Radiolabeled CTMs in Early Phase Development under GLP

By Wayland Rushing, Ph.D.

Senior Scientific Advisor

ABC Laboratories

www.abclabs.com

Radiolabeled products are used extensively during pre-clinical studies in BA/DMPK studies. The material used for these studies is typically research grade material released under Good Laboratory Practices (GLP’s). However radiolabeled drugs are also used during ADME and bio-availability studies. Since the products are now intended for use in human studies, they now must comply with CGMP regulations in terms of its manufacture and release testing.

While the processes by which CGMP’s are applied to the synthesis, control and testing of non-labeled materials is well understood, we have found there is a fair amount of confusion in terms of the regulatory requirement and how to apply those to radiolabeled products.  Here I want to address one specific aspect of this: Analytical Methods and Testing.

Typically during the point in development that CGMP radiolabeled materials are needed, significant work has been performed on the unlabeled material.  This normally means that analytical methods and testing specifications have already been developed and validated accordingly.  There are two issues which may occur in implementing these analytical methods for testing of the labeled material:

·       Impurity profiles: The impurity profile of the radiolabeled material may be significantly different than the un-labeled material.  This may be the result of the synthetic route having to be altered to prepare the labeled material and/or  radio-induced degradation which can lead to new impurities being formed.  This requires evaluation of the existing methods to ensure that they still properly work for determination of the chemical purity without interferences.

·       Radio-purity determination: One of the key specifications of the labeled material is the radio-purity of the final material.  The existing analytical methods are not able to determine this as it requires the use of a radio-detector (typically in-line with HPLC).

Since the testing of the final material is required to be CGMP compliant then the methods used are required to be developed and phase-appropriately validated for their intended use.  As a result the analytical testing for radio-labeled materials can be a complex process requiring: method transfer (of existing methods), method development and phase appropriate method validation.  Hence it is critical that at the initiation of a CGMP radiolabeling program a thorough plan is designed and implemented to ensure that not only is the material synthesis accordingly to meet the regulatory needs, but also that the analytical methods are also appropriate for use for the testing and release of the final product.

I will expand on this topic at the 12^th International Symposium on the Synthesis and Application of Isotopically Labelled Compounds on the campus of Princeton University June 7-11.  Join me at 10:30 AM June 11 for a podium presentation titled, “CGMP Radiosynthesis for Early Clinical Trials: A Unique Challenge.”