How the EAEU Regulates Radiopharmaceuticals with a Six-Hour Shelf Life — GMP and Registration Rules
Here is a drug with a shelf life of six hours. While a Qualified Person waits for the results of a sterility analysis — which takes at least fourteen days — the preparation has long since decayed to background radiation levels. It has already been administered to a patient, or discarded.
This is precisely how radiopharmaceutical medicinal products (RMPs) work. They represent a distinct class where the active substance is a radioactive isotope: PET scanning with fluorodeoxyglucose (FDG), scintigraphy with technetium-99m, targeted therapy with lutetium-177. All of these operate according to physical laws that do not align easily with standard regulatory timelines.
The Eurasian Economic Union (EAEU) has established a separate regulatory framework for RMPs covering both Good Manufacturing Practice (GMP) and registration dossier requirements. Below is a breakdown of the fundamental differences and their practical implications for manufacturers and regulatory professionals.
Four Categories: From Generators to Cold Kits
Before discussing regulation, it is necessary to understand what is actually being regulated. The umbrella term «radiopharmaceutical medicinal product» covers four distinct categories with significantly different requirements.
| Category | Description | Example |
|---|---|---|
| Finished RMP | A preparation ready for administration to the patient | Technetium-99m solution for scintigraphy |
| Radionuclide Generator | A «mother-daughter» system where a daughter nuclide is eluted from a parent nuclide | Molybdenum-99 / Technetium-99m |
| Radioactive Precursor | A radionuclide for labeling another molecule before administration | Fluorine-18 for FDG synthesis |
| Cold Kit | A non-radioactive set of reagents to be labeled with an isotope on-site | Kits for technetium labeling in a PET center |
One practically important point: cold kits are not radioactive at the time of manufacture and delivery. Nevertheless, they are subject to mandatory state registration as medicinal products. Their labeling must include a detailed description of the labeling procedure and the storage time of the final labeled preparation.
Why Standard GMP Rules Do Not Apply
Any sterile medicine is typically produced under positive pressure: clean air «pushes» contaminants out of the zone. This is a fundamental principle of sterile production under Annex No. 1 of the EAEU GMP Rules.
For RMPs, this principle is reversed.
Open sources of radioactive radiation cannot be kept in a room with positive pressure: radioactive aerosols and gases would disperse throughout the building. Therefore, in areas where the product is exposed, negative pressure is maintained relative to adjacent rooms. This requirement is established in Paragraph 24 of Annex No. 3 to Decision of the Council of the EAEU Commission No. 77 (as amended by Decision No. 76 dated July 4, 2023) and in the corresponding Paragraph 24 of Annex No. 3 to Order of the Ministry of Industry and Trade of the Russian Federation No. 916.
Sterility is achieved through barrier technology and a cascade of airlocks. The product is protected by hot cells equipped with HEPA filtration and laminar airflow inside the working zone, while the room itself remains under negative pressure.
A hot cell is an isolated or non-isolated shielded workstation for the production and handling of radioactive materials (as defined in Annex No. 3 to Decision No. 77). Lead or tungsten shielding protects personnel; manipulations are performed remotely or through glove boxes. In essence, this represents a fundamentally different production philosophy compared to conventional sterile manufacturing.
Air recirculation from RMP production zones is generally not permitted. The exhaust system must capture radioactive particles and gases before they are released into the atmosphere.
Batch Release Before Completion of All Testing
This is perhaps the most unconventional regulatory solution for RMPs.
Technetium-99m has a half-life of six hours. Fluorine-18 decays in one hundred and ten minutes. By the time a preparation completes the full quality control cycle, it no longer exists — neither physically nor therapeutically.
The legislation accounts for this. Paragraph 39 of Annex No. 3 to Decision No. 77 and Paragraph 41 of Annex No. 3 to Order No. 916 explicitly permit the release and use of RMPs based on batch documentation review, without waiting for all chemical and microbiological test results.
In practice, this operates as a two-stage release. First, the Qualified Person evaluates the batch dossier based on results that can realistically be obtained before shipment: visual inspection, pH, radiochemical purity, and volumetric activity. The preparation is dispatched to the clinic with a «quarantine» status. Subsequently, after receiving the final results (including sterility), the Qualified Person issues the definitive release authorization.
If a sterility test result proves unsatisfactory after the preparation has been administered to a patient, the manufacturer is obligated to have a written procedure for notifying the medical organization and a plan of action to minimize consequences.
For preparations with a longer half-life — lutetium-177 at approximately 6.7 days or iodine-131 at approximately 8 days — two-stage release is used less frequently, as there is sufficient time to complete all quality control testing before shipment.
Specific Quality Parameters
In addition to standard tests for parenteral preparations (sterility, bacterial endotoxins, particulate matter, pH), the EAEU Pharmacopoeia and registration dossier require several specific measurements for RMPs.
Radionuclidic Purity: The fraction of total radioactivity attributable to the stated radionuclide. Extraneous isotopes arise from imperfections during reactor or cyclotron irradiation. For diagnostic RMPs this affects image quality; for therapeutic ones it affects the safety profile.
Radiochemical Purity: The fraction of the radionuclide present in the required chemical form. For technetium-99m this is a particularly critical parameter: if the carrier molecule degrades, free technetium accumulates in the thyroid gland or stomach rather than in the target organ. The standard control method is thin-layer chromatography with radiometric scanning.
Volumetric Activity and Specific Activity. Volumetric activity in Becquerels per milliliter is required for precise dosing before administration. Specific activity (Becquerels per unit mass of labeled compound) is especially important for receptor-targeted preparations: excess non-radioactive molecules occupy receptors and render the diagnostic procedure ineffective.
All activity measurement instruments (dose calibrators) must undergo metrological verification and regular calibration against reference sources. Compliance is verified during GMP inspections.
The Registration Dossier — Additions to the Standard Common Technical Document
Registration of RMPs under Decision of the Council of the EAEU Commission No. 78 follows the same Common Technical Document (CTD) structure as conventional medicinal products. However, there are sections specific to this category.
Module 1 (Administrative Information) requires a license for working with ionizing radiation sources — both generating and open. A standard GMP certificate and manufacturing license are insufficient. In Russia, this license is issued by Rospotrebnadzor (the Federal Service for Consumer Rights Protection and Human Wellbeing).
The Summary of Product Characteristics (SmPC) for RMPs includes two special sections absent from standard drug applications:
The «Dosimetry» section contains data on internal radiation dosimetry: the absorbed dose received by different organs upon administration. These are calculations based on biodistribution data, typically using the MIRD (Medical Internal Radiation Dosimetry) methodology.
The «Instructions for Preparation» section is mandatory for generators and cold kits. It must include detailed labeling and quality control instructions for the prepared product, including the maximum storage time for the finished labeled preparation. This requirement is established in the EAEU Rules for compiling instructions for medicinal products (Paragraphs 124–126).
Module 3 (Quality) requires a separate description of the radionuclide production method: target characteristics for cyclotron or reactor irradiation, and purification parameters. For generators, the stability of the parent nuclide and the permissible level of «breakthrough» into the eluate must be documented.
Modules 4 and 5 (Non-clinical and Clinical) place particular emphasis on biodistribution studies and absorbed dose calculations. Without this data, it is impossible to justify the safety of first-in-human administration or to establish the therapeutic window.
PET Centers and In-Hospital Preparation
The growth of PET-CT diagnostics has created a specific regulatory situation. PET centers frequently synthesize FDG and other preparations on their own cyclotrons — which technically constitutes medicinal product manufacturing, with all associated GMP requirements.
At the same time, Annex No. 3 to the GMP Rules explicitly states that its scope does not extend to the preparation of RMPs in pharmacy organizations. The boundary between pharmacy compounding and industrial manufacturing in the context of PET centers remains a subject of ongoing debate; EAEU regulators have not yet reached a consistent position.
Decision No. 77 specifically identifies «radiopharmaceutical medicinal products for PET» as a separate category, and requirements for this category may differ from those applicable to standard RMPs. Specific approaches for centers with an industrial synthesis cycle are currently being developed.
What to Do Right Now
1. Identify the product type. Finished RMP, generator, precursor, or cold kit — the choice determines the structure of Module 3 and the scope of special sections in the SmPC. Misclassifying the category at the application stage typically results in a request for revision with a delay of several months.
2. Verify the licensing package. Beyond the GMP certificate and manufacturing license, a separate Rospotrebnadzor license for working with ionizing radiation sources is required. Confirm that it correctly specifies the permitted types of activities: generating and/or open sources.
3. Develop a two-stage release procedure. If the nuclide’s half-life does not allow waiting for all QC results before shipment, this procedure must be documented in writing and approved by the Qualified Person. Include the list of tests mandatory before shipment and an action algorithm for cases where unsatisfactory results arrive post-administration.
4. Prepare the dosimetry section. Biodistribution data with absorbed dose calculations are required as early as the non-clinical stage. Without them, the dossier is incomplete. Engage a medical physicist with MIRD calculation experience well in advance.
5. Audit the production facility. Open-product zones require negative pressure; exhaust systems must capture radioactive emissions; hot cells must be qualified through IQ/OQ/PQ. Radiation monitoring systems must operate in real time. These are the minimum requirements for a successful GMP inspection.
Radiopharmaceuticals belong to the few drug classes where the physics of the process literally dictates the regulatory framework. Two-stage release, negative pressure, and dedicated dosimetry sections in the SmPC — each of these requirements exists for a specific physical reason. Understanding this logic makes it considerably easier to build compliant documentation and avoid surprises during inspections.
Regulatory basis:
1. Decision of the Council of the EAEU Commission No. 77 dated November 3, 2016 (as amended by Decision No. 76 dated July 4, 2023), Annex No. 3 «Radiopharmaceutical Medicinal Products»
2. Decision of the Council of the EAEU Commission No. 78 dated November 3, 2016 «On the Rules for Registration and Expert Evaluation of Medicinal Products for Medical Use»
3. Order of the Ministry of Industry and Trade of the Russian Federation No. 916 dated June 14, 2013, Annex No. 3
4. Federal Law No. 61-FZ dated April 12, 2010 «On the Circulation of Medicines»
5. Pharmacopoeia of the Eurasian Economic Union, Part 3