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***MOLECULAR ISOTOPE TECHNOLOGIES, LLC***

Dr. John P. Jasper, Chief Scientific Officer

8 Old Oak Lane, Niantic, CT 06357-1815 U.S.A

860-739-1926 (Office) 860-739-3250 (Fax)

<JPJasper@MolecularIsotopes.com>

[www.MolecularIsotopes](http://www.MolecularIsotopes/).

Dr./Esq. Ilisa B. G. Bernstein October 20, 2003

Office of Policy

HF-11, Room 17-35

5600 Fishers Lane

Rockville, MD 20857

Re: FDA Anti-Counterfeit Drug Initiative: Multi-Stable Isotope Analysis:
A Forensic Identification Method for Combating Drug Counterfeiting.

Dear Dr./Esq. Bernstein:

This written comment is submitted in connection with Docket No.
2003N-0361. This comment respectfully urges the FDA Task Force on Drug
AntiCounterfeiting in its final report to include an express reference
to multi-stable isotopic analysis ("MSIA") as a potential forensic
identification method that can be used in combating drug counterfeiting.
Among the reasons that MSIA merits express reference in the final report
are:

-   It represents a technology that is available and widely in use
    today.

-   It relies upon inherent, natural properties of pharmaceutical
    materials themselves, and thus does not require addition of foreign
    substances or "taggants" and their inherent impurities.

-   It has been the subject of joint studies with the FDA.

-   It is a cost-effective forensic identification method.

I. [Background]{.underline}. From a scientific perspective, there are at
least 252 naturally-occurring stable isotopes. A ratio of any two of
those isotopes in a given pharmaceutical component can be used as a
tracer of a product's identity. We typically use a combination of
stable-isotope ratios of 3-4 elements (Carbon, Nitrogen, Oxygen, and
Hydrogen) with great success as tracers of stable Isotopic Product
Authenticity with both pharmaceutical clients and with our FDA
collaborators (see below).

Basic facts regarding MSIA, agreed upon by leading authorities of
stable-isotope chemistry, can be summarized as follows:

>  \
> 1.  That the mass spectrometric technology is in place for use in such
> application. 
>
> 2\. That stable isotopes are natural components of pharmaceutical
> materials.\
> 3.  The observed, batch-to-batch variability in stable-isotopic
> compositions of Active Pharmaceutical Ingredients is highly
> significant.  Particularly when isotopic compositions of Carbon,
> Oxygen, and at least one other element can be compared, it provides a
> strong basis for determining the origins of these substances.

-   John M. Hayes, Ph.D. Director, Accelerator Mass Spectrometry
    Laboratory. Woods Hole Oceanographic Institution, MS 8. Woods Hole,
    MA 02543-1539.

Tel: 508-289-2585. Fax: 508-457-2183

-   J. Thomas Brenna, Ph.D. Professor & Director of Undergraduate
    Studies, Division of Nutritional Sciences. Member, Graduate Fields
    of Chemistry and Chemical Biology and of Geological Sciences.
    Cornell University. Savage Hall. Ithaca, NY 14853. Tel:
    607-255-9182. Fax: 607-255-1033.

II\. [FDA Joint Studies]{.underline}. The FDA's Center for Drug
Evaluation Research (CDER) and Molecular Isotope Technologies have
jointly undertaken a number of studies of the identity of Active
Pharmaceutical Ingredients and other pharmaceutical components. The
results of a blind study on the "isotopic provenance" of a suite of APIs
are scheduled for accelerated publication in 2003 (see accompanying
manuscript by J. P. Jasper, B. J. Westenberger, J. A. Spencer, L. H.
Buhse, and M. Nasr, "*Stable Isotopic Characterization of Active
Pharmaceutical Ingredients*," in the *Journal of Pharmaceutical and
Biomedical Analysis*.). Joint studies showing the isotopic provenance of
a single API (*viz*., Naproxen) produced by a variety of manufacturers
from many countries have been recently presented at international
meetings this year (the annual *Am. Soc. Mass Spectrom.* meeting in
early June; the Oak Ridge National Laboratory Meeting on "*Mass
Spectrometry and Homeland Security*" in mid-September; and most
recently, at the FDA's Anti-Counterfeit Drug meeting on October 15th).

III. [The MSIA Technology Exists Today]{.underline}. The instrumental
     technology ("isotope-ratio mass spectrometry") and international
     standards for the technique of MSIA already exist and are widely
     deployed. The instruments ("mass spectrometers") are produced by
     major manufacturers including ThermoFinnigan (see accompanying
     literature and their website
     [www.thermofinniganmat.de](http://www.thermofinniganmat.de/)) and
     GVI (www.gvinstruments.co.uk). International standardization of the
     method is provided by the International Atomic Energy Agency
     (IAEA).

IV\. "[No Added Impurities": Neither Taggants nor Other Foreign
Substances Need be Added.]{.underline} The use of naturally-existing
stable isotopes in their ambient concentrations adds no additional
impurities to pharmaceutical products. As intrinsic components of
regulatorily pre-approved materials, stable isotopes are natural tracers
that are simply transported along the pharmaceutical supply chain "from
cradle to grave." Stable isotopes naturally trace the combined effects
of raw materials and synthetic pathways (*i.e*., combined thermodynamic
and kinetic variables), they have tracked the isotopic provenance of
materials since the origin of the Universe.

V. [Multiple Stable-Isotopic Analysis is a Cost Effective Forensic Tool
to Combat Drug Counterfeiting]{.underline}. The use of MSIA as a
forensic tracer of identity has proven value in highly-specifically
identifying the origin of pharmaceutical components in the late research
and development stage. As previously observed in the petroleum industry,
optimization of the application of stable-isotopic tracers in the
manufacturing environment minimizes cost and increases effective use of
the technique.

VI. [Conclusion]{.underline}. Thank you for your consideration of these
    formal Comments. The author appreciates both the opportunity to have
    presented background on MSIA at the Task Force' public meeting on
    October 15, 2003 in Bethesda, Maryland, as well as to submit these
    comments.

> Respectfully Submitted,
>
> Dr. John P. Jasper
>
> Cc.: Dr. Moheb Nasr

Dr. Frederick Fricke

> Dr. Lucinda Buhse
>
> Dr. Moheb M. Nasr
>
> Office of New Drug Chemistry (ONDC, CDER, FDA)
>
> 5600 Fishers Lane, 13B31
>
> Rockville, MD 20857
>
> Dr./Esq. Ilisa B. G. Bernstein
>
> Office of Policy
>
> HF-11, Room 17-35
>
> 5600 Fishers Lane
>
> Rockville, MD 20857
>
> Dr. Fred Fricke
>
> FDA Forensic Chemistry Center
>
> 6751 Steger Drive
>
> Cincinnati, OH 45237
>
> Dr. Lucinda Buhse
>
> FDA, Center for Drug Evaluation and Research
>
> 1114 Market St., Room 1002
>
> St. Louis, MO 63101