## 5 Regulatory Aspects of Cyclotron-Produced \({}^{68}\)Ga Radiopharmaceuticals  
Recently, the direct production of cyclotron-based \({}^{68}\)Ga, particularly the proton irradiation of enriched \({}^{68}\)Zn target route, has expanded and been practiced elsewhere. Currently, most medical cyclotron produces \({}^{68}\)Ga radiopharmaceuticals to cater for in-house use, which does not require marketing authorization (MA) from regulatory bodies. To produce medicinal products for human use, each country follows a set of national or international guidelines that are being enforced by local regulatory bodies, such as the US Food and Drug Administration (US FDA), World Health Organization (WHO), the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), or Pharmaceutical Inspection Co-Operation Scheme (PIC/S) [59]. Producing radiopharmaceuticals compound may be categorized under Good Manufacturing Practices (GMP) or Good Preparation Practices (GPP). The main differencesbetween GMP and GPP are summarized in Table 11. The nature of cyclotron-produced \({}^{68}\)Ga radiopharmaceuticals falls under the grey area. Although the criteria mostly fit the elements listed under GMP, the radioisotope's short half-life limits the labeled compound's distribution to other centers or institutions. As mentioned, most medical cyclotron facilities produce \({}^{68}\)Ga radiopharmaceuticals for in-house use only; thus, it is considered a small-scale preparation. EANM recently released a Guideline on the current Good Radiopharmacy Practice (cGRPP) for the small-scale preparation of radiopharmaceuticals to cater to in-house radiopharmaceutical preparations [60]. The cGRPP guidance was not much different from the PIC/S GPP guidance document practices elsewhere. EANM position for in-house radiopharmaceutical preparation also clearly stated that MA is not mandatory [61]. However, using a solid target to produce \({}^{68}\)Ga radiopharmaceuticals may yield a different opinion from manufacturers and regulators. The capacity to produce \({}^{68}\)Ga radiopharmaceutical through a solid target using a medical cyclotron can be considered a large-scale production with a range of minimum EOP and EOB between 3.7 to 18 GBq and 6.3 to 31 GBq, respectively [34; 38]. With this range of [\({}^{68}\)Ga]GaCl3 produced, the \({}^{68}\)Ga radiopharmaceutical could be distributed to other centers. This scenario may require MA approval from local authorities, which requires a GMP license to produce the dedicated radiopharmaceuticals as well as registration of products. There are a few options on how cyclotron-based \({}^{68}\)Ga radiopharmaceuticals can be supplied either as [\({}^{68}\)Ga]GaCl3 or as a labeled radiopharmaceutical such as [\({}^{68}\)Ga]Ga-DOTA-TATE or [\({}^{68}\)Ga]Ga-PSMA. The nature of the \({}^{68}\)Ga radiopharmaceutical also significantly determines the need for MA approval. Generally, medicinal products required to be registered and obtain MA are intended for human use to diagnose, cure, treat or prevent any ailment or disease. Thus, [\({}^{68}\)Ga]GaCl3 does not fit the definition of the medicinal product, unlike [\({}^{99 mTc}\)Tc]TcO4- in pertechnate, from where it can be given directly for thyroid scintigraphy. The [\({}^{68}\)Ga]GaCl3 cannot be administered in free form unless it is radiolabeled with a precursor, such as DOTA-TATE and PSMA. In this case, [\({}^{68}\)Ga]GaCl3 needs to be supplied as an active pharmaceutical ingredient requiring full quality testing and documentation for approval by regulatory bodies. Besides that, there are also arguments that the labeled [\({}^{68}\)Ga]Ga-DOTA-TATE or [\({}^{68}\)Ga]Ga-PSMA does not fit the manufacturing elements as the nature of the production process is more towards reconstitution instead of manufacturing. The radiolabeling process