To follow up, blind isotopic studies were initiated by the Division of Pharmaceutical Analysis of the US Food and Drug Administration (St. Louis, MO) to determine whether isotopic analyses of drugs could be used to identify the manufacturing source. In the first of two studies, researchers demonstrated that stable-isotopic analyses could distinguish among individual manufacturers and batches of four active pharmaceutical ingredients (APIs) produced by nine manufacturers (4). A second study examined the ability of stable-isotopic analyses to differentiate manufacturer sources of an API as it was transported across national borders. All six manufacturers of the API (naproxen) were recognized successfully (5).
The results demonstrate the utility of stable-isotopic analysis for monitoring and identifying pharmaceutical products and manufacturers, thus providing a new tool for product security and drug authentication. It also can be used to monitor process consistency (i.e., the changes or modifications that occur during the various synthetic steps in a pharmaceutical drug-manufacturing process).Another area that is of interest for stable-isotopic analysis is its use as a forensic tool in cases of process patent protection. Two sets of variables are pertinent: the stable-isotopic compositions of the starting materials and synthetic intermediates, and the isotopic fractionations that occur during production. Understanding the extent of isotopic fractionation that occurs at each step in a synthetic route can provide valuable insight into which process was used.
To fully elucidate the isotopic fractionations that occur between reaction steps, it is ideal to have at least 0.1 mg of all intermediates and products for each stable-isotope ratio being measured.