Untangling the web of European regulations for the preparation of unlicensed radiopharmaceuticals

Abstract

Radiopharmaceuticals are highly regulated, because they are controlled both as regular medicinal products and as radioactive substances. This can pose a hurdle for their development and clinical use. Radiopharmaceuticals are fundamentally different from other medicinal products and these regulations are not always adequate for their production. Strict compliance may have a huge resource impact, without further improving product quality. In this paper we give an overview of the applicable legislation and guidelines and propose a risk-based approach for their implementation. We focus on a few controversial Good Manufacturing Practice topics: cleanroom classification, air pressure regime, cleanroom qualification and microbiological monitoring. We have developed an algorithm to assess the combined risk of microbiological contamination of a radiopharmaceutical preparation process and propose corresponding Good Manufacturing Practice classification levels. In our opinion, the risk of carry-over of radiopharmaceuticals by individuals cannot be contained by pressure differences, and complicated regimes with underpressured rooms are not necessary in most situations. We propose a sterility assurance level of 10 for radiopharmaceuticals that are administered within a working day, irrespective of their use. We suggest the adoption of limits for environmental monitoring of microbial contamination, as proposed by Bruel and colleagues, on behalf of the French Society of Radiopharmacy. Recently launched regulatory documents seem to breathe a more liberal spirit than current legislation and recognize the need for the use of risk assessment. We argue that future legislation be further harmonized and state risk assessment as the gold standard for implementation of drug quality regulations for the preparation of unlicensed radiopharmaceuticals.

68Ga-Based Radiopharmaceuticals: Production and Application Relationship

“…The contribution of EANM, SNM and researchers around the world to the current advances in the regulatory aspects of PET radiopharmaceutical is considerable. Such issues as: regulatory documentation regarding small scale preparation of radiopharmaceuticals and the impact of the obligation to apply for manufacturing authorization or clinical trial; compliance with regulatory requirements for radiopharmaceutical production in clinical trials; quality of starting materials and final drug products/radiopharmaceuticals were thoroughly analyzed [55,56,57,58,59,60]. Guidelines on Good Radiopharmacy Practice (GRPP) [61]; patient examination protocols, interpretation and reporting of the patient examination results [62,63]; Investigational Medicinal Product Dossier; and Exploratory Investigational New Drug that reduce the demand on toxicity studies and respective cost burden as well as allow easier understanding of the regulatory requirements [64,65,66] improve professional communication and standardization.…”

Clinical translation of theranostic radiopharmaceuticals: Current regulatory status and recent examples

“…Several articles summarize the regulatory framework for radiopharmaceuticals in Europe and specifically the regulation on early‐phase clinical trials . Radiopharmaceuticals are defined as medicinal products, also including kits, radionuclide precursors, and generators.…”

Initiierung klinischer Multicenter-Studien mit lokaler Radiotracer-Herstellung

“…Der Aufsatz richtet sich an Studien-leiter und Fachkräfte aus Radiopharmazie und Nuklearmedizin und soll im Sinne von "Lessons learned" Anregungen in Ergänzung zu den vielen Gesetzen, Verordnungen, Normen, Leitlinien und Standards geben, die zur gesetzeskonformen Herstellung und Verteilung von (radioaktiven) klinischen Prüfpräparaten (engl. Investigational Medicinal Product, IMP) für prospektive klinische Studien bereits veröffentlicht und allgemein zu beachten sind [11][12][13]. Als Grundlage dienten den Autoren neben der Fachliteratur insb.…”