# Risk Management in Good Manufacturing Practice (GMP) Radiopharmaceutical Preparations
## 4 Discussion  
In general, the radiopharmaceutical manufacturing process starts with the production of the radionuclide and continues with the synthesis of the radiopharmaceutical according to the formulation described in the Marketing Authorization (MA) dossier or Pharmacopoeia Monograph [14]. The production of PET radiopharmaceuticals is extremely complex due to a series of factors [15]: the delivery of the final product that takes place with the sterility control still in progress; the short half-life of the tracer; the very high number of batches produced compared to conventional drugs; the activity carried out mainly during the night; and the handling of radioactive substances. The complexity of this system implies that risk assessment is even more necessary than in other production systems. Fortunately, the GMP standard helps us keep the critical aspects of the production process under control by indicating the tools to be used \"to manage\" the risk [16; 17]. Our GMP experience has allowed us to develop a risk assessment, which is conducted by separately considering organizational and management risks and operational risks. This report describes the experience of a public radiopharmaceutical site that has adopted the GMP standards and which, therefore, produces radiopharmaceuticals following the indications of the EU-GMP for industrial production [18]. Since the start of GMP  
Figure 7: Main causes of lot rejection. radiopharmaceutical production, the site has used an approach founded on risk-based thinking and followed regulatory updates over the years. In 2021, the production site radically changed the production process, moving from production with final sterilization in an autoclave to production using aseptic techniques. Before starting with the new production process, a risk assessment was carried out, which identified the most critical segments of the process. Twenty-one months after the restart of the production, which was intended for distribution on the national territory, the data that emerged were collected and analyzed to verify if the risk assessment process carried out ex ante had been able to identify the main risks. Compared to the initial risk assessment, the evidence collected during these twenty-one months allows us to state that the method, adopted both for the assessment of management risks and operational risks, is a suitable tool for identifying the critical phases of the process. At the managerial level, the greatest criticality was mainly linked to personnel management. The results of the analysis also show that production is the most critical phase of the process (asepsis and radioactivity). In particular, the dispensing phase has proven to be the most critical, implying a delay or even a loss of production along with customer dissatisfaction. In addition, there are problems during the dispensing phase; as an example, the breakage of a product vial could result in personal and environmental contamination and put an operator's safety in danger (Table 2). In general, the preventive actions to be undertaken to mitigate the risk can be grouped into two main types: the continuous training of staff, with attention to motivation and awareness of the complexity of the system, and the increasingly detailed processes so that the risks can be reduced as much as possible and, therefore, achieve an overall risk reduction. In conclusion, having a risk management process in place is critical for GMP production facilities, and the identification of risks in the matrix is a useful tool. Our implemented model has identified and quantified the risks, and, given the overlap between the risks identified and the analysis of real data, the proposed method could be used by other similar radiopharmaceutical production sites to identify the critical phases of the production process, improve the performance, and prevent damages to the entire cycle of the radiopharmaceutical product. Conceptualization, M.P., G.I. and L.G. ; methodology, A.Z., S.P. and M.T. ; software, M.Q. ; validation, M.T. and A.Z.