**Anti-Counterfeiting Drug Initiative: Fluorescent Materials**

**Docket \# 2003-0361**

Dr. William Coyle

Angstrom Technologies, Inc. 1895 Airport Exchange Blvd.,

Suite 110, Erlanger, KY 41018.

**SUBMITTION DATE (October 8, 2003)**; bcoyle@angtech.com

It is our belief that fluorescent materials could have a significant
role in a comprehensive drug authentication program due to their
ease-of-use, compatibility, sensitivity, and their usefulness as both
overt and/or covert taggants. The use of fluorescent materials as
security taggants is well known and the cost-to-benefit ratio of
selected fluorophores is excellent when compared to most other security
materials. The application methods used to encode various substrates are
numerous and include typical printing methods such as offset, flexo,
thermal transfer, ink-jet, gravure, litho, intaglio, and coating
methods. The authentication of fluorescent materials is done visually
and/or machine-read, depending on the design of the security feature.

As our core product line consists of organic fluorescent materials we
examined some possible uses for these and other fluorescent materials in
the Anti-Counterfeiting Drug Initiative. It is our goal to provide an
overview of the problem and suggest some possible areas of focus, along
with possible products that could be useful for this program.

For a drug authentication program to be successful the solution must
offer protection from the point of manufacture to sale to the consumer.
This presents a particular problem in that the consumer may not
comprehend the use of certain security features and can not be expected
to purchase a specific device necessary for authentication of the
particular drug they are consuming. Another problem is the variability
of the substrate (the drug supply) itself, with many different types
(over 4,000 in the Physician's Desk Reference alone**^1^**); different
dosage levels; many different forms, including pills, capsules,
injectables, liquids, etc.; and many different sources, i.e.
manufacturers, wholesalers, distributors, etc.

With respect to these problems and others, it seems necessary to design
a system with multiple security levels for each progressive step in the
delivery of the drug to the consumer. This would involve the
incorporation of security features into one or more of the following
areas:

1)  [Labeling]{.underline}: This would include features that are
    incorporated into the product label of the drug. These features
    could be identical for a specific drug or the same for all products
    from a certain manufacturer. An additional aspect would be to offer
    a detailed explanation of the actual drug, i.e. a complete
    description of the pill or capsule including size, shape, color,
    visible markings, etc.

2)  [Packaging]{.underline}: Each package could incorporate features
    such as tamper-evident seals, radio-frequency ID tags, or other
    features incorporated directly into the bottle or foil pack itself.
    An excellent example of packaging security is the DID® system
    developed by West Pharmaceutical Services**^2^**. This system uses
    custom designed Flip-Off® buttons commonly used for injectables to
    encode customer-designed information in full color graphics and can
    carry authentication technology, such as fluorescent taggants. This
    system has been adapted for use with injectables without changing
    the current methods of packaging.

3)  [Direct Incorporation]{.underline}: A much more complicated approach
    would entail incorporation of security features directly into the
    drug. This approach is thought to be the most secure, involving
    safe, edible taggants that would be authenticated with a random
    sample by an automated method. This approach would not likely be
    useful for medications that are directly injected into the
    bloodstream, but rather would involve oral drugs and taggant
    materials that would be non-toxic, have little to no
    bioavailability, or those materials that would be destroyed, or
    rendered harmless, in the stomach acid.

> This option is a possible long-term solution that would require
> significant capital for a discovery program and extended toxicological
> studies. It is thought that encapsulation of taggants with specific,
> non-toxic polymers would be the safest, quickest, and least expensive
> method for this option. The encapsulation of the taggant materials
> would have to be complete, providing zero bioavailability of the
> taggant, but if possible would allow the design of numerous taggant
> systems with a great deal of internal variety. This method is thought
> to be the most favorable since toxicological testing could be focused
> on the encapsulant material rather than each specific taggant.
>
> The use of naturally occurring fluorophores, such as proteins or other
> biochemicals, would be useful in this regard as well. Green
> fluorescent protein, quinine, FAD, FMN, NADH, riboflavin, algal
> proteins, phytochromes,
>
> and coral reef proteins are some well-known examples of this
> class**^3,4^**. These materials would generally be less toxic,
> however, also more expensive and less stable then other synthetic
> fluorophores.
>
> The direct incorporation of fluorescent materials into the coating of
> oral pharmaceuticals would offer another possible method. This is
> possible only if very small amounts of the fluorophore are necessary
> and the specific materials used were to pass toxicological testing.

4)  [Supporting Document Security]{.underline}: Incorporation of
    security features into the supporting documents of drug purchases,
    shipping and delivery documents, and licenses for the components of
    the distribution chain ("pedigree") would decrease the possibility
    that these documents were forged and would add to the overall
    security of the program.

There are many different types of commercially available security
features available for use in the labeling, packaging, and documentation
areas. These areas of security are very well developed when compared
with the concept of direct incorporation. Specific examples of these
features would include those placed into the paper, such as threads,
fibers, holograms, microtaggants, liquid crystals, watermarks, etc.
Ink-based taggants are an important example and offer a great deal of
variety in the number and types currently available. Ink-based features
can be readily changed and routinely include multiple types of taggants,
such as those based on UV-fluorescence and IR fluorescence. Ink-based
security features are readily machine authenticated and have the
potential to deliver data in the form of serial numbers, barcodes,
full-color pictures, etc. These features would generally be less
expensive because they do not have to cover the entire document, only a
small portion of it.

The advantages of fluorescent materials over other anti-counterfeiting
technologies is that they are useful in all of the areas discussed;
including labeling, packaging, document security; and although unproven
to date, offer the most promising method of the direct incorporation of
security features into the drug itself.

While Angstrom Technologies currently offers over 25 different
fluorescent materials, including both organic and inorganic UV- and
IR-fluorescent materials, our core product line involves organic
UV-fluorescent materials. We also have a number of proprietary organic
fluorescent compounds that have not yet been sold, but are ready for
large volume production. All of these compounds have unique properties
and fluorescent colors and are designed to offer minimum visibility
under normal lighting. An overview of our fluorescent compounds is shown
below in figure 1.

> ![](media/image1.jpeg){width="2.376388888888889in"
> height="2.5506944444444444in"}
>
> [Figure 1]{.underline}: **Selected Overview of Angstrom Fluorescent
> Chemicals**
>
> The left side of each circle represents the color of the compound
> under normal light (visible), while the right side of the circle
> represents the color under ultraviolet light (UV).**^5^**

Our Invisible Ink-Jet Printing System (patent pending**^6^**) was
developed as a method to quickly print an invisible security feature
after capture of an image -- preferably a full-color portrait. The
system was specifically developed using ordinary ink-jet printers
because of their cost, versatility, ease of use, and separate color
cartridges. These inks can also be used in commercial ink-jet printers
and have been tested for "on-demand" printing on a high-resolution
setting.

Black and white and/or monochromatic printing is also possible, but
still uses the same three color ink system. There are many different
modifications possible, particularly those involving different
substrates, images, and ink level modifications. Some examples of ink
modifications include the use of fluorescent materials that have
specific emission / excitation characteristics and additions to the
inks, such as IR-absorptive or emitting dyes, and short-wave dyes or

pigments. An example of the Invisible Ink-Jet Printing System showing a
normal print on top and the invisible print below is illustrated below
in figure 2.

> ![](media/image2.jpeg){width="2.1569444444444446in" height="3.25in"}
>
> ![](media/image3.jpeg){width="2.227777777777778in"
> height="3.222916666666667in"}
>
> **Under Normal (visible) light Under UV (ultraviolet) light**
>
> [Figure 2]{.underline}: **Invisible Ink-Jet Printing System Example**

These are digital photos of actual ink-jet prints under regular tungsten
and UV lighting. The photos were digitally edited for size and color
correction solely to compensate for the limitations of the camera under
UV light, mainly due to limitations in the detection of yellow light.
The UV lighting does impart a purple hue to the image that could not be
corrected, which is not present when the image is seen with the naked
eye. **As illustrated, the picture on the left bottom half of the print,
under visible light, does not show an image; whereas the picture on
right bottom half, under UV light, gives a complete, full color,
high-resolution reproduction of the original.**

Another specific product suitable for this program is Angstrom's
patented Secure Toner technology. This product is currently available in
three types, Secure Toner™, Secure Toner with MICR™, and Invisible
Secure Toner™. This technology incorporates fluorescent materials into
specially developed laser toner. The Secure Toner type looks like normal
black print when viewed under normal, ambient lighting, but when
illuminated with UV light, it fluoresces in a specific color. While this
technology is currently limited to the use of organic fluorescent
materials, it has to date only been produced in blue, green, yellow, and
yellow-green fluorescent colors. This product is currently available in
many Hewlett Packard and Minolta brand laser printer cartridges, and can
be custom developed for most other brands of printers and/or with
proprietary fluorescent compounds. The Invisible Secure Toner is not
visible under normal, ambient lighting, but becomes visible only when
illuminated with UV light, and along with the Secure Toner types, has
been designed to withstand extreme temperature, humidity, and light
exposure without a noticeable loss of resolution compared to the
original toner. This technology is inexpensive as well, with an
estimated cost of \$0.06 per page based on an 8.5 x 11" sheet of paper
with 5 % coverage, similar to that of a typical business letter. For a
standard address label the cost has been estimated at \$0.002 per label.

Authentication of the security features is extremely important in a
program such as this due to the complexity of the distribution chain,
the number of people involved, and the need for fast and reliable
detection. For certain applications machine authentication is the
preferred method, however, the instrument requirement limits the scope
of people that can readily authenticate the feature and adds a
significant cost to the program. Fluorescent materials are commonly used
as public security features and can be found in the currency of many
different countries. In this regard, primary authentication is
accomplished by simple illumination with UV light. Machine
authentication of fluorescent materials is most often based on
measurement of emission wavelength and intensity (concentration) of one
or more compounds. A more secure method of authentication includes
determination of the emission decay time (fluorescence lifetime)**^7^**.
Angstrom Technologies offers a complete line of authentication devices
(scanners) for fluorescence detection. In most cases, these
authentication devices cost between \$1,000 -- 8,000, and similar to the
fluorescent chemicals, the pricing is volume dependant.

The scope and complexity of the Anti-Counterfeiting Drug Initiative
seems to have much in common with the problems faced by our government
and others in the creation of secure currency. While the similarities
are obvious, the major difference would be the lack of a single
controlled source and the inherent difficulties this presents. It is
thought that a model similar to that used in currency could be developed
that would incorporate both public (overt) and covert security features,
allowing for both visual and machine authentication of the products
involved. This would reduce the dependence on a single technology and
increase the complexity of the system, while increasing the number of
individuals that could authenticate the product, at least on a primary
level. Forensic features could also be included in many different areas,
and would likely serve as the most secure features, however, they would
also be the most expensive, difficult, and slowest to authenticate.

Equally important as the technical aspect, is the administrative
framework under which this initiative is developed and managed. It is
within the scope of the FDA to develop and enforce standards; however,
there remain a number of questions as to how these standards are to be
implemented. These are important questions to the technology provider in
that the administrator of this initiative will exert significant control
over the technology market. It is our belief that creation of uniform
standards will foster competition and increase innovation in the type,
number, and complexity of new and existing anti-counterfeiting
technologies.

Acknowledgements:

> I would like to thank the following individuals: Brian Dempsey for his
> work with the photography and digital editing of the photographs;
> George Littrell, Dr. Marshall Wilson, and Steven Brooks, M.D. for
> helpful discussions.

Notes / References:

1)  Information obtained from the internet.

2)  Information obtained from the internet:
    <http://www.westpharma.com/products/did.asp>.

3)  Information obtained from the internet:
    <http://www.bdbiosciences.com/clontech/gfp/index.shtml>

4)  Lakowicz, J. R. *Principles of Fluorescence Spectroscopy*; Kluwer
    Academic/Plenum, New York, 1999; 2^nd^ Ed., p 82-89.

5)  The colors illustrated have been digitally edited to match, as close
    as possible, the colors seen with the naked eye due to photographic
    constraints. Standard photographic lighting was used for the same
    reasons.

6)  Coyle, W.; Smith, J. U.S. Provisional Patent \# 60/460,599; 2003.

7)  Jones, G.; Yan, D. U.S. Patent \# 6,402,986; 2002.