Scientists have used stable isotopes to trace the isotopic provenance of natural materials for decades, via isotope-ratio mass spectrometry. In just the last few years, multiple stable-isotopic analysis (MSIA) has garnered interest as a means of authenticating or fingerprinting APIs and drug products. Such analysis, a forensic or analytical means of product security, can complement overt and covert methods, such as RFID.
Stable isotopes exist naturally as mass variants of chemical elements, and are therefore part of every active ingredient or drug compound. Carbon-12, composed of six protons and six neutrons, accounts for just about ninety-nine percent of all carbon. By contrast, carbon-13, consisting of seven neutrons and six protons, accounts for one percent. The variation in the 13C/12C and other isotopic ratios of pharmaceutical components serve as tracers of identity.
Two factors affect isotopic ratios during batch reactions: the isotopic makeup of the raw materials and the process by which they are manufactured into APIs and drug products. Following a reaction, a numerical isotopic provenance can easily be established by measuring the isotopic ratios of the components. In other words, MSIA can help to identify which lot, and which manufacturer, produced a drug. It can also suggest the process by which the drug was made.
Molecular Isotope Technologies LLC, a Niantic, Conn.-based firm, is pioneering the application of this authentication technology. The company recently conducted studies with FDA to analyze the API naproxen. In 26 blind samples, it was able to distinguish product from six separate manufacturers.
We talked with MIT LLCs CSO John P. Jasper to see where MSIA is now, and where it is headed, as a drug security tool.
Note: While stable isotopes have gained a foothold in product authentication, MIT LLC and Johnson & Johnson are investigating ways of using them for process analysis. Initial studies look promising. Well talk with Jasper about the potential use of isotopes for process analysis in PharmaManufacturing.coms next PAT Insider newsletter.
PM: Isotopic analysis has been around for a while. Why is it just catching on as a means of product authentication?
JPJ: Before the mid-1990s, virtually no one that I had met in the pharmaceutical industry (or in specialty and bulk chemicals) was familiar with naturally-existing stable isotopes in pharmaceutical materials. As a marine organic and stable-isotopic chemist, it was immediately apparent to me that, since the production of pharmaceuticals is a batched and controlled process, isotopes had potential for product authentication.
PM: How will pharmaceutical firms use your services?
JPJ: We will have a two-pronged approach to supplying our stable-isotopic services: as an outsourced method in which samples are sent to us for analysis and as a licensed in-house procedure for pharmaceutical manufacturing firms. Our approach, with patents pending in seven of the G8 countries, is in the late R&D stages.
PM: What exactly can your company do for pharmaceutical firms?
JPJ: We have tested the method with a number of large pharmaceutical companies and with FDAs Division of Pharmaceutical Analysis and met with scientific approval. While many pharmaceutical companies have decided upon overt and covert methods for pharmaceutical security, the pharmaceutical community has not converged on a particular forensic (or analytical) solution. I believe that the search for optimal forensic methods is still underway and that MSIA is well considered because stable-isotopic tracers are intrinsic to all pharmaceutical materials, with nothing addedno impurities addedto those pharmaceutical products.
PM: What can isotopic analysis do that other analytical (or forensic) approaches to product authentication cant?
JPJ: Some major advantages of multi-stable-isotopic analysis are that:
- because stable isotopes exist in everything naturally, acting as natural tracers of origin or of isotopic provenance, there is no need to add any additional tracers with their attendant impurities to ones products;
- because the data are simple and numerical, they can be easily recorded and scanned by computerized search methods;
- because of the high precision with which they can be measured i.e., they have a high dynamic range (= observed range/1ï³ standard deviation) they individually and even more so in aggregate have a high specificity for batch-specific identification;
- the stable-isotope ratios are already internationally standardized by the International Atomic Energy Agency so all measured values can be directly compared.
JPJ: Isotopic analysis does not affect the product at all since stable isotopes compose all matter and they literally have been here since the origin of the Universe. They have been marching through pharmaceutical manufacturing plants since the first one was built and will continue doing so until the last closes. We just measure and record them.
PM: In your studies with FDA, isotopic analysis was able to distinguish between different manufacturers of the same APIs. How can it do this?
JPJ: For the blind samples that were provided to us by the FDA-DPA, we were given no indication of their provenance or source. When we plotted their carbon, oxygen, and hydrogen isotopic results in isotope bivariate plots, certain values clustered into relatively tight groups. We took these clusters to indicate similar sources. The DPA then informed us that our isotopic evaluation of sources corresponded directly to their known manufacturing sources.
PM: How should isotopic fingerprinting fit in with a firms multi-faceted (overt, covert and analytical or forensic) approach to drug product safety?
JPJ: Multi-stable-isotopic analysis is clearly a forensic or analytical method that would very likely be used in combination with other overt and covert techniques. While many overt and covert techniques typically focus on packaging, many forensic techniquescertainly stable-isotopic analysisfocus on the consumable drug product itself. As an organic chemist, I have always thought the most important thing was the consumable drug itself.
For detailed information and publications on the topics discussed above, and on Molecular Isotope Technologies, visit www.molecularisotopes.com/pdfs.html. To learn more about overt, covert and forensic product security methods, read Go Undercover from the October 2004 issue of Pharmaceutical Manufacturing.