Targeted radionuclide therapy (TRT) for internal pathway-directed treatment is a game changer for precision medicine. TRT improves tumor control while minimizing damage to healthy tissue and extends the survival for patients with cancer. The application of theranostic-paired TRT along with cellular phenotype and genotype correlative analysis has the potential for malignant disease management. Chelation chemistry is essential for the development of theranostic-paired radiopharmaceuticals for TRT. Among image-guided TRT, ⁶⁸Ga and ^99mTc are the current standards for diagnostic radionuclides, while ¹⁷⁷Lu and ²²⁵Ac have shown great promise for β- and α-TRT, respectively. Their long half-lives, potent radiobiology, favorable decay schemes, and ability to form stable chelation conjugates make them ideal for both manufacturing and clinical use. The current challenges include optimizing radionuclide production processes, coordinating chelation chemistry stability of theranostic-paired isotopes to reduce free daughters [this pertains to ²²⁵Ac daughters ²²¹Fr and ²¹³Bi]-induced tissue toxicity, and improving the modeling of micro dosimetry to refine dose–response evaluation. The empirical approach to TRT delivery is based on standard radionuclide administered activity levels, although clinical trials have revealed inconsistent outcomes and normal-tissue toxicities despite equivalent administered activities. This review presents the latest optimization methods for chelation-based theranostic radiopharmaceuticals, advancements in micro-dosimetry, and SPECT/CT technologies for quantifying whole-body uptake and monitoring therapeutic response as well as cytogenetic correlative analyses.

Objective: Current good manufacturing practice (cGMP) guidance for positron emission tomography (PET) drugs has been established in Europe and the United States. In Japan, the Pharmaceuticals and Medical Devices Agency (PMDA) approved the use of radiosynthesizers as medical devices for the in-house manufacturing of PET drugs in hospitals and clinics, regardless of the cGMP environment. Without adequate facilities, equipment, and personnel required by cGMP regulations, the quality assurance (QA) and clinical effectiveness of PET drugs largely depend on the radiosynthesizers themselves. To bridge the gap between radiochemistry standardization and site qualification, the Japanese Society of Nuclear Medicine (JSNM) has issued guidance for the in-house manufacturing of small-scale PET drugs under academic GMP (a-GMP) environments. The goals of cGMP and a-GMP are different: cGMP focuses on process optimization, certification, and commercialization, while a-GMP facilitates the small-scale, in-house production of PET drugs for clinical trials and patient-specific standard of care. Among PET isotopes, N-13 has a short half-life (10 min) and must be synthesized on site. [¹³N]Ammonia ([¹³N]NH₃) is used for myocardial perfusion imaging under the Japan Health Insurance System (JHIS) and was thus selected as a working example for the manufacturing of PET drugs in an a-GMP environment. Methods: A [¹³N]NH₃-radiosynthesizer was installed in a hot cell within an a-GMP-compliant radiopharmacy unit. To comply with a-GMP regulations, the air flow was adjusted through HEPA filters. All cabinets and cells were disinfected to ensure sterility once a month. Standard operating procedures (SOPs) were applied, including analytical methods. Batch records, QA data, and radiation exposure to staff in the synthesis of [¹³N]NH₃ were measured and documented. Results: 2.52 GBq of [¹³N]NH₃ end-of-synthesis (EOS) was obtained in an average of 13.5 min in 15 production runs. The radiochemical purity was more than 99%. Exposure doses were 11 µSv for one production run and 22 µSv for two production runs. The pre-irradiation background dose rate was 0.12 µSv/h. After irradiation, the exposed dosage in the front of the hot cell was 0.15 µSv/h. The leakage dosage measured at the bench was 0.16 µSv/h. The exposure and leakage dosages in the manufacturing of [¹³N]NH₃ were similar to the background level as measured by radiation monitoring systems in an a-GMP environments. All QAs, environmental data, bacteria assays, and particulates met a-GMP compliance standards. Conclusions: In-house a-GMP environments require dedicated radiosynthesizers, documentation for batch records, validation schedules, radiation protection monitoring, air and particulate systems, and accountable personnel. In this study, the in-house manufacturing of [¹³N]NH₃ under a-GMP conditions was successfully demonstrated. These findings support the international harmonization of small-scale PET drug manufacturing in hospitals and clinics for future multi-center clinical trials and the development of a standard of care.