Development and preparation of radiopharmaceuticals

Radiopharmaceuticals (RPs) are considered as drugs or Medicinal Products, either for diagnostic or therapeutic applications. Thus, RPs undergo a preclinical development phase needed to obtain the scientific and technical data to be submitted to the adequate drug-regulatory authorities for the clinical translation of novel products. This include chemical, radiochemical, pharmaceutical parameters required to guarantee the quality of the novel RPs. Additional tests in the proper cellular and animal models, often referred to as “non-clinical” or “preclinical”, are also mandatory to predict the expected in vivo behavior in humans, namely to address safety and efficacy issues. In this process, specific guidance is rare, reflecting the wide range of RPs applications that involve a vast variety of targets, different radionuclides requiring variable chemical approaches for the RPs design and a great range of clinical applications, from oncology to neurology.

During the development of novel RPs, pharmacokinetic, biodistribution, and dosimetry studies are usually performed under non-GLP conditions (GLP stands for Good Laboratory Practice). In contrast, non-clinical safety studies performed with the non-radioactive component, in particular toxicity studies, must run in GLP-certified laboratories. For their clinical translation, a radiopharmaceutical to be evaluated in clinical trials must be also obtained under Good Manufacture Practices (GMP), which is facilitated through the use of automated processes. In this context, GMP compliant processes should be considered in the preparation of RPs with the novel PRISMAP radionuclides, which can be inspired on processes and methods applied to prepare related and clinically approved RPs, namely radiometal-based RPs for which monographs are already available at the European Pharmacopeia (Ph. Eur.).

This portal provides information useful to guide radiopharmaceutical scientists, Nuclear Medicine specialists, and regulatory professionals to bring innovative diagnostic and therapeutic radiopharmaceuticals into the clinical evaluation, namely to elaborate the respective IMPD Investigational Medicinal Product Dossier (IMPD) containing data on the quality, production and control of the RP undergoing a clinical translation.

PRISMAP Deliverable D4.1

 

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.

Related publications

 
PSMA-1007Radiopharmacology & Clinical Studies
  • Recurrent Prostate Cancer Diagnostics with 18F-PSMA-1007 PET/CT: A Systematic Review of the Current State.
    Diagnostics 12, 3176 (2022). doi: 10.3390/diagnostics12123176. Archive: PMC
Cu-64, Cu-67Radiochemistry & chelation La-135Radiochemistry & chelation
  • Improved procedures for production and purification of 135La from enriched [135Ba]BaCO3 on a 16.5 MeV cyclotron.
    Applied Radiation and Isotopes 192, 110612 (2023). doi: 10.1016/j.apradiso.2022.110612. Archive: DTU Orbit
Sm-153Radiochemistry & Preclinical Studies

Guidelines

 

Volume 4 of "The rules governing medicinal products in the European Union" containing guidance for the interpretation of the principles and guidelines of good manufacturing practices for medicinal products for human and veterinary use health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-4_de

Guideline on current good radiopharmacy practice (cGRPP) for the small-scale preparation of radiopharmaceuticals ejnmmipharmchem.springeropen.com/articles/10.1186/s41181-021-00123-2

Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials www.ema.europa.eu/en/documents/scientific-guideline/guideline-requirements-chemical-and-pharmaceutical-quality-documentation-concerning-investigational-medicinal-products-clinical-trials-revision-2_en.pdf

Requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials - Scientific guideline www.ema.europa.eu/en/requirements-chemical-and-pharmaceutical-quality-documentation-concerning-investigational-medicinal-products-clinical-trials-scientific-guideline#current-effective-version-section

Other documents

 

Chapter of Pharm. Eur. dedicated to “EXTEMPORANEOUS PREPARATION OFRADIOPHARMACEUTICAL PREPARATION” serfaradiofarmacia.com/wp-content/uploads/2014/03/Pharmeuropa_Extemporaneous_Radiopharmaceutical.pdf