EMA Draft Guideline on Quality of Radiopharmaceuticals

Radiopharmaceuticals present unique quality challenges due to their radioactive nature, short shelf lives, and frequent need for on-site or near-patient preparation. To reflect scientific and technological advances since the original 2007 guideline, the European Medicines Agency has released the draft Guideline on quality of radiopharmaceuticals – Revision 2 for public consultation. Adopted by CHMP in December 2025, this revision provides updated expectations for quality documentation in marketing authorisation applications and variations involving radiopharmaceuticals.

The draft guideline applies to ready-for-use radiopharmaceuticals, radionuclide generators, radionuclide precursors, and kits for radiopharmaceutical preparation, as well as associated chemical and radionuclide substances. Radiopharmaceuticals based on monoclonal antibodies are excluded, as they are covered by separate guidance. The principles outlined also apply, with appropriate flexibility, to investigational radiopharmaceuticals used in clinical trials.

Active Substance and Quality Documentation

A key concept in the guideline is that the radiolabelled active substance administered to patients often cannot be isolated or fully characterised. As a result, quality assurance must focus on upstream components such as the chemical precursor, radionuclide precursor, or generator parent radionuclide. EMA clarifies how Module 3.2.S should be structured depending on the product type and expects full GMP compliance for manufacturers of these substances, including inclusion in the Qualified Person declaration. draft-guideline-quality-radioph…

Manufacturing and Process Control

EMA places strong emphasis on manufacturing process understanding, particularly for radionuclide production via cyclotrons, reactors, or mass separation. Applicants must clearly describe production parameters, nuclear reactions, and downstream processing steps. For automated synthesis or dispensing systems, detailed information on equipment, software, cleaning, and safeguards is required. Where release occurs before completion of all quality control tests due to short half-life, EMA expects strong validation, in-process controls, and a well-justified control strategy.

Specifications and Control Strategy

Quality specifications must address both chemical and radiological attributes, including radionuclidic identity and purity, radiochemical purity, radioactive concentration, chemical purity, and, where applicable, sterility and endotoxins. EMA includes an annex outlining minimum specification parameters for different radiopharmaceutical categories. Pharmacopoeial monographs should be applied where available but may need supplementation to address novel production methods or impurities.

Stability: Adapting Conventional Principles

The guideline acknowledges that conventional ICH stability concepts cannot be fully applied. Stability testing must consider radioactive decay, very short shelf lives, and in-use conditions. For ready-for-use products, stability data must cover the entire proposed shelf life, even if only a few hours. For kits, conventional stability applies prior to radiolabelling, but additional data are required for the radiolabelled preparation after reconstitution and during in-use periods. Shelf life must be defined relative to the activity reference time and justified scientifically. draft-guideline-quality-radioph…

Product Information and SmPC

EMA clarifies that radiopharmaceutical SmPCs must clearly describe the radionuclide, production method, decay characteristics, radioactivity per container, preparation instructions, and shelf life after radiolabelling. For generators and kits, step-by-step preparation instructions must be provided to ensure safe and reproducible use in clinical settings.

For more information, see the official guidance:  Guideline on quality of radiopharmaceuticals – Revision 2