Technetium Generator and Safe use of radiopharmaceuticals. By T. R. B.

Technetium 99m generator and safe use of radiopharmaceuticals with brief introduction of the radioactivity cyclotron and nuclear reactor.

1. Technetium 99m Generator Thumba Raj Baruwal Roll No. :162

2. Key Factors Affecting Nuclear Stability Neutron-to-Proton Ratio (N/Z Ratio): Light Nuclei: For light elements (with atomic numbers up to around 20), stable nuclei generally have a neutron-to-proton ratio (N/Z) close to 1:1. Heavy Nuclei: As the atomic number increases, stable nuclei require more neutrons than protons to counteract the increasing electrostatic repulsion between protons. For heavy elements, the stable N/Z ratio is closer to 1.5:1.

3. Binding Energy The binding energy per nucleon is a measure of the stability of a nucleus. It is the energy required to separate the nucleus into individual protons and neutrons. Nuclei with higher binding energy per nucleon are more stable. The binding energy curve shows that iron-56 and nickel-62 have the highest binding energies, making them among the most stable nuclei.

4. Radioactivity Radioactivity is the process by which unstable atomic nuclei lose energy by emitting radiation. This phenomenon occurs naturally in certain elements and can also be induced artificially. The emitted radiation can be in the form of particles or electromagnetic waves, and the process results in the transformation of the original nucleus into a different nucleus or a different energy state.

5. Decay Scheme

6. Artificial Radioactivity Artificial radioactivity, also known as induced radioactivity, is the process by which stable nuclei are transformed into radioactive nuclei through artificial means, typically by bombarding them with particles such as neutrons, protons, or alpha particles.

7. Process of Artificial Radioactivity Particle Bombardment: A stable nucleus is bombarded with a particle (neutron, proton, or alpha particle), which can be introduced using a particle accelerator or a nuclear reactor. Nuclear Reaction: The interaction between the incoming particle and the target nucleus results in a nuclear reaction, creating an unstable (radioactive) nucleus. Decay of Radioactive Isotope: The newly formed radioactive nucleus undergoes radioactive decay, emitting radiation until it reaches a stable state.

8. Cyclotron-Produced Radionuclides Cyclotrons produce radionuclides by bombarding stable nuclei with high-energy charged particles. Positively charged ions such as protons ,deuterons ,and alpha particles as well as negatively charged hydrogen ions (H-) are commonly used to produce radionuclides used in medicine. Charged particles must be accelerated to high kinetic energies to overcome and penetrate the repulsive coulombic barrier of the target atoms’ nuclei.

9. Fig : Schematic diagram of cyclotron.

10. Cyclotron A cyclotron has a vacuum chamber between the poles of an electromagnet. The vacuum chamber is a pair of hollow, semicircular electrodes, each shaped like the letter D and referred to as dees . The two dees are separated by a small gap. An alternating high voltage is applied between the two dees. When positive ions are injected into the center of the cyclotron they are attracted and accelerated toward the negatively charged dee. The static magnetic field constrains the ions to travel in a circular path, whereby the radius of the circle increases as the ions gain kinetic energy.

11. Cyclotron Half way around the circle, the ions approach the gap between the dees; at this time, the polarity of the electrical field between the two dees is reversed, causing the ions to be accelerated toward the negative dee. This cycle is repeated again and again, with the particles accelerated each time they cross the gap, acquiring kinetic energy and sweeping out larger and larger circles. As the length of the path between successive accelerations increases, the speed of the particle also increases; hence, the time interval between accelerations remains constant. The cyclic nature of these events led to the name cyclotron.

12. Cyclotron The final kinetic energy achieved by the accelerated particles depends on the type of particle diameter of the dees, and the strength of the static magnetic field. As the ions reach the periphery of the dees, they are removed from their circular path by a negatively charged deflector plate (if positive ions are accelerated) or electron stripping foil (if H-)ions are accelerated), emerge through the window, and strike the target. Depending on the design of the cyclotron, particle energies can range from a few million electron volts (MeV) to several hundred MeV.

13. Cyclotron The accelerated ions collide with the target nuclei, causing nuclear reactions. An incident particle may leave the target nucleus after interacting, transferring some of its energy to it, or it may be completely absorbed. For example :68Zn (p,2n) 67Ga. where the target material is zinc-68 (Zn-68), the bombarding particle is a proton (p) accelerated to approximately 20 MeV, two neutrons (2n) are emitted, and Ga-67 is the product radionuclide. Most cyclotron-produced radionuclides are neutron poor and therefore decay by positron emission or electron capture. The production methods of several cyclotron-produced radionuclides important to nuclear medicine.

14. Nuclear Reactor –Produced Radionuclides Nuclear reactors are another major source of clinically used radionuclides. Neutrons, being uncharged, have an advantage in that they can penetrate the nucleus without being accelerated to high energies. There are two principal methods by which radionuclides are produced in a reactor: Nuclear fission Neutron activation.

15. This Photo by Unknown Author is licensed under CC BY-SA-NC

16. Nuclear Reactor

17. Fig: Fission Yield of Molybdenum from Uranium

18. Beta-Minus (Negatron) Decay

19. Molybdenum Decay Scheme

20. Radionuclide Generators Radionuclide generators are devices used to produce short-lived radioactive isotopes from longer-lived parent isotopes, essential in various fields like medicine, industry, and research. These generators allow for the on-demand, site-specific production of isotopes, enhancing convenience and safety by reducing the need to handle highly radioactive materials directly. The continuous decay of the parent isotope within the generator ensures a steady supply of the daughter isotope, making these devices highly valuable in clinical and industrial settings. Radionuclide generators also contribute to cost efficiency by minimizing the need for frequent shipments of radioactive materials, thus optimizing resource utilization and operational logistics.

21. Radionuclide for Imaging In evaluating the choice of a radionuclide to be utilized in the nuclear medicine laboratory, the following characteristics are desirable: Minimum of particulate emission . Primary photon energy between 50 and 500 Kev. Physical half life greater than the time required to prepare material for injection. Effective half life longer than the examination time. Suitable chemical form and reactivity. Low toxicity. Stable or near stability of the product. Should remain sterile and pyrogen free.

22. Chemistry of Technetium Technetium is a transition metal of silvery gray color belonging to group VIIB (Mn, Tc, and Re) and has the atomic number 43. No stable isotope of technetium exists in nature. The electronic structure of the technetium atom is 1s2 2s22p63s23p63d104s24p64d6 5s1. Technetium can exist in eight oxidation states, namely, -1 to +7. The +7and +4 states are most stable and exist in oxides, sulfides, halides, and pertechnetates.

23. Introduction to Tc99m Technetium 99m fulfills earlier criteria of ideal radionuclide and accounts for over 70% of nuclear imaging procedures. Technetium-99m when used as radioactive tracer can be detected in the body by medical equipment such as gamma cameras. It is well suited to its role because it emits readily detectable 140kev gamma rays and a half life of 6 hrs.

24. Decay Scheme of Tc99m

25. Fig: Different components of Tc 99m generator

26. 1. Glass Column : This column contains an alumina column where the molybdate (Mo-99) is bound. When a saline solution is passed through the column, Tc-99m is eluted, separating it from Mo-99. 2. Needles : These are used for introducing the saline solution and collecting the eluted Tc-99m. One needle is typically for input (saline) and the other for output (Tc-99m solution). 3. Lead Shielding :Provides radiation protection to the user by absorbing the gamma rays emitted by Mo-99 and Tc-99m, ensuring safe handling of the radioactive materials.

27. 4. Bacteriological Filter :Ensures that the saline solution used for elution is sterile, preventing contamination of the eluted Tc-99m. 5. Volume Controller : Regulates the volume of saline solution that passes through the glass column, ensuring proper elution of Tc-99m and preventing overflow or underflow. 6. Bushing : Provides a secure fitting for the needles, ensuring they are properly aligned and connected to the glass column and other components. 7. Shielded Container : Houses the Mo-99 and the entire elution system, providing additional radiation shielding and structural support.

28. Column Rubber stopper : This component ensures a tight seal, preventing any leaks or contamination of the column. Glass Wool : This layer is used to distribute the saline evenly and act as a preliminary filter to remove any large particulates. Silica Gel : This layer absorbs moisture and prevents it from reaching the other components , which is crucial for maintaining the effectiveness of the column’s materials.

29. Column Band of 99Mo: Molybdenum99 is the parent radionuclide, which decays to produce Tc-99m . Alumina: This adsorbs free molybdenum-99 to minimize its breakthrough into eluate. Glass Filter : This filter retains aluminum oxide particulates, preventing them from being carried over into the eluate.

30. Working of Tc-99m Generator In a molybdenum-99/technetium-99m radionuclide generator, Mo-99 (produced by nuclear fission of U-235 to yield a high-specific-activity, carrier-free parent) is loaded in the form of ammonium molybdenate (NH4+)(MoO4 -), onto a porous column containing 5 to 10 g of an alumina (Al2O3) resin. The ammonium molybdenate becomes attached to the surface of the alumina molecules ,a process called adsorption. The porous nature of the alumina provides a large surface area for adsorption of the parent.

31. Working of Technetium-99m Generator In the Mo-99/Tc-99m or moly generator, the Tc-99m is much less tightly bound than the Mo-99. The daughter is removed (eluted) by the flow of isotonic 0.9%saline (eluant) through the column. When the saline solution is passed through the column, the chloride ions easily exchange with the TcO4-but not the MoO4- ions, producing sodium pertechnetate, Na+(99mTcO4-). Technetium-99m pertechnetate (99mTcO4-) is produced in a sterile, pyrogen-free form with high specific activity and a pH (~5.5) that is ideally suited for radiopharmaceutical preparations.

32. Working Technetium-99m Generator Commercially moly generators have a large reservoir of oxygenated saline (the eluant) connected by tubing to one end of the column and a vacuum extraction vial to the other. On insertion of the vacuum collection vial (contained in a shielded elution tool), saline is drawn through the column and the eluate is collected during elution which takes about 1 to 2 min. Sterility is achieved by a millipore filter connected to the end of the column, by the use of a bacteriostatic agent in the eluant, or by autoclave sterilization of the loaded column by the manufacturer.

33. Working of Technetium-99m Generator Moly generators are typically delivered with approximately 37 to 740 GBq (1 to 20 Ci) of Mo-99, depending on the workload of the department. The larger activity generators are typically used by commercial radiopharmacies supplying radiopharmaceuticals to multiple nuclear medicine departments. The generators are shielded by the manufacture with lead, tungsten or in the case of higher activity generators depleted uranium. Additional shielding is typically placed around the generator to reduce the exposure of staff during elution.

34. The Activity of daughter depends on The activity of the parent. The rate of formation of the daughter, which is equal to the rate of decay of the parent. The decay rate of the daughter. The time since the last elution. The elution efficiency (typically 80% to 90%).

35. Fig :Activity curve for generators

36. Transient Equilibrium Between elutions , the daughter (Tc-99m) builds up or grows in as the parent (Mo99) continues to decay. After approximately 23 h, the Tc-99m activity reaches a maximum, at which time the production rate and the decay rate are equal and the parent and daughter are said to be in transient equilibrium. Once transient equilibrium has been achieved, the daughter activity decreases, with an apparent half-life equal to the half-life of the parent. Transient equilibrium occurs when the half-life of the parent is greater than that of the daughter by a factor of approximately 10

37. Transient Equilibrium In the general case of transient equilibrium, the daughter activity will exceed the parent at equilibrium. If all of the (Mo-99) decayed to Tc-99m, the Tc-99m activity would slightly exceed (~10% higher) that of the parent at equilibrium. However, approximately 12% of Mo-99 decays directly to Tc-99 without first producing Tc-99m, Therefore, at equilibrium, the Tc-99m activity will be only approximately 97% that of the parent (Mo-99) activity.

38. Secular Equilibrium When the half-life of the parent is much longer than that of the daughter (i.e., more than about 100 times longer), secular equilibrium occurs after approximately five to six half-lives of the daughter. In secular equilibrium, the activity of the parent and the daughter are the same if all of the parent atoms decay directly to the daughter.

39. Fig : Time activity curve demonstrating secular equilibrium

40. Liquid Column Generator 99mTc is extracted with methyl ethyl ketone (MEK) from a 20% NaOH solution of pH (10–12) of 99Mo. After extraction, the organic phase was evaporated and the 99mTcO4- is dissolved in isotonic saline for clinical use. The basic principle involves placing the 20% NaOH solution of 99Mo in a glass column and then letting MEK flow through the column from the bottom. MEK will extract 99mTcO4- leaving 99Mo in the aqueous solution. The advantage of this generator is that the cost of 99mTc is low. But the disadvantage is that it needs a lot of manipulation in the overall method.

41. Solid Column Generator Moly generator is constructed with alumina (Al2O3) loaded in a plastic or glass column. There are two types of Moly generators, wet column generators and dry column generators, supplied by different commercial firms. In a dry column generator after routine elution the leftover saline in the column is drawn out by using an evacuated vial without adding any more saline. The suggestion for a dry column generator came from the fact that radiation can cause radiolysis of water in a wet generator resulting in the formation of hydrogen peroxide (H2O2)and per hydroxyl free radical.

42. Hot Lab Hot labs, also known as radio pharmacy laboratories, are specialized facilities designed for the preparation, handling, and dispensing of radiopharmaceuticals. Which include: Lead-lined workstations and fume hoods for shielding and containment . Radiation monitoring tools like Geiger counters and dosimeters, with strict safety protocols . Cleanrooms and laminar flow hoods for ensuring sterility. Specialized equipment like synthesis modules and dose calibrators for precise preparation . Radioactive waste containers and decay storage for safe waste management

43. Hot Lab

44. Dose Calibrators The dose calibrator is one of the most essential instruments in nuclear medicine for measuring the activity of radionuclides for formulating and dispensing radiopharmaceuticals. s. It is a cylindrically shaped, sealed chamber with a central well and is filled with argon and traces of halogen at high pressure. Its operating voltage is about 150 V. current produced by 1 mCi (37 MBq) 99mTc is different from that by 1 mCi (37 MBq) 131I. Isotope selectors are the feedback resistors to compensate for differences in ionization (current) produced by different radionuclides so the equal activities produce the same reading.

45. Dose Calibrators In most dose calibrators, the isotope selectors for commonly used radionuclides are push-button types, whereas those for other radionuclides are set by a continuous dial. The settings of isotope selectors are basically the calibration factors for different radionuclides, which are determined by measuring the current produced by one millicurie of each radionuclide. The unknown activity of a radionuclide is then measured by its current divided by the calibration factor for that radionuclide, which is displayed in the appropriate unit on the dose calibrator.

46. Dose Calibrators For measurement of the activity of a radionuclide, one first sets the calibration factor for the radionuclide using the appropriate push button or dial setting. Then the sample in a syringe, vial, or any other appropriate container is placed inside the chamber well of the dose calibrator. The reading of activity is displayed on the digital meter of the dose calibrator

47. Dose Calibrators

48. 99Mo Breakthrough This is 99Mo contamination in the 99mTc-eluate and originates from the small quantity of 99Mo that may be eluted with 99mTc. The 99Mo contamination is measured by detecting 740-keV and 780-keV photon The eluate vial is shielded in a lead pot (about 6 mm thick) to stop all 140-keV photons from 99mTc and to count only 740-keV and 780-keV photons from 99Mo . US pharmacopeia limit 0.15 micro Ci 99Mo/ mCi (0.15 kBq /MBq) 99mTc per administered dosage at the time of administration.

49. Aluminum Breakthrough The aluminum contamination originates from the alumina bed of the generator. The presence of aluminum in the 99mTc-eluate interferes with the preparation of 99mTc-sulfur colloid. Aluminum may causes RBC agglutination. USP limit is s 10 micro gram Al/ml 99mTc for fission-produced 99Mo. The presence of aluminum can be detected by the colorimetric method using aurin tricarboxylic acid or methyl orange, and can be quantitated by comparison with a standard solution of aluminum.

50. Safe handling and use of radiopharmaceuticals Radiopharmaceuticals are radiation emitting substances used in medicine for radiotherapy and imaging diagnosis. The main motto is to establish procedures to minimize the exposure to personnel preparing and administering radiopharmaceuticals , and to ensure safety for the general public. ALARA , principle should be followed by specialist to carefully select the amount of radiopharmaceutical that would provide an accurate test with least amount of radiation exposure to patient. The introduction of DRL can probably help the optimization of radiation protection in nuclear medicine.

51. Attire Protective clothing , disposable gloves should be used entire time while handling radioactive materials. If compounding a multi-dose kit, appropriate attire as outlined in policies for compounding of sterile pharmaceuticals.

52. Product preparation Use appropriate kit vial shields when compounding radiopharmaceuticals. Use syringe shields for reconstitution of radiopharmaceutical kits and administration of radiopharmaceuticals to patients, except when their use is contraindicated (e.g., recessed veins, infants). Use tongs, when possible, when manipulating syringes during compounding or assaying . Do not eat, store food, drink, smoke, or apply cosmetics in any area where licensed materials is stored or used. Never pipette by mouth.

53. Product labelling The name of product, radionuclide , product identification code, name of manufacturer, id no(batch no) should be mentioned. For liquid preparations, the total radioactivity in the container, or radioactive conc. per ml ,at a stated date and if necessary hour and volume in container. For solid preparations such as freeze dried preparations the total radioactivity at a stated date and if necessary hour.

54. Product labelling For capsules, the radioactivity of each capsule at a stated date and if necessary hour and no of capsules in the container . In addition, the label on package should state: Qualitative and quantitative composition. The route of administration. Expiry date. Any special storage condition. Package labels

55. Product Dose Verification For prepared dosages, assay each patient dosage in the dose calibrator (or instrument) before administering it . Verify that the activity falls within the acceptable range, as defined in the study protocol.

56. Monitoring of Employee radiation exposure After each procedure, or before leaving the area, monitor your hands for contamination in a low-background area using an appropriate survey instrument. Wear personnel monitoring devices, if required, at all times while in areas where radioactive materials are used or stored. Wear extremity dosimeters, if required, when handling radioactive material.

57. Monitoring and surveying for radioactive materials Wipe-test unsealed radioactive material storage, preparation, and administration areas weekly for contamination. If necessary, decontaminate the area. Survey with a radiation detection survey meter all areas of licensed material use, including the generator storage, kit preparation, and injection areas daily for contamination .If necessary, decontaminate the area. Areas used to prepare and administer radiopharmaceutical therapies must be surveyed daily (except when administering therapy dosages in patients’ rooms when patients are confined). Store radioactive solutions in shielded containers that are clearly labeled.

58. Disposal of radioactive waste : Dispose of radioactive waste only in designated, labeled, and properly shielded receptacles. Disposal of radioactive waste into a shielded container

59. Spill and Accident It is the most common radiation emergency that occur in a nuclear medicine facility. In case of spill instruction following measures should be taken: Clear the area- notify all the person present to vacate the area. Notify- report the incident to the supervisor. Prevent spread-cover the spread absorbent pad. Call for assistance- secure the area and request the assistance from the radiation safety officer.

60. cushioned for transport Package survey

61. References The Essential Physics of Medical Imaging 3 rd Edition. Chat GPT.

62. THANK YOU.