# Risk Management in Good Manufacturing Practice (GMP) Radiopharmaceutical Preparations
## 1 Introduction  
Positron Emission Tomography (PET) is a nuclear medicine technique used mostly for the diagnosis, staging, and follow-up of cancers [1]. \({}^{18}\)F-FDG is the most widely used radiopharmaceutical in PET clinical investigations; it is used in over 95% of the PET examinations performed [2].  
Over the years, alternative radiopharmaceutical to \({}^{18}\)F-FDG have been studied, but research in this environment is complex due to the high costs for development (from 20 to 60 million dollars in 2013), the long period for development (minimum 7-9 years) [3], and high risk (one new radiopharmaceutical for clinical use out of ten thousand molecules tested at the beginning) [4].  
\({}^{18}\)F-FDG will still be the most used radiopharmaceutical in nuclear medicine for years to come, although there are malignant diseases with poor uptake of F-FDG and other benign diseases that could cause false positives [5].  
The radiopharmaceutical industrial production requires compliance with Good Manufacturing Practice (GMP): the guidelines for GMP implementation are enclosed in Volume 4 of the Eudralex \"The rules governing medicinal products in the European Union\" [6].  
The GMP rules should be applied to all phases of a drug's life cycle, starting from clinical trials through technology transfer and production until the final product's retirement [6].  
The Eudralex also suggests the use of other guidelines, among which ICHQ 10 guidelines (ICHQ:International Conference on Harmonisation of Technical Requirements forRegistration of Pharmaceuticals for Human Use) were finalized at setup for the pharmaceutical quality system (PQS) to be applied throughout the product life cycle.  
ICHQ10 guidelines recommend the integration of the GMP regulations with the ISO 9001:2015 quality concepts related to the whole process [7], with the aim of harmonizing the entire production cycle of the drug.  
A key aspect of the PQS is represented by Quality Risk Management (QRM), as described in another ICHQ guideline (ICHQ 9) [8].  
In fact, to date, QRM has assumed a pivotal role in the (radio)pharmaceutical industries for the assessment, control, and communication of the risks associated with product safety and quality.  
The literature reports several cases of QRM applied to radiopharmaceutical production, which are mostly applied to segments of the production process but not to the whole process [9; 10; 11] or are intended to prevent injury to the operators or patients [12] but without quantification of the risk throughout the product life cycle.  
The analyzed literature also shows that the integrated application of some quality standards, such as GMP, ISO 9001, ICHQ, and EFQM (European Foundation for Quality Management), could contribute to obtaining the quality of a radiopharmaceutical [13] through quality risk assessment and guaranteeing performance and efficacy in the entire process.  
Therefore, the application of different quality standards, such as GMP, ISO 9001, and ICHQ, guarantees the quality and safety of a radiopharmaceutical [13] and contributes to optimizing the performance and efficacy of the entire production process.  
This paper describes the conceptualization and the setting up of a quality risk assessment methodology to be applied to the production of sterile PET radiopharmaceuticalects under the GMP regulations.  
This methodology has been developed in our public research institution, taking into consideration all phases of the product life cycle, starting from development, passing through technology transfer, and finally, commercial delivery.  
This methodology of quality risk management has been performed by integrating the recommendations reported in Eudralex, ICHQ, and ISO 9001, and its validity has been evaluated by applying it to real data collected in 21 months of activities of 18F-FDG production at Officina Farmaceutica, CNR-Pisa (Italy), to confirm whether the critical aspects, which have previously been identified in the quality risk assessment, were effective.