- Annex 3 of EudraLex Volume 4, titled Manufacture of Radiopharmaceuticals, provides specific Good Manufacturing Practice (GMP) guidance for the preparation, manufacture, and control of radiopharmaceuticals used for human medicinal purposes. Radiopharmaceuticals are unique substances that contain a radioactive component and are primarily used for diagnostic imaging (e.g., PET and SPECT scans) or therapeutic applications (e.g., cancer treatment). Due to their short half-lives, complex handling requirements, and radiation-related safety concerns, Annex 3 tailors standard GMP principles to meet the particular needs of this product class.
- The annex applies to a broad spectrum of radiopharmaceutical types, including kit-based preparations, cyclotron-produced products, and generator systems, as well as non-commercial (hospital-based or small-scale) preparations. It acknowledges that radiopharmaceuticals are often manufactured and administered in a very short timeframe, sometimes within hours, making traditional GMP practices—such as extended sterility testing or long release timelines—impractical. As such, the annex permits adapted approaches, provided that product safety, quality, and efficacy are not compromised.
- A key focus of Annex 3 is the requirement for aseptic processing, particularly because many radiopharmaceuticals cannot undergo terminal sterilization due to heat sensitivity or short shelf lives. Manufacturing areas must comply with stringent cleanroom classifications (Grades A to D), with Grade A environments used for critical aseptic operations. The use of automated synthesis modules, shielded isolators, and hot cells is encouraged to protect both the product from microbial contamination and the operators from radiation exposure. These systems must be properly validated and regularly maintained.
- Given the risks associated with radiation, personnel training and protection are emphasized throughout the annex. Operators must be trained not only in GMP principles but also in radiation safety, contamination control, and emergency procedures. Protective equipment, remote handling tools, and time/distance/shielding principles are all expected to be employed to minimize exposure.
- Batch documentation, quality control, and product release processes are also covered in detail. Due to the perishable nature of many radiopharmaceuticals, real-time release testing may not be feasible for every parameter. Annex 3 allows parametric release or conditional release under defined and validated conditions—particularly for sterility—provided that a robust aseptic process is in place, and retrospective sterility results are reviewed. Furthermore, radiochemical purity, radionuclide identity, specific activity, and pH are typically tested before release, while sterility and endotoxin testing may occur afterward.
- Labeling and packaging controls are adapted to reflect the specific needs of radiopharmaceuticals, including clear labeling of radioactive contents, activity levels, and expiry times. The annex also outlines expectations for transport and distribution, emphasizing radiation protection and compliance with applicable transport regulations (such as IAEA or ADR guidelines for radioactive materials).
- Importantly, Annex 3 recognizes small-scale, hospital-based, and non-commercial manufacturing environments, particularly for PET drugs or custom preparations. While such facilities may not operate on the same scale as industrial manufacturers, they are still expected to implement GMP principles appropriate to their scope of activity, including quality assurance systems, SOPs, validated equipment, and documented risk assessments.
- In summary, EudraLex Volume 4 – Annex 3 provides essential GMP guidance adapted for the radiopharmaceutical sector, taking into account the unique challenges posed by radioactive decay, short product lifespans, aseptic handling, and radiation safety. It strikes a balance between regulatory rigor and operational practicality, ensuring that radiopharmaceuticals—whether produced in hospitals or commercial settings—are manufactured and controlled to high standards, with patient safety and product integrity as top priorities.
Further reading:
- EudraLex – Volume 4 – Good Manufacturing Practice (GMP) guidelines
- EudraLex – The Rules Governing Medicinal Products in the European Union, Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use Annex 3: Manufacture of Radiopharmaceuticals
