Mo99 - Tc99m Generator

Issues of Concern

Basic Characteristics

One of the indispensable characteristics of an ideal radiopharmaceutical is a short half-life. Larger doses could be used with minimal radiation burden to the patient for better imaging quality. Besides, the radionuclide produced should have high specific activity with minimal impurities.[1] The radionuclide should be easily labeled with an appropriate pharmaceutical, such as a peptide, colloid, or ligand. These essential characteristics are satisfied by a generator system involved in producing 99m-Tc with excellent radiation characteristics. Tucker and Greene developed the first Tc-99m generator in 1958. In 1960, Richards used it as a medical tracer for the first time.[2][3][4]

When a freshly loaded generator is first eluted, only the Tc-99m formed since the time of loading is extracted. However, because Tc-99m is continually generated from the decay of Mo-99, generator activity regenerates over time. Maximum yield is typically achieved by eluting approximately 23 to 24 hours after the previous elution, when transient equilibrium between Mo-99 (half-life: 66 hours) and Tc-99m (half-life: 6 hours) has been reached. Eluting at shorter intervals reduces Tc-99m activity due to incomplete regeneration. However, elution can be carried out more than once a day for emergency studies since 50% of the maximum activity is reached within 4 to 5 hours of initial elution.[5] This elution pattern reflects the kinetics described by the Bateman equations, which govern the activity of a daughter radionuclide in relation to its parent. The generator column consists of approximately 5 to 10 g of acid-washed aluminum oxide (Al₂O₃), onto which fission-produced Mo-99 is adsorbed.[6] Tc-99m is extracted into an evacuated vial using 0.9% normal saline without removing molybdenum, colloquially known as moly cow (milking), through column chromatography. This process is also defined as an elution.[7] The eluate, sodium pertechnetate (TcO4−) volume is about 2 to 3 mL and expires in 12 hours.

Types of Generators

Two types of generators are available commercially—wet and dry type systems. The wet system has a 0.9% normal saline reservoir, and the eluate is accumulated in a particular sterile evacuated vial at a collection port. In contrast, a dry system is commonly available in imaging laboratories and has 2 ports for elution and evacuated vials.[8]

Theoretical Yield of Technetium-99m

The level of Tc-99m varies due to both growth and decay effects. The radioactive decay is continuous within the generator system. A transient equilibrium is attained as the half-lives of Mo and Tc differ by a factor of 11. Approximately 87% of molybdenum decays into 99m-Tc and 13% into stable Tc-99 (2.1×10⁵ years). Subsequently, 99m-Tc decays to Tc-99 by isomeric transition with the emission of 140-KeV gamma rays.[9]

Although 99-Tc and 99m-Tc have similar physical and chemical properties, they differ in labeling efficiency. Nevertheless, it is not problematic from a health standpoint.[10]

In certain clinical situations, particularly for add-on emergency studies, estimating the theoretical yield of 99m-Tc from a Mo-99 generator may be necessary at a specific time. The yield can be calculated using the following equation:

• A_Tc = 0.957(A_Mo)i [e^−0.0105t − e^−0.1155t] + [(A_Tc)i (e^−0.1155t)] [11]

Because molybdenum has a half-life of 66 hours (2.8 days), a generator can be used for up to 2 weeks.

Institutional set-ups often utilize this calculation to purchase an appropriately sized generator to calculate enough residual activity on the last day of the workweek.[12]

Clinical Significance

Quality Control of Technetium-99m Eluate with Clinical Implications

Before administering radiopharmaceuticals to patients, performing quality check steps with every elution is mandatory. This additional step results in minimal radiation exposure with maximum clinical benefit. The chances of having impurities in an eluate increase when elution is not carried out daily.[13] Some of the most common impurities are discussed briefly below.

Molybdenum-99 breakthrough/radionuclide impurity: Mo-99 breakthrough typically occurs as the generator nears expiry date, when Mo-99 contamination may be eluted with 99m-Tc. However, the determination of Moly's breakthrough is inescapable with every elution. The United States Pharmacopeia's standard limit is less than 0.15 µCi of Mo-99 per mCi of 99m-Tc at the administration time, which can be easily calculated by placing a generator equivalent in the lead container designed only to detect energetic 740-KeV and 780-KeV gamma rays of Mo-99.[14] The particulate emissions (beta−) by 99m-Mo can be detrimental to a patient's health in the long run due to a longer half-life.

Additional radionuclide contamination tests are typically conducted by the manufacturer.[15]

Table 1. Important Critical Contaminants with Safe Permissible Limits

Reference for the table.[16]

Aluminum breakthrough/chemical impurity: The alumina column in the generator bed contributes to contamination, especially when preparing 99m-Tc-labeled sulfur colloid for lymph nodes studies.[17] The former interferes with its preparation and leads to the precipitation of colloids. Besides, it affects the distribution of radiopharmaceuticals. There is an increased lung activity with 99m-Tc sulfur colloid in an aluminum-containing eluent and increased liver uptake with 99m-Tc-methylene diphosphonate. Agglutination of 99m-Tc-labeled red blood cells is another issue encountered with aluminum. The standard limit is less than 10 µg/mL, measured using a qualitative spot test with aurin tricarboxylic acid.[18]

Radiochemical impurity: Pertechnetate exhibits a varied range of valency, between −1 and +7, depending on pH and the presence of a reducing or an oxidizing agent. Sodium pertechnetate (TcO⁻₄) is the desired form with a valency of +7. Other reduced oxidation states, such as +4, +5, or +6, are called radiochemical impurities and are detected using thin-layer chromatography. Although infrequent, determining these radiochemical impurities is often considered if labeling has a low yield. More than or equal to 95% of 99m-Tc activity should be in the +7 oxidation state for ideal labeling with a pharmaceutical.[19]

Clinical Applications of Technetium-99m

The radionuclide Tc-99m is widely used for imaging techniques, including:

• Cardiac imaging: Radiopharmaceuticals such as Tc-99m-sestamibi and Tc-99m-tetrofosmin are commonly used in myocardial perfusion scans,  a type of nuclear medicine scan performed using single-photon emission computed tomography.[20]
• Bone scans: Tc-99m-labeled diphosphonates, such as Tc-99m-methylene diphosphonate, detect metastases, fractures, or infections.[21]
• Lung scans: Tc-99m macroaggregated albumin is utilized in perfusion/ventilation scans for pulmonary embolism.
• Infection and inflammation imaging: Radiopharmaceuticals such as Tc-99m-citrate and Tc-99m-antibiotics are used to detect sites of infection and inflammation.[22]
• Hepatobiliary imaging: Tc-99m-labeled iminodiacetic acid derivatives are used to assess hepatobiliary function and diagnose acute cholecystitis.
• Renal imaging: Tc-99m-mercaptoacetyltriglycine and Tc-99m-diethylenetriaminepentaacetic acid are used in assessing renal perfusion and excretion function.
• Brain imaging: Tc-99m is used in brain perfusion imaging to assess cerebral blood flow in conditions such as stroke and epilepsy. Tc-99m-hexamethylpropylene amine oxime and Tc-99m-ethyl cysteinate dimer are commonly used agents.[23]

Disposal of Molybdenum-Technetium Generator

After the use of a molybdenum-technetium generator in clinical settings to produce Tc-99m from Mo-99, the generator must be disposed of according to regulatory guidelines to ensure safety and compliance. The disposal process involves 4 essential steps, which are as follows:

• Decay in storage: The generator should be stored until its radioactivity decays to safe levels. Federal regulations typically require storage for a period equivalent to 10 half-lives of the longest-lived radioactive material in the generator. For 99Mo, with a half-life of 66 hours, this corresponds to approximately 660 hours or 28 days. This process ensures that 99Mo and its daughter products decay to background levels before disposal.[24]
• Label removal: All labels indicating Caution—Radioactive Material must be removed from the generator before disposal with regular medical waste.
• Compliance with regulations: Disposal must comply with the Nuclear Regulatory Commission regulations. 
• Radioactive waste management: If the generator still contains residual radioactivity, it should be managed as low-level radioactive waste. This process requires adherence to institutional protocols for radioactive waste disposal, which may include transferring the waste to a licensed radioactive waste disposal facility.[25][26]

Nursing, Allied Health, and Interprofessional Team Interventions

The generator plays a central role in nuclear medicine imaging and therapeutics. Despite various advancements over the years, its function continues to rely on the fundamental principle of column chromatography. With an increasing number of generator manufacturers entering the market, there is a need to standardize safe permissible impurity limits to minimize unnecessary radiation exposure to healthcare professionals and patients. In addition, there is a need to explore alternatives to 99m-Tc due to a global shortage of Mo-99.[27]