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Radiopharmaceuticals are considered Medicinal Products, thereby they must be prepared and applied within the regulated area of pharmaceuticals. This includes radionuclides, which have seen extraordinary advancements in research and development over the last decade in regards to theranostics. The governing EU directives and regulations, including regulatory guidance, cannot keep pace with this development. PRISMAP, the European Medical Radionuclide Program, brings together key nuclear research centres and leading clinical translational research facilities across Europe to provide a sustainable source of high purity grade new radionuclides for the starting research community. One of PRISMAP`s paramount aims is to standardise and harmonise research and development activities with novel radionuclides to cope with pharmaceutical regulatory requirements and provide guidance for clinical translation. The PRISMAP workshop: “Radionuclide Production to Nuclear Medicine Clinical Applications: Regulatory Standards and Harmonisation of Quality and Safety”, held in February 2022, provided the basis for this document, which gives guidance for the early phase clinical research with novel radionuclides. It describes the current standards and a harmonised view of the European regulatory framework. The document complements the existing regulatory framework and is not considered legally binding. Six chapters cover different aspects in radiopharmaceutical development. Each chapter includes dedicated guidelines and guidance documents from regulatory authorities and professional organisations, as well as references to scientific publications on the respective topic. An introduction of PRISMAP and the project scope is followed by a definition of terms and nomenclature for specification of novel radionuclides within PRISMAP. The following chapter focuses on the production of radionuclides and implementation of GMP in the radiopharmaceutical development process. It provides relevant definitions and gives recommendations where GMP compliant processes should be introduced in the production of novel radionuclides. Guidance for controls of radionuclides including starting materials, process validation, in-process controls, chemical precursors and production of radiopharmaceuticals are briefly addressed. The subsequent chapter covers quality specifications and quality control. It includes details on relevant European Pharmacopoeia texts and guidance for compliance, summarises other regulatory texts from the EMA and ICH, giving general considerations on specifications and specific guidance for validation of analytical methods. It provides definitions on drug substance and drug product and addresses all relevant specific quality criteria for novel radionuclides. The next chapter deals with metrology and medical physics aspects in clinical translation. The relation to the Basic Safety Standards of the Council Directive 2013/59/Euratom is described, which includes aspects of therapy planning and dosimetry for novel radionuclides. Standardisation in relation to traceability is addressed in a dedicated part on Metrology. The role of Medical Physics in the context of standardisation and harmonisation of the clinical use of novel radionuclides for imaging equipment, image acquisition, processing parameters, and quality control implementation of new technologies is summarised. The final chapter covers Non-Clinical Safety and Pharmacology aspects and provides an overview of the current guidance documents to assess preclinical dosimetry, toxicity (new EMA guideline specific for radiopharmaceuticals), and pharmacology of radiopharmaceuticals, which are developed with the aim to be used in human clinical trials. Recent specific guidance documents on this topic, particularly from the IAEA are summarised and included. This guidance document serves as an essential and comprehensive guide for radionuclide producers, radiopharmaceutical translational scientists, clinical and hospital based radiopharmaceutical development researchers through the complex jungle of pharmaceutical regulations and guidelines. It provides a harmonised view to standardise data required for clinical translation of novel radionuclides. |
