m ( Sn – In) Generator : Basing on the excellent absorption-kinetics and capacity of hydrous zirconium oxide prepared by us a very simple and effective 113m technology for the production of chromatographic In generator was developed 32 Phosphorus- 32 : P isotope was produced according to two nuclear reactions : 32 32 31 32 S (n,p) P ; P (n,γ) P 32 The first reaction was used for the production of injectable carrier-free P 32 solution, the second for that of P –isotope applicators for skin disease treatment 32 P solution of radioactivity of ten mCi scale was First the injectable 32 produced from irradiated MgSO4 target using magnesia as absorbent to separate P isotope from MgSO4 solution In the case of Ci scale production, the large amount of waste produced from this technology caused storage problems Recently, we 32 have introduced the distillation technique to separate P from reactor irradiated elemental sulfur [6] Our glass apparatus for this production process is shown in Fig 8; it can be used for distillation either in the vacuum or in the N2 gas flow by changing the upper stopper of the distillation vessel The distillation parameters and 32 post-distillation purification of P solution were adopted as described in literature [3] 32 The P applicators for skin disease treatment were produced by neutron irradiation of a soft plate preformed from cloth binder and a covering mixture of red phosphorus and glue [6] After irradiation in the reactor the radioactive plate was impregnated with plastic and covered with Scotch adhesive The mechanical strength of the preformed plate was not lost under 75 hour irradiation in a thermal 12 -2 -1 neutron flux of 5*10 n.cm sec Under this irradiation a plate containing 65 32 mg P per square centimeter gives a radioactivity of 15 mCi P The absorbed dose -1 rate on the surface of the plate of size 50 x 40 mm was measured as 110 Rad.min -1 at the center and 75 Rad.min on the edge Medical doctors’ experience over ten years showed that with repeated treatment of three or five 15-minute applications the following diseases will be cured : Eczema, skin cancer, bump scar, etc At present 32 more than 75 Ci P in applicator form are used annually in our country 51 Cr-51 isotope: The production of Cr isotope was carried out based on the Szilard-Charmel reaction using reagent grade K2Cr04 target The chemical 51 separation of recoiled Cr nuclide was based on the selective adsorption of this isotope on an inorganic ion exchanger Si-ZrP (Silica gel supported zirconiumphosphate) synthesized by us [5] 10 0ther isotopes were also produced when requested in small amounts for industrial and agricultural applications The methods for production of these isotopes were selected from different reference sources.[3] 99m Production of Kits for labelling with Tc : 99m In furthering the application of Tc isotope the local availability of Kits for 99m Tc plays an important role With IAEA support the basic labelling with equipment for the production of Kits was installed in our laboratory At present Kits have been successfully prepared by us and put to use in our country, they are : Phytate, Gluconate, Pyrophosphate, Citrate, DMSA, HIDA, DTPA, Maccroaggregated HSA and EHDP (1-hydroxy ethylidene-1, 1-disodiumphosphate) The studies on the preparation of Radioimmuno-assay Kits and therapeutic agents and/or radionuclides were also carried out The future production of the above mentioned items is foreseen and planed 5- Quality control Radioisotope and radiopharmaceutical quality control was carried out for all batches of our products The gamma spectrum analysis using Ge-Li detector coupled with a multichannel analyser is used for radionuclide purity control, the thin layer-, paper-, and gel-chromatography techniques for radiochemical purity, and the spectrophotometry and neutron activation analysis for chemical purity Biodistribution assay, biological tests (apyrogenity, sterility, toxicity) and physicochemical tests (pH, turbidity) are also carried out regularly REFERENCES 99m [1] Le Van So, Production of Tc isotope from the chromatographic generator using zirconium-molydate and titanium-molybdate targets as column packing materials Research Co-ordination Meeting, Bandung, Indonesia, 0ctober 1987 99m [2].-Le Van So, Production of chromatographic Tc generators using titaniumand zirconium-molybdate gel type targets J Radional Nucl Chem., Letters (to be published) [3].-Radioisotope production and quality control Technical Reports Series No 128 IAFA, Vienna, 1971 131 [4].-Le Van So, Chu Van Khoa and Tu Van Nghia, Dry Distillation of I from reactor irradiated titanium- and zirconium-tellurate targets J Radioanal Nucl Chem., Letters (to be published) [5].-Le Van So, Investigation on the silica gel supported form of micro crystalline zirconium-phosphate ion exchanger and its applications in chemical separation I.- Preparation, ion exchange properties and stability of Si-ZrP, J Radioanal Nucl Chem., (Articles).9 (1) 17-30 (1986) [6].-Le Van So, Richard M Lambrecht, Development of alternative technologies for 99m a gel-type chromatographic Tc generator J Labelled Compd Radiopharm 35 : 270 (1994) 11 View publication stats ... production volume and demand: The routine production of radioisotopes in Dalat Nuclear Research Institute has been focussed on the main radionuclides used in nuclear medicine such as: - 32P in. .. 113mIn and 153Sm radioisotopes in clinical diagnosis and therapeutics the preparation of radiopharmaceuticals in KIT forms was carried out The following Kits have regularly been manufactured in. .. Nuclear Medicine Centers in Vietnam 3- Production laboratory and facilities Nuclear Reactor description and its operation : The Dalat Reactor includes the reactor tank, shielding and graphite