Radiochemistry & manufacturing
Making one of these medicines means attaching a radioactive atom to a targeting molecule and getting it sterile and out the door within hours, before it decays away — a manufacturing problem unlike almost any other medicine.
Overview
Radiopharmaceutical chemistry starts by conjugating a chelator (most commonly DOTA or DOTAGA for metal radionuclides) onto a targeting ligand — a peptide, small molecule or antibody — via amine, thiol or click chemistry, then radiolabelling it with the chosen isotope, purifying it and formulating a sterile, injectable dose, all under current Good Manufacturing Practice. Antibody-based agents (e.g. 89Zr- or 177Lu-labelled antibodies) traditionally use random lysine conjugation, which gives a heterogeneous chelator-to-antibody ratio; site-specific conjugation methods are increasingly used to improve consistency and preserve binding affinity, though the benefit has to be demonstrated for each individual product (EJNMMI Radiopharm Chem, 2024).
Regulatorily, radiopharmaceuticals are treated as their own category: the EMA's draft revised guideline on the quality of radiopharmaceuticals (consultation closed 30 April 2026) sets out that manufacturing dossiers must describe the process from the nuclear transformation step onward, and that radionuclidic and radiochemical impurities need their own control strategy distinct from ordinary small-molecule drug substances. In the UK, amended Clinical Trials Regulations (in force 28 April 2026) set out which manufacturing and QP-certification steps for radiopharmaceutical investigational medicinal products can be split between an MIA(IMP) licence holder and an MS-licensed radiolabelling site.
The unresolved manufacturing problem is scale-up: batch sizes are defined by total radioactivity rather than mass, decay clocks run throughout production and shipping, and sterility testing often cannot be completed before a short-lived product must be released and administered, which is why radiopharmaceutical GMP release strategies (parametric release, real-time release testing) are an active area rather than a solved one.
Notes
top- Sterility testing of short-lived radiopharmaceuticals often cannot be completed before the product must be released and injected, because the isotope decays before the assay returns — this is a structural, not a compliance, problem.
- Site-specific conjugation improves consistency over random lysine labelling for antibody-based agents, but the clinical benefit has to be shown for each product individually; it is not yet a universal standard.
- The EMA's revised radiopharmaceutical quality guideline (public consultation closed April 2026) has not yet been finalised as of this record's date.