Development, validation and regulatory acceptance of improved purification and simplified quality control of [13N] Ammonia

Abstract

Background: [ 13 N]Ammonia is a cyclotron produced myocardial perfusion imaging agent. With the development of high-yielding [ 13 N]ammonia cyclotron targets using a solution of 5 mM ethanol in water, there was a need to develop and validate an automated purification and formulation system for [ 13 N]ammonia to be in a physiological compatible formulation of 0.9% sodium chloride since there is no widely available commercial system at this time. Due to its short half-life of 10 min, FDA and USP regulations allow [ 13 N]ammonia to be tested in quality control (QC) sub-batches with limited quality control testing performed on the sub-batches for patient use. The current EP and the original USP method for the determination of the radiochemical purity and identity of [ 13 N]ammonia depended on an HPLC method using a conductivity detector and a solvent free of other salts. This HPLC method created issues in a modern cGMP high volume PET manufacturing facility where the HPLC is used with salt containing mobile phase buffers for quality control analysis of other PET radiopharmaceuticals. Flushing of the HPLC system of residual salt buffers which may interfere with the [ 13 N]ammonia assay can take several hours of instrument time. Since there are no mass limits on [ 13 N]ammonia, a simplified TLC assay to determine radiochemical identity and purity could be developed to simplify and streamline QC. Results: We have developed and validated a streamlined automated synthesis for [ 13 N]ammonia which provides the drug product in 8 mL of 0.9% sodium chloride for injection. A novel radio-TLC method was developed and validated to demonstrate feasibility to quantitate [ 13 N]ammonia and separate it from all known radiochemical impurities.

A Reliable Production System of Large Quantities of [13N]Ammonia for Multiple Human Injections

“…Given the duration of PET scans usually performed at rest/stress, batches of around 26-33 GBq (717-885 mCi) are normally produced back-to-back to fulfill patient demands in our PET unit. The production time and yields were similar to those using other prototype systems [11,18,19] or commercial synthesis modules [12,20]. Therefore, our simplified manufacturing method allows the production of large quantities of [ 13 N]ammonia with less automation or manual interventions, thus providing an alternative to laboratories without access to automated technology.…”

“…In fact, each batch takes approximately five minutes for completion. Considering the presence of radionuclide impurities that come from the activation of HAVAR foils and niobium material and the natural presence of 0.2% oxygen-18 in target water (that produces fluorine-18) [15][16][17], most [ 13 N]ammonia production processes use in-series anion-cation cartridges aided by valves to purify [ 13 N]NH 3 [11,12,18]. Hence, an anion exchange resin is mainly utilized to trap negatively charged impurities ([ 18…”

“…Several examples can be found in the literature, with a synthesis time of around five minutes and RCYs of 90% or higher. Notably, Yokell et al [12] set out a simple method that could also be adapted and validated on commercially available synthesis units. This approach utilizes quaternary methyl ammonium (QMA) and carboxymethyl (CM) cartridges in series to accomplish the purification, formulation, and sterile filtration of [ 13 N]ammonia (21 ± 2 GBq, 572 ± 60 mCi) in about five minutes.…”

Recent Advances in Cardiovascular Diseases Research Using Animal Models and PET Radioisotope Tracers

“…Another radiopharmaceutical approved in clinical practice alongside 82 Rb is [ 13 N]ammonia ([ 13 N]-NH 3 ) [156]. [ 13 N]-NH 3 is highly efficient in an on-site cyclotron [157]. The high first-pass ejection fraction of the myocardium, metabolism to [ 13 N]-glutamine, and the imprisonment in the cardiomyocytes are responsible for the high resolution of the clinical images [158].…”