Masterarbeit

Chemical precursors for radiopharmaceuticals – regular active pharmaceutical ingredients or do they require special considerations ***

Sandra Hofmann (2025)

Summary 

Language: English

Radiopharmaceuticals are a niche segment of the pharmaceutical industry with increasing sales. In comparison to conventional pharmaceuticals there are main differences in the production process by combining the chemical precursor and the radionuclide in a radiolabelling reaction. The production is being done immediately before use, this is caused by the short half-life of the used radioisotopes. The production is either done with a ready to use kit eg. 99mTechnetium radiopharmaceuticals or via synthesis modules. The module synthesis is very common with fluorinated radiopharmaceuticals. Both preparation methods are batch-synthesis. Usual batch sizes reach from 1 to about 30 patients. Caused by this small batch size the handling and quality control differs from conventional pharmaceutical production, which should be reflected in the legal requirements and required specifications for radiopharmaceuticals. Like other medicinal products, radiopharmaceuticals need a marketing authorization according to article 6 of Directive 2001/83/EC before placing on the market. However, when considering further regulation governing radiopharmaceuticals, it becomes challenging. 

Especially, for the term chemical precursor for radiopharmaceutical preparations the European, German, US, and Australian pharmaceutical legislation was searched for a definition. Furthermore, several guidelines, Ph.Eur. and USP were searched for a definition of the term chemical precursor. At the end only the definition in Ph.Eur. 2902 could be found. No definition could be found in German legislation or in the laws of the USA and Australia. Furthermore, the limits specified in Ph.Eur. 2902 were not used for all chemical precursors, as the guideline on radiopharmaceuticals Rev. 1 defines chemical precursors in kits as active substances. In this case the use of Ph.Eur. 2034 caused reducing the limits of any unspecified impurities in the specification of the chemical precursor and this reduces the amount of these impurities from 0.60 µg to 0.15 µg per patient dose. Both limits are far below the TTC of 1.5 µg per day as defined in ICH M7 (R2) (ICH, 2023) and the question about improvement of patient safety occurs. The specification defined in Ph.Eur. 2902 is therefore applicable for all chemical precursors, independent of the further production process of the chemical precursor for radiopharmaceutical preparations.

Since the definition of a chemical precursor is currently only enshrined in Ph.Eur. and not in pharmaceutical legislation, there is room for improvement. Examples of improvement are the current revision of EU Pharma package, which still does not include the definition of a chemical precursor or the adaptation of Guideline on radiopharmaceuticals, which is still under revision. Within the Update of the Guideline on radiopharmaceuticals, the fragmentation of CMC documentation into 3.2.S(1) part for the chemical precursor, 3.2.S(2) part for the radiolabelled drug substance and 3.2.P part for the finished formulated drug product should be described to clarify in which sections of the dossier the quality information about the chemical precursor is depicted. 

Beside the Eudralex Volume 1, Eudralex Volume 4 Annex 3 should be adapted and the definition of a chemical precursor could be added to the glossary of this annex. 

Furthermore, after the definition will be implemented into EU Pharma package the AMG in Germany should be adjusted. In this regard, legislators should ensure that all definitions are transposed into German law. Currently, not all definitions from Directive 2001/83/EC have been implemented in the German Medicines Act (AMG), e.g. the definition of a kit is still missing, which leaves room for interpretation.

Other competent authorities can then follow the European example and adopt their legislation, such as the FDA with the amendment of the Code of federal regulation in the USA or the Therapeutic Goods Administration with the Therapeutic Goods Act in Australia. This would provide further legal certainty and a uniform assessment of chemical precursors for radiopharmaceutical production. This is particularly necessary in view of the continuing increase in the number of oncological diagnoses, the resulting growth in diagnostic methods, and the improving individualized medicine, and would ensure consistent quality of medicinal products and patient benefits.

Pages: 56

Annexes: 0; Pages: 0