Common Sense: Reference Material

What is being used as reference materials in more complex medication leans towards the defiance of logic. Complex medication include but are not limited to the association of a drug substance and/or active pharmaceutical ingredient with a carrier entity. These entities may be antibodies as seen with antibody drug conjugates. They may also include the association of an active drug with a liposome, virus, bacteria, dendrimer, cyclodextrins, etc, etc, etc, In a very simple case this may include an active pharmaceutical ingredient with a salt that makes it more stable.

In any of these cases logic indicates that the way to assess any of the primary bioanalytica and PK/PD parameters id to use the drug substance or active pharmaceutical ingredient as the reference material. This is the primary touchstone of the analytical work and supports the ability to assess stability, interference, etc., etc., etc. Using the drug product increases the uncertainty of the assay and the assay results. Comparing recovery and stability of the analyte using drug product as the reference may give us measures that relate only to the drug product but not to the drug substance. For example, we may measure recovery of analyte from samples using drug product as a reference. Closer examination may show that the sample and reference result are identical. Because we are using drug product as the reference they may be identical but would differ from result using free drug-drug substance as the reference. This would be true for any experimental result where drug product but not drug substance is used as the reference.

These results are driven even further from what is accurate when other items are considered. For example, antibody drug ratios will vary widely as will the ratios or drug substance associated with dendrimers, liposomes, viruses and cyclodextrins. The only way to get accurate measures of the drug substance associated with any of these delivery systems is to use the drug substance-free drug- as the reference.

In addition however, total drug must also be measured after some manipulation to isolate the active drug from its carrier. Here again though, the measurement of total drug must also be made using free drug- drug substance-as the reference.

Two measures must be made to demonstrate accuracy of the measures- both using drug substance as the reference. In this approach the value of associating the drug substance with a carrier producing a drug product would be seen in terms of stability and PK profile, hopefully with the bound drug showing extended half life compared to free drug.

I would appreciate hearing from linked in members on this topic. Please review and post your thoughts