UNIT OPERATION / PRODUCTION PROCESS


Technetium Generation

Tc-99m Radionuclide

Technetium is a transition metal with an atomic number of 43. It has no stable isotopes but with 16 radioisotopes ranging from 92 to 107. All isotopes of technetium are artificially-produced hence its name (Technetium in Greek means artificial). Among its radioisotopes, only one is of clinical value- Technetium 99m- currently the most commonly-used radionuclide in nuclear medicine.

Technetium 99m is obtained from the radioactive decay of Molybdenum 99 via the emission of beta electron (Figure 2). This creates the excited state Tc-99m which can return to its ground state Tc 99 by releasing a gamma photon. The excited state Tc-99m is unique in having an extremely long duration of magnetic decay with a gamma emission half-life of 6.03 hours. Typical emission half-lives are around 1 x 10-16 seconds. With such a long half-life, the excited state of Tc-99 is considered metastable hence the designation Tc-99m. Its nuclei emits 140keV of gamma rays without accompanying beta rays; this property makes Tc-99m highly desirable for nuclear medicine.

Figure 2. Radioactive decay of Molybdenum 99 generating the excited state Technetium 99m and ultimately the ground state Technetium 99

Clinical Application of Tc-99m Radionuclide

Technetium-99m is the most widely-used radionuclide in nuclear pharmacy accounting for 85% of all radionuclides in clinical use. With its development in the early 1960s, Tc-99m radiopharmaceuticals drove the evolution of nuclear pharmacy industry as a whole. An estimated 25million procedures make use of Tc-99m each year with an annual growth rate of 15%.

The occurrence of multiple oxidation states of technetium allows for its chemical versatility making it possible to produce a variety of complexes with specific desired characteristics. As such Tc-99m radiopharmaceuticals are at a wide range with a number of applications.

FIRST GENERATION Tc IMAGING AGENTS

Also known as Tc essentials, they are produced and developed by taking advantage of the simple absorption, distribution, metabolism and excretion properties of the common complexes of Tc-99m.

First Generation Imaging Agents

Application

Tc-99m?DTPA,

DTPA = diethylenetriaminepentaaceticacid

Kidney imaging

Tc-99m-MDP

MDP = methylenediphosphonate

Bone Imaging

SECOND GENERATION Tc IMAGING AGENTS

Modern analytical tools such as nuclear magnetic resonance (NMR) spectroscopy, mass spectroscopy (MS) and x-ray diffraction has led researchers to identify the exact molecular structure of the coordination compounds of Tc-99m. This opened a better understanding of structure-activity relationship behind the biological effects of technetium compounds. As a consequence, carefully-designed ligands and their Tc-99m complexes produced imaging agents for perfusion in the myocardium and brain.

Second Generation Imaging Agents

Application

Tc-99m?MIBI

MIBI = methoxyisobutylisonitrile

Myocardial perfusion imaging

Tc-99m?HMPAO

HMPAO= hexamethylpropyleneamineoxime

Brain imaging

Tc-99m- ETC

ETC = ethyl cysteinate dimer

Brain imaging

Tc-99m Lidofenin

Hepato-biliary imaging

Tc-99m Mebrofenin

Hepato-biliary imaging

Tc-99m Disofenin

Hepato-biliary imaging

Tc-99m-MAG3

MAG = mercaptoacetyltriglycine

Renal imaging

THIRD GENERATION Tc IMAGING AGENTS

Radionuclide generators in recent production involve more specific biological targets such as receptors and transporters. These agents are driving the development of more sophisticated radiolabeling approaches that go beyond current technologies.

Third Generation Imaging Agent

Application

Tc-99m-HYNIC-TOC

Receptor studies in the brain

Tc 99m Radionuclide Generator

GENERATOR SYSTEM

A radionuclide generator operates on the principle of the decay-growth relationship between a long-lived parent radionuclide (Mo-99, 66hours) and a short-lived daughter radionuclide (Tc-99m, 6hours). Figure 3 shows the basic structure and components of a radionuclide generator.

The generator column contains Mo-99 in the form of the molybdate ion MoO42- which is adsorbed onto a bed of aluminum oxide (Al2O3). The decay of Mo-99 is a random process that does not require intervention thus Tc-99m is continuously produced by the system. The only requirement for a radionuclide generator is for the parent and daughter radionuclides to have distinct chemical properties such that they can be separated easily. In this case, Mo-99 binds more readily with aluminum oxide than Tc99m. Therefore, in the presence of aluminum oxide, Mo-99 and Tc-99m can be separated via a simple elution process. When an isotonic saline solution (0.9% NaCl) is charged into the generator column from the elution vial A, Tc-99m is easily washed-off the column towards the collecting vial B in the form of pertechnetate ion (TcO4-). Collecting vial B provides a vacuum that drives the eluted Tc-99m out of the generator system.

Figure 3. Basic components of a Tc-99 generator

COMPONENTS

Generator column – usually made of glass, it contains a bed of aluminum oxide that serves as support for the parent radionuclide Mo-99. Molybdate will bind strongly with the support medium such that subsequent elution of the daughter radionuclidecan’t wash it off.

Tubing system – holds the eluting solvent and the eluted solution containing the daughter radionuclide. The tubing material requires regulatory approval as it must hold parenteral solutions.

Lead shield – serves as protection for the operator, the glass generator column provides a primary layer of protection but incapable of stopping gamma radiation.

Lead is widely accepted as a highly-effective material providing protection against radiation such as neutron emission, gamma emission and x-ray. It is capable of attenuating radiation intensity due the combination of high atomic mass and short atomic radius. This means that a large amount of electrons is packed closely together to form the lead structure. As a result, incoming radiation is scattered by the lead atoms and with enough thickness, completely blocked. This phenomenon is known as Bremsstrahlung - occurs when a high speed electron traveling in a material is slowed or completely stopped by the forces of any atom it encounters.

Filters – are present in the generator in the form of porous frits which serve to contain the alumina inside the generator column. The usual pore size is 0.22um allowing separation of small particles from the eluate and ensuring its sterility.

Plastic housing covers the entire generator system and contains additional features such as labels, handles or straps to allow mechanical of manual lifting. A cover can also be installed to protect the inlet and outlet needles.

ELUTION PROCEDURE

The procedures for elution in radionuclide generator systems are intended for the production of sterile, pyrogen-free eluate either parenteral use or for elaboration into other radiopharmaceutical preparations. Technetium generators are widespread in the market thus many variations are available. This may entail differences in the precise method of elution but the general principles will apply to all designs.

Common generator set inclusions:

  • Sterile isotonic saline solution used as the eluent
  • Sterile evacuated vials of various sizes
  • Sterile needles
  • Sterile wipes
  • Elution vial shield
  • Finished eluent labels and packing inserts

Basic process of Elution:

  1. Remove the radionuclide generator from its shipping container. In some cases, an auxiliary shield is used to reduce the operator radiation dose.
  2. Insert the eluting solvent into the radionuclide generator.

There are two common variations in generator design related to this step:

  1. Generators with internal saline reservoir – the volume of saline solution contained within the generator system is enough to supply all elutions that will be performed during its lifetime. Hence there is no need to inject a saline solution into the generator.
  2. Generators without internal saline reservoir – ensure the sterility of the system. Wipe the sterile isotonic solution vial with sterile wipes and allow it to dry. Open the inlet spike on the generator and attach the vial by piercing the spike into the vial.
  1. Prepare the sterile evacuated vial of sufficient volume to hold the eluate to be drawn. Place this in the elution vial shield. The shield will absorb radiation produced by the eluate. Wipe the septum (outlet tube) with sterile wipes or alcohol swab and allow to dry. Remove the protective cap of the septum and insert a sterile needle. The elution vial covered with a vial shield is then pierced into the septum. The vacuum provided by the vial will cause the saline solution to be drawn out of the generator system. This step may take a few minutes as the saline solution travels through the generator column. The volume to be collected is controlled by the amount of saline solution injected and the size of the collecting vial used.
  2. Upon filling of the collecting vial, remove it from the generator and re-cap the septum. The vial must be taken into the laboratory for activity assay and quality control tests (i.e. Molybdenum-99 breakthrough test and Aluminum contamination test). Before release for dispensing. Ensure proper labeling and inventory control of the product. Adequate radiation shielding must be maintained at all times.
  3. For subsequent elutions, the same general procedure mentioned is to be followed. Depending on the design of the generator, it may be necessary to replace the eluent vial with a fresh supply of saline solution. The needle used as outlet elution port must be replaced in every elution.

PERFORMANCE INDICATORS OF Mo-99/Tc-99m GENERATOR SYSTEM

The European Pharmacopeia states the following criteria for the evaluation of Technetium radionuclide generator system:

  1. Elution efficiency

This is the fraction of eluted Tc-99m activity of the theoretically-available radioactivity at the time of elution, usually presented as a percentage value. Different generator systems vary in yield but the usual value ranges from 80-100% of the theoretical.

  1. Radionuclidic Purity

The presence of radiation-emitting impurities in the eluate is directly related to the method of production of Mo-99 parent radionuclide (referrer to last section: Production of Mo-99). For irradiation-produced Mo-99, impurities are limited to 0.01% of total radioactivity. Identified impurities include Sn-113, Au-198, Au-199, Cs-134 and Nb-92. Fission-produced Mo-99 on the other hand may contain various impurities listed in the table below with their limits. Regardless of the method of production, Mo-99 serves to be the most significant product contaminant.

                             Table 1. Limits of radionuclidic impurities in the eluate of fission-produced Mo-99

Radionuclide

Limit (%) activity of total radioactivity

Mo-99

1 x 10 -1

I-131

5 x 10 -3

Ru-103

5 x 10 -3

Sr-89

6 x 10 -5

Sr-90

6 x 10 -6

α-emitters

1 x 10 -7

γ- emitters

1 x 10 -2

  1. Radiochemical Purity

The eluate produced from the Mo-99/Tc-99m generator system is sodium pertechnetate in which Tc has an oxidation state of VII. However, six other oxidation states of technetium exists and their presence in the eluate is considered an impurity. The USP has set the standard for pertechnetate purity to not less than 95%.

  1. Chemical Purity

The presence of the ionic form of Aluminum (Al3+) in the eluate is referred to as Aluminum Breakthrough. Aluminum ions (Al3+) are washed off from the column during elution. This is a rare occurrence in generator systems that indicates the breakdown of the generator column containing aluminum oxide.

Every eluate must be checked for aluminum breakthrough because it poses critical changes to radiopharmaceutical preparations which may lead to unwanted uptake of activity (i.e. lung uptake for formulations intended for bone imaging). The following limits were set by the USP for the presence of Al3+ in radionuclide preparations:

  1. Fission-prepared Mo-99 = 10ug/ml
  2. Thermal neutron-activation-prepared Mo-99 = 20ug/ml
  1. pH

pH range allowable for the Tc-99m product is between 4.0 and 8.0. 

 

PERFORMANCE EVALUATION OF Mo-99/Tc-99m GENERATOR SYSTEM

  1. Determination of Elution Efficiency

In practice, Mo-99 activity is provided by the generator supplier as part of pre-calibration of the generator prior to distribution to end-user facilities. However, the time difference between calibration and actual elution may be significant such that there is an observed build-up in the level of Tc-99m activity. Therefore, a test elution must always be performed upon receipt of the radionuclide generator to determine both elution efficiency and Mo-99 content of the eluate.

Determination may be done as follows:

Calculation of available Tc-99m activity

  1.  , indicates parent activity at any time
  2. , indicates daughter activity at any time

where:

A0 = Mo-99 activity at the time of calibration

A1 = Mo-99 activity at time t

A2 = Tc-99m activity at time t, indicates the build-up of daughter activity from zero to maximum with respect to time

λ1 = decay constant of Mo-99 = 0.0105/h

λ2 = decay constant of Tc-99m = 0.1155/h

ATC = Tc-99m activity at any time, this may be used to determine elution yield as follows:

  1. Determination of Radionuclidic Purity

As Mo-99 is the major contaminant for all eluted Tc-99m products, the activity of this radionuclide is required to be determined for all elutions. The measurement is most commonly done using a dose calibrator. This instrument is required in all facilities handling radiopharmaceuticals. The method involves the use of molybdenum shield in measuring the radioactivity of the eluate.

The decay of Mo-99 involves the release of high-energy gamma rays. When the Tc-99m eluate is placed into a metallic Molybdenum shield, lower energy emissions of Tc-99m are absorbed but higher-energy emissions from Mo-99 penetrate the shielding. The dose calibrator will therefore detect radiation that is released only by Mo-99 and consequently determine the Mo-99 activity of the sample.    

  1. Determination of Radiochemical Purity

Descending paper chromatography may be used in the analysis of technetium species present in the eluate. An ethanol-water (8:2) solvent system may be used for this purpose. The chromatogram is developed for 2 hours, dried and measured. The spot that corresponds to pertechnetate ion must contain 95% of the radioactivity. Ascending thin layer chromatography may also be used for analysis where acetone is used as the mobile phase.

  1. Determination of Chemical Purity

Aluminum ions may be readily measured in the eluate via colorimetric methods. A version of the test makes use of a standard aluminum solution to be contrasted with the eluate. For the eluate to pass the test, it must produce a spot with a colors that are less intense than the standard.

  1. pH Determination

pH of the eluate may be easily determined using a pH meter.

PRODUCTION OF Mo-99

  1. Reactor neutron activation of Mo-98

This method of manufacture makes use of non-reactive Mo-98 which is placed inside a nuclear reactor and irradiated by a flux of neutrons. The neutrons will enter the nucleus of Mo-98 and alter its structure to produce Mo-99. The process renders the product neutron-rich which entails that the isotope will decay via release of beta particles.

Neutron activation is a straight forward process and produces a well-defined product that does not require extensive processing before it can be used as a source of Tc-99m. However, this reaction is not widely-used in the industry for several reasons:

  • Molybdenum has 7 naturally-occuring isotopes and the availability of a pure isotope is difficult to achieve
  • Only a small portion of Mo-98 atoms are actually converted to Mo-99 during irradiation. The product will therefore be a combination of Mo-99 and Mo-98 which cannot be practically separated.
  1. Fission of Uranium-235

Fission occurs as a mechanism whereby an unstable nucleus splits to two smaller nuclei releasing energy in the process. Fission may be induced from U-235 by bombardment of neutrons. A neutron enters the nuclei of a stable U-235 atom to form U-236 which is very unstable. U-236 almost instantaneously decays by fission to produce two nuclei with the subsequent release of free neutrons. This process also produces energy in the form of heat which becomes the source of energy in nuclear reactors. In this case, the interest is in the nuclei that are formed. A mixture of nuclei will be present as product of the fission reaction. Just like the neutron-activation this method poses some disadvantages:

  • Enriched U-235 foils used in production are expensive.
  • U-235 can be used for the production of nuclear weapons therefore a highly-secured facility is required for housing the isotope.
  • Manufacturer will have to address multiple issues with containment and disposal
  • The product is expected to have higher amounts of impurities such as but not limited to I-131, Ru-103, Cs-134, Cs-137, Rb-86, Co-68, Sb-124, te-132, Ag-112, Pd-112, Sr-89 and Sr-90.

 

REFERENCES

Hobbie, Russell K., 1988. Intermediate Physics for Medicine and Biology, 2nd ed. Wiley: USA.

International Atomic Agency, 2016. Virtual Course in Radiopharmacy. Available online at https://humanhealth.iaea.org/HHW/Radiopharmacy/VirRad/index.html

Lead Industries Association Inc. A guide to the use of lead for radiation shielding. Available online at http://www.canadametal.com/wp-content/uploads/2016/08/radiation-shielding.pdf