CGMP Radiosynthesis for Early Phase Clinical Trials: A Unique Challenge and Development of a Standard Process

WHITE PAPER

Wayland Rushing, Ph.D., Kevin Roberson

ABSTRACT

Purpose Radiolabeled drugs are used in Human ADME and bio-availability studies. While the regulatory requirements for traditional “cold” clinical trial materials are well understood, the regulatory requirements for radiolabeled are much less understood by industry. The synthesis of radiolabeled compounds sometimes requires development of new synthetic pathways which can be significantly different from the traditional synthetic pathway. The radiolabeled drug can have significantly different stability and impurity profiles from the non-labeled drug and thus require special considerations. These special considerations may pose challenges in terms of ensuring CGMP compliance and safety for the patient during the clinical trial. This presentation discusses the challenges associated with radiolabeled synthesis coupled with maintaining CGMP compliance for the synthesis and analytical portions of the program.

Methods A standardized process has been in development for implementing CGMP requirements for early phase clinical compounds to radiolabeled drugs for human studies. The typical procedure for generation of the final compound for dosing requires blending the radiolabeled drug with the nonlabeled drug to meet a certain radioactivity (specific activity). Both the labeled and non-labeled drugs need to be manufactured under CGMP requirements prior to the blending process. The release testing, under CGMP, is complicated by the need to determine not only the chemical purity, but also the radiochemical purity of the drug substances or drug products. Our standardized process addresses these challenges that are inherent in developing and validating specific analytical methods required for the radiolabeled drug substances and drug product.

Results A standard process for ensuring regulatory compliance is presented and discussed. Case studies are presented for different scenarios.

Conclusions By implementing the standard process, radiolabeled drugs are produced which meet phase appropriate CGMP compliance.

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