Frequently-Asked Questions
Regarding Stable-Isotope Identification of Pharmaceuticals

When some members of the pharmaceutical industry first hear about the use of naturally occurring isotopes as a tool to prevent drug counterfeiting, they initially have some concerns about how the technique might bear on quality and efficacy. But as illustrated below, neither of these is affected at all, for the following reasons.

Background: A number of questions are ultimately based on the very high precision with which natural stable isotope ratios can be measured by isotope-ratio mass spectrometry. Measurement of such variations is typically reported in the "δ " notation; that is, "difference" in isotopic composition relative to internationally-accepted (NIST/IAEA) standards. Such changes typically occur in the fourth-to-fifth significant figures of the ratio measurements (0.0001 to 0.00001).

Question 1: What about "quality" matters? It is widely accepted in pharmaceutical and regulatory quarters that the isotopic variations observed in individual drug batches do not relate to "drug quality" such as efficacy, trace contamination, etc., but to the overall manufacturing "fingerprint" or "isotopic provenance" of drugs. The manufacturing fingerprinting is caused by two factors: raw materials and synthetic processes. (To a chemist, these factors are explicitly equivalent to "thermodynamics" and "kinetics." In other words, the system is wholly and rigorously defined.) With the acceptance that stable-isotopic composition does not relate to "quality," it is accepted as a "fingerprint" of source and "manufacture."

Question 2: What about "efficacy"? Natural isotopic variations are typically so very small that their effects on efficacy are so miniscule as to be unmeasurable. To an excellent approximation, stable-isotopic measurements are much more precise than any measurement of efficacy.

Question 3: "Radioactivity"? No. Stable isotopes are by definition non-radioactive.

Question 4: "Why not previously recognized?" An investigation in 1995 indicated that there was only one isotope-ratio mass spectrometer in the whole pharmaceutical industry indicating that natural stable isotopes were little known or used the industry. In fact, very few pharmaceutical chemists had any experience with natural levels of stable isotopes. With that, it has been a rewarding challenge to educate pharmaceutical colleagues – who are generally disposed to learning new chemical methods – on the utility of natural stable isotopes.