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 Ab

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 99m Tc and for quality control, as well as the production rate are mentioned

The methods used for production of 131 I, 99m Tc, 51 Cr, 32 P, 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 131 I-Hippuran 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 4 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

1 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 1 and Fig 1

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

Figure 1 : Total Radioactivity of radioisotopes produced at NRI,Dalat

Table 1: The supply / demand for radioisotopes and diagnostic Kits in Vietnam

Product Supply Demand Limitation &

Remarks 131

I- Diagnostic and

therapeutic

capsule/solution

3 Ci/month –

15 Ci/month –

– –

99m

Tc-Generator 3 generators

(500mCi/each) /month

20 generators (500mCi/each) /month

Low neutron flux

of our reactor

32

P- Solution 100 mCi/month 100 mCi/month

Kits for 99mTc-Labelling

- MDP

- DTPA

- Macro Agregated HSA

- PHOSPHON

- PHYTATE

- HIDA derivatives

- Others (HM-PAO,

MIBI, MAG-3, ECD)

–

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

Not enough chemical supply

Radioimmunoassay Kits

- T4

- T3

- TSH

- Others

5 Kit/ month

5 Kit/ month

20 Kit/ month

20 Kit/ month

20 Kit/ month

30 Kit/ month

0 50 100 150 200

2 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 3 : 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 4 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

7 (2 safety rods, 4 shim rods, 1 regulating rod)

B4C for safety and shim rods, Stainless steel for automatic regulating rod

9 (6 CFC, 3 CIC)

4 (neutron trap, 1 wet channel, 2 dry channels) and 40 holes at the rotary rack

4 (1 tangential, 3 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 2.1x 1013n.cm-2.sec.-1, cadmium ratio RCd=2.5

• Rotary specimen rack providing 40 wet irradiation positions with thermal

neutron flux of 5.0 x 1012n.cm-2.sec.-1, cadmium ration RCd=3.4

•Channel for fast neutron irradiation with flux of 1 x 1013n.cm-2.sec.-1

• Pneumatic transfer channels at core perimeter with a thermal neutron flux of

5.0 x 1011n.cm-2.sec.-1

• Thermal column and 4 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

Figure 4 Cross-section view of the reactor core

Fuel assembly

Control rod

Regulating rod

Irradiation channel Beryllium block Neutron trap

Graphite reflector Irradiation hole

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)

STATI STI CS OF OPERATI ON TI M E OF THE DALAT REACTOR

1215 1203 1206 1370 1351 1302

966

1486 1654 1505 1343 1286

993

1387

1120

1771

1113

1228 1220

0

500

1000

1500

2000

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 production consist of one hot cell with master slave manipulator, one 131I isotope production line equipped under Technical Cooperation Project No-VIE/0/002 of IAEA (1987) with 4 shielded cells, ball-joint manipulators and five shielded fume hoods for isotope labelling and emitted isotope processing 0ne 99mTc generator production line (using fission 99Mo solution and (n, γ ) 99Mo 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

Equipment for the production of Kits to be labeled with 99mTc 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 :

ß- 130Te (n,γ ) 131Te ->131I 1.2 d

The method of dry distillation separation of carrier-free 131I from irradiated Te02 was used The distillation apparatus was purchased from ISOCOMMERZ (GDR) with finance support of IAEA In Fig 6 , 131Iproduction process is shown

Figure 6 I-131 radioisotope production line at NRI

99 m

Tc generator : Among the two reactions of choice for production of 99Mo parent isotope, the large investment for use of 235U(n,fission) 99Mo reaction let us

to opt for the 98Mo(n,γ)99Mo reaction to produce 99m

Tc generator

In order to separate 99mTc from its parent 99Mo 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 IAEA-coordinated research programme on the “Development of 99mTc 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 particularly with respect to eliminating the need for fission 99Mo

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 (Solid-Solvent-extraction)

- The chromatographic generator using dilute saline as eluant and 99mTc concentration column

Figure 8 : Tc-99m generator production line at Dalat NRI

( 113 Sn – 113m In) Generator : Basing on the excellent absorption-kinetics and

capacity of hydrous zirconium oxide prepared by us a very simple and effective technology for the production of chromatographic 113mIn generator was developed

Phosphorus- 32 : 32P isotope was produced according to two nuclear reactions :

32

S (n,p) 32P ; 31P (n,γ) 32P The first reaction was used for the production of injectable carrier-free 32P solution, the second for that of 32P –isotope applicators for skin disease treatment

First the injectable 32P solution of radioactivity of ten mCi scale was produced from irradiated MgSO4 target using magnesia as absorbent to separate 32P 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 have introduced the distillation technique to separate 32P 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 post-distillation purification of 32P solution were adopted as described in literature [3]

The 32P 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 neutron flux of 5*1012n.cm-2.sec.-1 Under this irradiation a plate containing 65

mg P per square centimeter gives a radioactivity of 15 mCi 32P The absorbed dose rate on the surface of the plate of size 50 x 40 mm2 was measured as 110 Rad.min-1

at the center and 75 Rad.min-1 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 more than 75 Ci 32P in applicator form are used annually in our country

Cr-51 isotope: The production of 51Cr isotope was carried out based on the Szilard-Charmel reaction using reagent grade K2Cr04 target The chemical separation of recoiled 51Cr nuclide was based on the selective adsorption of this isotope on an inorganic ion exchanger Si-ZrP (Silica gel supported zirconium-phosphate) synthesized by us [5]