[18F]Fluoromisonidazole ([18F]FMISO) as nitroimidazole derivative with 18F radioisotope is a widely known and studied hypoxia marker for PET imaging. A number of automated synthesis modules and purification strategies for production of [18F]FMISO have been described in recent years. The goal of this work was to develop [18F]FMISO synthesis process with Synthera module with solid phase extraction (SPE) Sep-Pak purification cartridges. To adjust the reaction conditions we synthesized [18F]FMISO under different reaction conditions and using various reversed-phase (RP) purification cartridges (HLB light, HLB plus, tC18, C18 environmental, Chromafix PS-RP). The synthesis was performed by nucleophilic substitution of commercial 1-(2′-nitro-1′-imidazolyl)-2-O-tetrahydropyranyl-3-O-toluenesulfonylpropanediol precursor and subsequent acidic hydrolysis. Further, the product mixture was purified by passing through the SPE cartridge. The produced [18F]FMISO was retained on the cartridge, while the impurities passed through the cartridge into a waste. The retained [18F]FMISO was then eluted with small amounts of ethanol in water and eluates were collected in the final product vial. The product sample was subjected to quality control tests, while for waste sample chemical and radiochemical tests were performed. We have developed an efficient synthesis method of [18F]FMISO with cartridge purification with good radiochemical yield (RCY) and high chemical and radiochemical purity in accordance with the Ph. Eur. Monograph for Fluoromisonidazole (18F) injection.
Sodium fluoride ([18F]NaF) is a PET radiopharmaceutical for vizualization of the skeletal system and microcalcification. In the originally designed in-house method, [18F]NaF is recovered in aqueous solution after cyclotron irradiation, sterilized by passage through a 0.22 µm sterile filter and dispensed under aseptic conditions. To ensure the microbiological safety of drugs produced under aseptic conditions, validation of aseptic procedures is always recommended. This is essential for radiopharmaceuticals because most of them are released for administration before any sterility test can be completed due to their radioactive nature.
This study reports the validation of the aseptic process applied to the internal production of [18F]NaF carried out in two phases: testing the number of viable microorganisms in radiopharmaceutical product prior to sterilization and process simulation studies (media fill tests). We found that all samples were sterile and the endotoxin concentration was well below the maximum acceptable level reported in the Ph Eur. monograph on [18F]NaF. The results confirmed that the entire production process of [18F]NaF can be carried out under strictly aseptic conditions following the validated procedures preserving the sterility of the final product.
[18F]Sodium Fluoride radiopharmaceutical is a sterile solution for intravenous administration, intendedfor skeletal visualization by positron emission tomography (PET). [18F]Sodium Fluoride for bone imaging wasintroduced in early 1960's, but with the increased availability of PET scanners in the last two decades, thisradiopharmaceutical has growing use in clinical practice for the detection of bone metastases. The productionprocess of [18F]NaF includes production of the radioisotope [18F]F- and purification and formulation of the [18F]NaFradiopharmaceutical. The radioisotope [18F]F- is produced by a cyclotron via the 18O(p,n)18F nuclear reaction,followed by recovery of [18F]F- from [18O] proton-irradiated water by adsorption and desorption from anionexchangeresins. The fluoride anions are trapped on the anion-exchange SPE (solid-phase extraction) cartridge, andall other cationic and water-soluble radionuclide impurities present in irradiated enriched water are collected in thewaste vial. Next step is desorption of the fluoride anions from the cartridge by elution with saline solution (0.9%NaCl). This study aimed to define the most appropriate type of anion-exchange SPE cartridge which could be usedfor routine production [18F]Sodium fluoride radiopharmaceutical which meets the quality requirements defined inEuropean pharmacopeia monograph. For that purpose, as part of development of in-house production method,manual productions with four different types of anion-exchange cartridges were performed. The influence of sorbentsubstrate and counter-ion of the cartridge on the final yield and the quality of the produced radiopharmaceutical wasinvestigated. The study also aimed to define the minimum volume of physiological solution required for the pHparameter to be within limits.The results have shown that the quality parameters: appearance, chemical purity, radiochemical purity andradionuclide purity were in defined acceptance criteria and did not differ when using different anion-exchangecartridges. The pH analyses have demonstrated that the type of cartridge and counter-ion influence the final pH of[18F]NaF solution. This study confirmed that the three types of anion-exchange resins (QMA-Cl-, QMA-CO32- andPS-OH-) could be used for production. In the experiments where QMA-Cl- was used, the required pH level wasobtained even without dilution. The other cartridges could be used in the [18F]NaF production process, but furtherdilution is necessary in order to obtain the pH value in acceptance criteria. On the basis of this study, the QMA-Cl- ischosen as a cartridge to be used in the further development of the in-house method for [18F]NaF radiopharmaceuticalproduction.
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