Abstract from Updated Presentation

John P. Jasper¹, Robbe C. Lyon², and Larry E. Weaner^3
1Molecular Isotope Technologies, LLC, 8 Old Oak Lane, Niantic, CT 06357-1815, USA;
²Division of Product Quality Research, CDER, FDA, White Oak Life Sciences Building 64, 10903 New Hampshire Avenue, Silver Spring, MD 20993-0002, USA;
³Johnson & Johnson Pharmaceutical Research and Development, L.L.C., PO Box 776, Welsh and McKean Roads, Spring House, PA 19477-0776, USA

Since 2001, there has been an incremental transition in the use of stable-isotopic analysis from pharmaceutical authentication to preliminary assessment for Process Analytical Chemistry (PAC). By way of background, the stable-isotopic compositions of such materials are a function of two variables: the initial stable-isotopic composition of the intermediates and reagents used in synthesis and the isotopic fractionation that occurs during manufacturing processes. This transformation follows the characteristic progress from observational science (pharmaceutical authentication) to mechanistic science (PAC). There have been five major steps in this transformation:

• The observation of batch-to-batch stable-isotopic composition of two over-the-counter analgesic drugs, performed with Micromass UK (Jasper et al., 2003, FIRMS Newsletter 1(3):4-5; Jasper et al., 2004, Pharm. Technol. 28(8):60-67);
• The ability to distinguish six manufacturers of a single Active Pharmaceutical Ingredients (API), Naproxen, in a blind study performed for the FDA-DPA (Jasper et al., 2003, FIRMS Newsletter 2(1):3; Wokovich et al., J. Pharm. Biomed. Anal., submitted);
• The ability to distinguish individual manufacturers and batches of four APIs produced by nine manufacturers also in a blind study performed for the FDA-DPA (Jasper et al., J. Pharm. Biomed. Anal., 2004, 35:21-30);
• A preliminary study with Johnson & Johnson to distinguish three synthetic pathways of one API, Topiramate, performed on archive samples in which the stable-isotopic composition of the reagent raw-materials was not isotopically controlled (Jasper et al., 2004, FIRMS Newsletter 2(2):8-9; Jasper et al., J. Pharm. Biomed. Anal., submitted); and,
• Fully-controlled studies are presently underway to constrain the major variables (i.e., the raw materials and synthetic pathways) that determine the isotopic composition of pharmaceutical materials. With that, the isotopic composition of pharmaceutical products can be predicted and synthetic processes plausibly monitored, finding useful application in the R&D laboratory as well as in pharmaceutical manufacturing and authentication.

The principles of stable-isotopic authentication of pharmaceutical materials (Jasper, 2004, Tablets and Capsules 2(3):37-42) have been widely accepted in the pharmaceutical and may be applicable to regulatory issues. This presentation is summarized in an invited article entitled “Progress from Stable-Isotopic Authentication to Process Analytical Chemistry” (Jasper, Lyon, and Weaner, Pharm. Mfg., 2005, 4(5):28-33).