Are PET Drugs Safe?
1. Drug Design Considerations
The active ingredient in a PET drug is typically present in very low mass quantities. For example, the quantity of active ingredient in a single injection of FDG is in the range of tens of nanograms. This means that the active ingredient in a PET drug is administered in sub-pharmacologic amounts. This is an important element of the “tracer principle” associated with diagnostic PET imaging studies: the active ingredient does not alter the physiology of the biochemical process it is designed to study. In effect, this means that PET drugs are inert substances from a pharmacological perspective. This means that the injection of a PET drug is the equivalent of an injection of sterile water or sterile saline.
The short half-lives of positron-emitting radionuclides further enhance the safety profile of PET drugs. Long-term storage of PET drugs is not possible, which means that PET drugs more closely resemble “immediate use” medicinal products than traditionally manufactured injectable drug products. Other characteristics of the manufacturing process also reduce the potential for microbiological contamination. These include the use of microbiologically hostile and often lethal synthesis steps, pre-sterilized components, aseptic component assemblies and manipulations, and the use of closed containers during the manufacturing process. This results in an extremely low – typically zero – bioburden process stream before sterile membrane filtration in the final production step.
Together, the properties of PET drugs and their manufacturing processes define a unique class of drug products that have a wide margin of safety relative to their clinical indications.
2. Quality Control Considerations
Regulatory agencies emphasize the fact that the level of quality of PET drugs is expected to be similar to non-nuclear drugs. Because of the short shelf life of PET products and the large number of batches produced per year, maintaining this level of quality requires substantial tailoring of the management of quality risk to deliver cost-effective drugs.
Specific provisions are made for release of a batch prior to availability of sterility test results, for the enhanced use of periodic quality indicator tests (PQIT), and by providing additional flexibility regarding raw materials management through the quality system [i] , such as more extensive reliance on certificate of analysis (CoA)/Conformance (COC) [ii, iii] , . FDA also recognizes the unique nature of PET products regarding sterility assurance and the critical role of media fill activities [iv].
FDA conducts pre-approval inspections similarly to other pharmaceutical products, with minor allowances for practical reasons as outlined in the FDA PET inspection policy manual [v]. Most observations relate to microbiological control points, as expected for products produced aseptically and released prior to sterility results being available.
To date, the manufacturing history of PET manufacturers shows an exemplary record of microbial product quality, in alignment with an extremely high patient safety profile for all PET drugs produced in the US. The robustness of systems represents a unique opportunity for further engineering approaches and supports the growth of nuclear medicine as indications expand rapidly.
3. PET Drugs Safety Reporting Standards
PET drugs are subject to pharmaceutical drugs safety reporting requirements, whether at the IND stage [vi] or post-approval [vii], which may be tied to post-approval marketing studies [viii]. Of note, because PET drugs are inherently ionizing teratogenicity and carcinogenicity studies are typically not considered critical to PET drug development programs and the labeling information reflects the absence of data related to lactation and fetal/embryonic toxicity. As real-world evidence is collected, the data suggest that some PET drugs (e.g. 18-FDG) may be safe enough to be administered to women in the early phase of pregnancy [ix].
Footnotes:
[i] https://www.fda.gov/media/75187/download
[ii] https://www.ecfr.gov/current/title-21/chapter-I/subchapter-C/part-212
[v] https://www.fda.gov/media/82370/download