Production & quality control of radioisotopes and radiopharmaceuticals
Research & development in the field of new radioisotopes and radiopharmaceuticals
Tc-99m Production Instant 99mTc Production
RIPD started producing instant 99mTc by irradiating natural MoO3 in the research reactor in 1987. A plant for production of instant 99mTc by solvent extraction was installed at RIPD by the former GDR under the Technical Cooperation Project of the IAEA. In this system the relative differences in the distribution coefficients of pertechnetate and molybdate for methyl ethyl ketone (MEK) was used as the basis of separation in the solvent extraction generator. Pertechnetate is preferentially extracted into MEK from alkaline molybdate solution. Produced 99mTc was routinely used in three nuclear medical centers located in Dhaka until 1997. Instant Tc-99m was not suitable for sending to hospitals remote from Dhaka due to its short half life.
In order to get rid off the problem of sending instant 99mTc to remote nuclear medicine centers of the country, a plant for production of column chromatographic 99mTc-generator was installed at RIPD through an IAEA Technical Project with the technological assistance from BRIT, India. RIPD produced four generators (15 GBq each) per batch fortnightly since 1998 and 105 batches of 99mTc-generator had been produced in this plant and supplied to the four nuclear medicine centers of the country. The user’s responses regarding the performances of these generators and quality of TcO4 - obtained from these generators were quite satisfactory.
This 99mTc-generator plant is capable of producing only four generators per batch but the country’s weekly demand is 17 generators. In order to meet the country’s entire demand, a new plant has been installed at RIPD on May 2005 which was going for routine operation from October 2005. This plant has been designed and installed in a collaboration with the German company Hans Waelischmiller GmbH and RIPD with the financial assistance from the IAEA.
A computer controlled on-line sterile filtration and loading system for production of 99mTc-generator has been developed and used in this plant. This plant is capable of producing 50 generators (15GBq) per batch and this generator production facility complies with the cGMP for radiopharmaceuticals.
A special type of filter is used for the on-line filtration. This filter is a combination of hydrophilic and hydrophobic membranes which allows passage of both aqueous solution and air. The same type of filtration unit is used in the generator assembly for terminal filtration.
The main obstacle in development of the on-line loading system was the existence of the air filter at one of the inlet needles of the generator hardware. This difficulty has been overcome by the introduction of a pneumatically controlled glass column adopter. First, the loading solution is transferred to the adaptor and then the adopter is pneumatically connected to the on-line system.
This new plant consists of two hot cells. One is used for chemical processing and dispensing of 99Mo solution and the other hot cell is used for sterile filtration and generator loading. Usually radioisotope hot cells are maintained under negative pressure to protect the release of any radionuclide during operation, but for aseptic loading of the generator positive pressure is required. To overcome this difficulty, a laminar flow module is installed above the loading area of the hot cell which provides class 100 clean environments during loading process and the overall pressure of the hot cell is maintained negative.
This chromatographic 99mTc-generator production is based on fission produced 99Mo. The main features of this generator are: (1) cold generator assembling (2) dry-column generator (3) terminal filtration (4) small elution volume (minimum volume for full elution is 3 ml) (5) elution volume can be selected by volume controller (6) adequate radiation protection for the users (7) sterile and non-pyrogenic 99mTc eluate (8) re-useable generator hardware etc.
The generators produced at RIPD are comparable with the best quality generators available in the world market. This facility enables Bangladesh to produce high quality 99mTc-generator locally.
A plant for production of 131I has been installed at RIPD in 1987. I-131 is produced by irradiatingTeO2 target in the 3MW TRIGA Mark-II Research Reactor. Te-130 (natural abundance 33.4%) captures neutron to produce 131Te, which transforms into 131I by beta emission.
TeO2 in a finely crystalline form sealed in quartz ampoule is irradiated in the reactor and after two days of cooling it is heated at about 730oC. Iodine -131 is released and transferred by air stream into a trap filled with Na2CO3/NaHCO3 buffer or 10 mM NaOH solution. More than 99% of the iodine is absorbed as sodium iodide at pH 7 to 9. This plant has the capacity of processing 370 GBq of 131I per batch.
RIPD produces 131I every week and the quality of the I-131 (radiochemical purity, radionuclidic purity, pH range etc.) was found within permissible limit. The produced isotope is supplied to the nuclear medicine centers for diagnostic and therapeutic applications. The users responses are satisfactory.
131I Capsule production
1.85, 2.78 and 3.70 GBq of 131I capsules are used for thyroid ablation therapy and 37-74 MBq of 131I capsules are used for diagnosis in the nuclear medicine centers. Present demand of 131I therapeutic capsules in the country is about 56 GBq/week.
In order to produce 131I capsules locally, a plant has been installed at RIPD in 2001. The facility can be used for the production of both diagnostic and therapeutic capsules. Inert filling material of the capsules is mixture of dry Na2HPO4, ascorbic acid and Na2S2O3 powder in 10:1:1 ratio.
RIPD is going to establish a facility for the production of Tc-99m in-vivo kits, which are the essential precursors of Tc-99m radiopharmaceuticals. The local production of cold kit would help to cut import. The facility will be established under the ADP project of the government. A supporting IAEA TC project has been also under taken in this regards.
Quality Assurance (QA) and Good Manufacturing Practices (GMP) at RIPD
The practice of radiopharmacy is a part of the broader practice of nuclear medical diagnosis, which itself may be treated as a quality system. The aspect that is designed to ensure that radiopharmaceuticals are safely and reproducibly prepared and handled in hospitals to a standard appropriate to their intended use
The quality of radiopharmaceuticals may affect not only the safety of the patient but also the outcome of the diagnostic or therapeutic procedure. QA is the responsibility of the organization to determine that systems, facilities and written procedures are both adequate and followed in order to assure that products will meet, in the final dosage form all the applicable specifications. QA becomes an overseeing function, often auditing operations to determine the procedures and systems are suitable and if not, to recommend the required changes. GMP is that part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to the intended use.
RIPD has written QA program which includes information pertaining to organizational structure, personnel, premises, processing/formulation, quality control testing etc. This QA program complies with the “Guide lines for good manufacturing practices of radiopharmaceuticals2” and “Quality Assurance (QA) Manual for Radiopharmaceuticals3” published under the East Asia and Pacific Regional Technical Co-operation Project (RAS/2/009) of the IAEA.
Research and Development of PZC based Tc-99m Generator.
Research on the Development of new Diagnostic and Therapeutic Radiopharmaceuticals.
RIPD substituted import of Tc-99m generators and I-131 solution by local production.
Completed the three IAEA Technical Cooperation Project and one IAEA Technical Cooperation Project is ongoing.
A new Tc-99m generator production plant has been installed at RIPD in 2005. A computer controlled on-line production system has been developed in this facility in a joint venture among RIPD, the IAEA and HWM, Germany. This facility has a production capacity of 50 generators per batch and complies with the cGMP for radiopharmaceuticals. This plant is now used for weekly production of Tc-99m generators.
I-131 production line has been renovated under another ADP project of the government. Two processing units have been installed in the same production hot cell for alternate use. This line is in use for weekly production of I-131 solution
Facility for the Production of Tc-99m Generator (old)
Facility for the Online Production of Tc-99m Generator (new)
Facility for the Production of Iodine-131 Solution
Facility for the Production of Iodine-131 Capsules
Facility for the Production of Hippuran
Facility for Animal Testing
HVAC (Humidity, ventilation and air cooling) facility
QC laboratory (well equipped)
Production of Lu-177 Radiopharmaceuticals for therapeutic use.
Production of PET Radiopharmaceuticals for diagnostic use.