Validation of a novel radiopharmaceutical according to EU GMP requirements at Turku PET Centre

Abstract

Radiopharmaceuticals are essential in Positron Emission Tomography (PET) imaging that is used for diagnostic and research purposes. Radiopharmaceuticals contains a biologically interesting molecule labelled with appropriate radionuclide that allows detection with a PET device. Radiopharmaceuticals have many characteristics that make them different from other conventional pharmaceuticals. Mainly the molar amount of the substance is significantly lower, so a radiopharmaceutical has no pharmacological effect. In addition, the half-life of the radionuclide is usually short (~2-110 min) and this limits their transport for off-site use or commercialization on a large scale. Indeed, many of the radiopharmaceuticals are produced in-house for direct use. European Medicines Agency (EMA) and national competent authorities like the Finnish Medicines Agency (FIMEA) in Finland supervice the manufacture and use of radiopharmaceuticals. In addition, the Finnish law and the Radiation and Nuclear Safety Authority (STUK) regulate the use of radioactive material. EMAs general comprehensive guidance on Good Manufacturing Practices (GMP) from which e.g. Annex 1: “Manufacture of Sterile Medicinal Products” (updated in 2023) and Annex 3: “Manufacture of Radiopharmaceuticals” guide the production of radiopharmaceuticals. However, there is a need for more practical interpretation. Thus, the Radiopharmacy Committee of the European Association of Nuclear Medicine (EANM) has provided interpretation and opinion of experts in the field on current Good Radiopharmacy Practice (cGRPP) for small-scale preparation of radiopharmaceuticals. Also, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) provides more interpretation. Currently, Turku PET Centre is in the process of setting up and validating the production of a novel [18F]fluoride labelled Exendin-4 based radiopharmaceutical. Exendin-4 is a Glucagon Like Protein-1 (GLP-1) receptor agonist which makes it a suitable marker to study e.g. pancreatic beta cells. This project is carried out in Turku PET Centre Radiochemistry Laboratory and the aim is to establish the production of the novel radiopharmaceutical in compliance with EU GMP requirements. The process includes the validation of the analytical methods and the production process. The preclinical evaluation of the novel pharmaceutical is also performed before clinical studies. However, in this thesis we will be focusing on the validation of the analytical methods which objectives are to show that the developed analytical methods are appropriate for the intended use and purpose. According to the guidelines we must confirm that the identity, concentration, quality and purity of the radiopharmaceutical are sufficiently characterized. Thus, our aim is to develop analytical methods that are specifically suited to our radiopharmaceutical and that meet GMP requirements. The methods can be qualitative or quantitative and radioHPLC is one of the relevant technics used and validated during this project. Guidelines will be studied and used to draw up and implement a Validation Plan for the analytical methods dedicated for the radiopharmaceutical.