7.3 Generator Quality Control & Breakthrough Testing

Generator Quality Control & Breakthrough Testing

Before the sodium pertechnetate eluate from a Mo-99/Tc-99m generator can be administered to patients or used to prepare other radiopharmaceuticals, it must undergo strict quality control (QC) testing. These tests ensure the eluate is pure, safe, and meets regulatory standards set by the Nuclear Regulatory Commission (NRC) and the United States Pharmacopeia (USP). The three primary QC tests are for radionuclidic purity (Mo-99 breakthrough), chemical purity (Aluminum breakthrough), and pH.

Radionuclidic Purity: Mo-99 Breakthrough

Radionuclidic purity refers to the proportion of the total radioactivity that is in the form of the desired radionuclide. In the context of a generator, we must verify that the alumina column successfully held onto the parent Mo-99 and that an unacceptably high amount did not wash off into the eluate. The presence of Mo-99 in the eluate is called Mo-99 breakthrough.

Mo-99 is an impurity that delivers an unnecessary and significant radiation dose to the patient (due to its long half-life and energetic beta emissions) without providing any diagnostic value.

Testing Procedure

The test exploits the different photon energies of Mo-99 and Tc-99m. Mo-99 emits highly energetic gamma rays (e.g., 740 keV and 780 keV), while Tc-99m emits much lower energy gamma rays (140 keV).

1. The technologist places the unshielded vial of generator eluate into a specialized, thick lead container known as a "Moly shield" or Mo-99 assay shield.
2. This shield is thick enough to completely absorb all of the 140 keV photons from Tc-99m, but it allows a portion of the high-energy Mo-99 photons to pass through.
3. The shielded vial is placed into the dose calibrator, which is set to the Mo-99 setting. The calibrator measures the Mo-99 activity in microcuries ($uCi$).
4. Next, the vial is removed from the lead shield and assayed on the Tc-99m setting to determine the total Tc-99m activity in millicuries ($mCi$).

Regulatory Limits and Calculation

The NRC and USP have established a strict limit for Mo-99 breakthrough: Limit: 0.15 $uCi$ of Mo-99 per 1 $mCi$ of Tc-99m at the time of administration.

Important consideration regarding decay: Because Tc-99m decays much faster (6 hours) than Mo-99 (66 hours), the ratio of Mo-99 to Tc-99m increases over time. An eluate that barely passes the test at 8:00 AM may fail the test by 12:00 PM. Therefore, the ratio must be calculated not just at the time of elution, but projected to the latest possible time of patient administration.

Calculation Formula: Ratio = (Mo-99 activity in $uCi$) / (Tc-99m activity in $mCi$) If a 400 $mCi$ elution contains 20 $uCi$ of Mo-99, the ratio is 20/400 = 0.05 $uCi/mCi$, which is well below the limit and passes.

Chemical Purity: Aluminum Breakthrough

Chemical purity refers to the fraction of the total mass of the desired chemical form. For the generator, we must ensure that the alumina ($Al_2O_3$) core did not break down or dissolve into the eluate during the elution process. The presence of aluminum ions ($Al^{3+}$) is known as Aluminum breakthrough.

Excess aluminum in the eluate can interfere with the chemical tagging of radiopharmaceuticals. For example, it can cause the formation of colloidal Tc-99m particles in sulfur colloid kits, leading to unwanted lung uptake. It can also cause Tc-99m labeled red blood cells to agglutinate.

Testing Procedure

Aluminum breakthrough is tested using a simple colorimetric spot test.

1. The technologist uses commercially available test strips impregnated with an indicator chemical, aurintricarboxylic acid.
2. A small drop of the generator eluate is placed on one end of the strip.
3. A small drop of a standard control solution containing exactly 10 $ug/mL$ of Aluminum is placed on the other end of the strip.
4. The indicator turns pink or red in the presence of aluminum. The technologist compares the intensity of the color of the eluate spot to the standard spot.

Regulatory Limits

The USP limit for Aluminum ion breakthrough is: Limit: 10 micrograms ($ug$) of $Al^{3+}$ per milliliter ($mL$) of eluate.

If the color of the eluate spot is less intense than the standard spot, the concentration is below 10 $ug/mL$ and it passes. If it is darker, the eluate fails and must not be used.

pH Testing

The pH of the generator eluate is also a measure of chemical purity. The elution of sodium pertechnetate in normal saline should result in a relatively neutral solution.

• Testing: The pH is tested by placing a drop of the eluate on broad-range pH indicator paper and comparing the resulting color to a reference chart.
• Limits: The USP specifies that the pH of the sodium pertechnetate eluate must be between 4.5 and 7.5.

Maintaining the proper pH is critical because highly acidic or highly basic conditions can severely disrupt the complexation chemistry required when adding the pertechnetate to various radiopharmaceutical "cold kits." An improper pH can lead to a high percentage of free (unbound) pertechnetate or the formation of hydrolyzed-reduced technetium, both of which will result in poor image quality.