Definition/Introduction

Radionuclide production is a crucial component in nuclear imaging and therapeutic modalities. More than 90% of its production is used for diagnostic purposes. The majority of the radionuclides are produced in a nuclear reactor and a cyclotron. However, it is impractical to set up an imaging laboratory near a nuclear reactor or a cyclotron; therefore, a generator serves as a convenient system for on-site production and extraction of commonly used radionuclides such as 99m-Tc (6 hours) from its parent nuclide molybdenum 99 (66 hours). Other less widely used generator systems include 132-Te (3.2 days)/132-I (2.3 hours), 68-Ge (271 days)/ 68-Ga (68 minutes).

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 the production of 99m-Tc with excellent radiation characteristics. Tucker and Greene developed the first technetium-99m generator in 1958. In 1960, it was used as a medical tracer for the first time by Richards.[2][3][4]

The generator consists of an alumina (Al2O3) anion exchange cylindrical column with fission-produced Mo-99 adsorbed onto it, contained within a lead shield for radiation protection. Lead blocks the gamma (Tc) and beta- (Mo) radiations. Around 5-10 g of alumina is used in the column.[5] Technetium-99m is extracted in an evacuated vial using 0.9% normal saline without removing Mo, through column chromatography, colloquially known as moly cow (milking). This is also defined as an elution.[6] 

After every 23 hours, the maximum activity of 99m-Tc is obtained. It gradually builds up according to the radioactive decay of molybdenum. Therefore, in most laboratories, elution is usually carried out every 24 hours to increase the generator's efficiency. However, elution can be carried out more than once a day for emergency studies since 50% of the maximum activity is reached with 4-5 hours of initial elution.[7] The eluate, sodium pertechnetate (TcO4-) volume is about 2-3 ml and has an expiration period of 12 hours.

Types of Generator

There are two types of generators 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 at imaging labs and has two ports for elution and evacuated vials.[8]

Theoretical yield of 99m-Tc

The level of technetium-99m varies according to 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 x 10^5years). Also, 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]

Sometimes, it becomes prudent to calculate the theoretical yield of 99m-Tc for add-on emergency studies. Equation 1 provides a theoretical yield of 99m-Tc via the Molybdenum generator at a given time. 

• ATc = 0.957(AMo)i [e^-0.0105t - e^-0.1155t] + [(ATc)i (e^-0.1155t)] (Eq. 1)[11]

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

This calculation is often employed by institutional set-up to purchase an appropriately sized generator to calculate enough residual activity on the last day of the workweek.[12]

Clinical Significance

Quality Control of 99m-Tc Eluate with Clinical Implications

Before administering radiopharmaceuticals to patients, it is mandatory to perform quality check steps with every elution. 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 below in brief.

Mo-99 Breakthrough/Radionuclide Impurity

This usually happens near the generator's expiry date, when Mo-99 contamination may be eluted with 99m-Tc. However, the determination of Moly's breakthrough is inescapable with every elution. USP's standard limit is less than 0.15 microCi 99-Mo/ mCi 99m-Tc at the administration time, which can be easily calculated by placing a generator equate in the lead container designed only to detect energetic 740-KeV and 780-KeV gamma rays of 99-Mo.[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.

The manufacturer usually performs other radionuclides contamination tests.[15]

Table 1 shows some important critical contaminants with safe permissible limits.[16]

Aluminum Breakthrough/Chemical Impurity

 The alumina column in the generator bed contributes to its contamination, especially when preparing 99m-Tc labeled sulfur colloid for lymph nodes study.[17] The former interferes with its preparation and leads to the precipitation of colloid. Besides, it affects the distribution of radiopharmaceutical. There is an increased lung activity with 99m-Tc sulfur colloid in an aluminum-containing eluent and increased liver uptake with 99m-Tc-MDP. Agglutination of 99m-Tc labeled RBCs is another issue encountered with aluminum. The standard limit is less than 10 micrograms/mL, measured using a qualitative spot test utilizing aurin tricarboxylic acid.[18]

Radiochemical Impurity

The pertechnetate exhibits a varied range of valency, between -1 to +7, depending upon pH, presence of a reducing, or an oxidizing agent. Sodium pertechnetate (TcO4-) is the desired form with a valency of +7. Other reduced oxidation states such as +4, +5, or +6 are called radiochemical impurities detected by thin-layer chromatography. Although infrequent, the determination of 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]

Nursing, Allied Health, and Interprofessional Team Interventions

The generator plays a central role in nuclear medicine imaging and therapeutics. Though multiple modifications have been made in the past years, they rely on a simple column chromatography technique. As more and more generator manufacturers are coming up in the market, there is a need to standardize safe permissible impurities limits to eliminate unnecessary radiation exposure to the healthcare workers and the patients. Also, there is a need to look up alternatives of 99m-Tc due to a global shortage of Molybdenum-99.[20]