A Harmonized GC–FID Method for Multi-Product Residual Solvent Analysis in Diagnostic and Therapeutic Radiopharmaceuticals
This paper presents the development and validation of a harmonized single-column GC–FID method that enables efficient, routine quality control of five residual solvents across diverse diagnostic and therapeutic radiopharmaceutical products, thereby reducing analytical complexity in GMP radiopharmacies.
Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). This is an AI-generated explanation of the paper below. It is not written or endorsed by the authors. For technical accuracy, refer to the original paper. Read full disclaimer
Imagine a hospital pharmacy that does not dispense pills or syrups, but instead manufactures tiny, glowing doses of medicine designed to find and treat cancer from the inside out. These medicines, known as radiopharmaceuticals, are created by attaching a radioactive atom to a molecule that naturally seeks out tumors. Because these substances are radioactive and often have very short lifespans, they must be made quickly and tested immediately before they can be given to a patient. A critical part of this safety check involves ensuring that no leftover chemicals from the manufacturing process remain in the final dose. These leftover chemicals, called residual solvents, are the liquids used to dissolve ingredients or clean equipment during synthesis. While necessary for making the drug, they offer no healing power and can be harmful to the human body if present in high amounts. To keep patients safe, strict international rules limit how much of these solvents can remain, requiring laboratories to measure them with extreme precision.
The challenge for the scientists at Karolinska University Hospital in Stockholm was that every different type of radiopharmaceutical usually required its own unique testing method. Because the drugs are made with different radioactive atoms and dissolved in different mixtures of water and stabilizers, the standard testing procedures often had to be customized for each product. This meant that a single laboratory might need to maintain dozens of different testing protocols, train staff on many separate techniques, and manage a complex web of documentation just to ensure safety. The researchers set out to see if they could replace this patchwork of individual tests with a single, unified method capable of checking many different drugs at once. They focused on five common solvents—ethanol, acetone, acetonitrile, tetrahydrofuran, and dimethyl sulfoxide—that frequently appear in the manufacturing process.
To solve this problem, the team developed a streamlined testing process using a machine called a gas chromatograph. This device works by turning a liquid sample into a gas and then pushing it through a long, thin tube where different chemicals travel at different speeds, separating them like runners in a race. The researchers optimized the temperature and flow of gas inside the machine so that all five target solvents would separate clearly from one another and be detected within a single run lasting just under twelve minutes. They proved that this single setup could accurately measure the amount of each solvent, even when the concentrations were very low. This was particularly important for one specific drug, [¹⁸F]FDG, which is often produced in such high radioactive concentrations that the sample must be diluted with water before testing. Diluting the sample makes the solvents harder to find, so the team created a special low-concentration version of their test to ensure they could still detect trace amounts of ethanol and acetonitrile in these diluted samples.
The researchers then put their new method to the test across a wide variety of real-world scenarios. They checked if the different liquid mixtures used to formulate the drugs would interfere with the results, running tests on samples containing [¹⁸F]FDG, L-[¹¹C]methionine, and [⁶⁸Ga]FAPI-46. They found that the different chemical backgrounds of these drugs did not confuse the machine or alter the results; the solvents separated cleanly regardless of what else was in the bottle. They applied the method to routine quality control samples from six different products, including both diagnostic scans and therapeutic treatments labeled with carbon, fluorine, gallium, and lutetium. In every case, the method successfully identified and measured the solvents, confirming that the drugs met safety standards. To be certain their new approach was reliable, they compared it against the existing, highly specific testing methods already in use at the hospital. The results from their new, unified system matched the old, specialized systems almost perfectly, with differences so small they were negligible.
The study concludes that a single, harmonized testing method can effectively replace multiple product-specific procedures for a wide range of radiopharmaceuticals. This does not mean the new method is more sensitive than every specialized test ever created, but rather that it is robust enough to handle the variety of drugs currently produced while simplifying the work required to keep them safe. By proving that one set of conditions can work for different radioactive atoms and different liquid formulations, the researchers have shown that laboratories can reduce the burden of maintaining dozens of separate protocols. This shift allows for more consistent training, easier maintenance of equipment, and a more streamlined workflow, ensuring that the critical safety checks for these life-saving medicines can be performed efficiently without compromising accuracy.
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