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Attention:

Division of Dockets Management (HFA-305)

Food and Drug Administration

5630 Fishers Lane,

Rm. 1061

Rockville, MD 20852

http://www.Regulations.gov

**RE: Docket No. FDA-2008-N-0121**

> **Technologies for Prescription Drug Identification, Validation, Track
> and Trace, or Authentication**

The Food and Drug Administration (FDA) has requested comments and
information regarding technologies used for the identification,
validation, tracking and tracing, and authentication of prescription
drugs.

FDA has asked specific questions to which we are responding with
comments below:

1.  **What are the RFID technologies, encrypting technologies and
    nanotechnologies that are relevant? What are other relevant
    technologies?**

Although RFID may have many good applications in the future to
potentially add track and trace security into the supply chain
throughout the distribution system for drugs, these benefits stop at the
point where the package that incorporates the RFID tag is no longer
relevant. In many cases, the package with the RFID tag does not make it
all the way to the patient due to repackaging that can happen at many
different places and for different reasons. Additionally, RFID and the
associated databases which would allow for true track and trace are
technologies that are probably a number of years away from being
technically feasible and fully utilized in the manner which has been
desired by FDA's Counterfeit Task Force

**[On-Dosage Anti-counterfeiting Technology Comments]{.underline}**

Protecting the dosage itself, which is ingested by the patient, should
be a critical concern in the hierarchy of counterfeit-resistant
technologies. Protection must start with the identification and
authentication of the dosage because the distribution process for drugs
involves repackaging, which is a vulnerable point for counterfeit
product introduction, where the dosage becomes separated from the
"protected package". "Salting" authentic products with counterfeit
products often occurs during repackaging. Counterfeit-resistant
technologies for "protecting the package and supply chain" will be far
more effective when the dosage itself is also protected with on-dosage
identification and authentication technology.

On-dosage identification and authentication technologies can help
mitigate the security concern of repackaging and "counterfeit salting".
On-dosage technology can ensure that the dosage itself is identifiable,
protected and authenticated.

Micro-taggant and/or chemical taggant technology is commercially viable
today, and ensures pharmaceutical product authenticity [at the dosage
level]{.underline}. These taggant technologies provide quick, confident,
and economical identification and authentication of pharmaceutical solid
dosages in the field. [The micro-taggant technology provides for
information-centric marker placement on each tablet to enable absolute
identification and authentication]{.underline}. New colorant
technologies can also be used to provide unique colors and images that
are recognizable by the patient but difficult to duplicate by the
counterfeiter.

***Micro-taggant Technology Comments***

Micro-tags are covertly applied to solid dosage forms as well as to
packaging, and package inserts. This technology employs commonly used
excipients on the surface of a pill, usually applied in a film coating
on the surface of tablets or incorporated into the shell of capsules.
The micro-tag, comprised of these commonly used excipients, is inert and
odorless, is not visible without magnification, and embodies unique
indicia (customized to the requirements of the pharmaceutical
manufacturer to include any desired information (such as encrypted
codes, NDC code, manufacturing site, export/import information, channel
of distribution, manufacturer logo, etc.) that can be readily identified
through optical magnification. The micro-tag is designed to not impact
the manufacturability of the dosage unit or the coating process control
and is designed to not impact chemical or physical stability or drug
release. Micro-tag technology is anticipated to be interoperable with
Track and Trace ePedigree systems (Relevant comments are included in our
response to Docket No. FDA-2008-N-0120) regarding interoperability with
Track and Trace ePedgree standards development). The micro-tag
information-centric indicia can include a 2D barcode for electronic
scan-ability of the individual pills. Encrypted codes can be
incorporated into the indicia. The information-centric indicia on the
pill can be linked to package serialization, bar codes, RFID codes or
similar micro-taggant indicia included on drug packaging. This linkage
establishes the parent-child relationship between the pill and the
package.

***Chemical Taggant Technology Comments***

Chemical-tags are covertly applied to solid dosage forms. This
technology employs FDA accepted excipients on the surface of a pill,
usually applied in a film coating on the surface of tablets or
incorporated into a capsule. Chemical tags are currently employed today
on a number of prescription pharmaceutical dosages in the United States.

A range of FDA and globally approved regulatory ingestible
authentication markers is available today, which can authenticate the
product itself. In such circumstances, ingestible markers are designed
to be inert, odorless, colorless and tasteless to ensure that the
finished product is not impaired in any way. Typically, ingestible
markers are inserted at parts per billion levels. At such low
concentrations, they cannot be detected by conventional chemical
analysis, but are detected unequivocally by customized readers and test
kits.

***Visual Identification Technology Comments***

Visual technology begins with color. A good color match is a challenge
for a counterfeiter when trying to replicate an innovator drug. Although
this may be able to be accomplished with enough time and effort, it is a
first step to protecting the public via visual identification. Uncoated
white tablets simply allow the counterfeiter to compress a core which
can be nothing more than a placebo. The nude tablet provides no
counterfeiting protection to the public in that it is not discernable
from a visual perspective.

State-of-the-art visual technology can now employ pearlescent, glossy
colors that are very difficult to replicate. The pearlescent colors are
compliant with FDA regulations. Each film coating system can be
customized-by-product via trade-secret formulation. This
quality-by-design (QBD) color match, pearlescence and gloss level is
extremely difficult to replicate by a counterfeiter. This is because the
color pearlescent gloss coatings provided by these systems are built
upon a double layer coating process which employs a color subcoating
with a top layer pearlescent coating. The levels of coating, the grade
of pearlescent pigment as well as the specific coating ingredients used
all have an impact on the final tablet color and image. All grades of
the pearlescent pigment are qualitatively the same and only vary in
their physical morphology thereby making it extremely difficult to
determine what is being used by analysis..

***Self Authenticating System Comments***

The "on-dosage" taggant technologies discussed above can also be applied
"on package" or linked to the package, for example via bar coded
information. In this way, the information contained in the on-package
taggant or bar code must "match" the information contained in the
on-dosage taggant. In its simplest form, a match provides a
"self-authentication" of the solid dosage without the need for a
sophisticated database for track and trace. A mismatch or pills with no
microtag indicia indicates a counterfeit replication of the drug. If,
for example, an on-dosage microtag contains a bar code that carries the
same information as a bar code on the package, then the dosage is
authenticated. Encryption of the information can further secure this
self authentication process. This information can be electronically
linked with RFID, thereby completing the ePedigree track and trace
objectives from the manufacturer to the patient at all levels of
distribution right down to the point of dispensing of the drug. With an
electronically scannable pill, the benefits can extend beyond
anti-counterfeiting authentication to include patient safety aspects of
reduced medication error in pharmacies, healthcare facilities, etc. by
eliminating human error during dispensing. ePrescribing could then be
linked to eDispensing to ensure that the right patient receives the
right drug at the right time.

2.  **Please provide information related to: Strengths for
    identification, validation, track and trace, or authentication;**

***Micro-taggant Technology Comments***

Micro-taggant technology provides absolute identification and
authentication and is expected to be interoperable with track and trace
systems. The identification and authenticating strength of the micro-tag
is derived from:

-   Its unique indicia link with each drug (e.g. manufacturer, NDC code,
    manufacturer logo, product name/logo, etc.)

-   The indicia is known only to the pharmaceutical manufacturer and the
    taggant manufacturer. The pharmaceutical manufacturer can change the
    taggant indicia at-will during production, and in this way only the
    pharmaceutical manufacturer will know the proper micro-taggant
    indicia for a specific drug manufacturing location, lot number, etc.

-   The indicia cannot be manufactured by the counterfeiter. It would be
    extremely hard for a counterfeiter to figure out how to produce
    these microtags due to a complex manufacturing process. If that
    capability were somehow to be overcome by the counterfeiter, then
    the pharmaceutical manufacturer could change or vary the
    micro-taggant indicia information as a moving target to prevent a
    supply chain security breach by a counterfeiter.

-   The supply chain for the microtag is secure (Proprietary trade
    secret & manufactured in the United States)

-   The pharmaceutical manufacturer can change the taggant indicia based
    upon manufacturing lot, location of manufacture, etc. The actual
    materials used in the taggant would remain the same. Only the
    indicia would change thereby mitigating any concern about changes in
    the qualitative formulation.

-   The application of micro-taggants does not add a manufacturing step
    and does not impact the manufacturability of the dosage form or the
    process controls.

-   Micro-taggants are manufactured from commonly used excipients.

-   Micro-taggants provide field investigators with a quick and easy
    test of suspect material.

***Chemical Taggant Technology Comments***

Chemical taggants provide absolute authentication. Chemical taggants are
not interoperable with electronic track and trace systems, but can link
with serialization to provide an effective authentication link of the
dosage to the track and trace ePedigree. Chemical taggants are covert,
and are not intended to enable product identification by the patient.
The authentication strength of the chemical taggant is derived from:

-   Its covert chemical identification with each drug

-   The chemical taggant is known only to the pharmaceutical
    manufacturer and the taggant manufacturer. The pharmaceutical
    manufacturer can change the chemical taggant at-will during
    production, and in this way only the pharmaceutical manufacturer
    will know the chemical marker for a specific drug manufacturing
    location, lot number, etc.

-   The chemical taggant cannot be easily reverse analyzed and included
    by the counterfeiter. If that capability were somehow to be overcome
    by the counterfeiter, then the pharmaceutical manufacturer could
    change or vary the chemical marker as a moving target to prevent a
    supply chain security breach by a counterfeiter.

-   The supply chain for the chemical taggant is secure (Proprietary
    trade secret & manufactured in the United States)

-   The pharmaceutical manufacturer can change the chemical taggant
    based upon manufacturing lot, location of manufacture, etc.

-   The application of chemical taggants does not add a manufacturing
    step and does not impact the manufacturability of the dosage form or
    the process controls.

-   Chemical taggants provide field investigators with a quick and easy
    test of suspect material.

***Visual Identification Technology Comments***

Pearlescent color and color shifting film coating systems are a strong
product identifier to help the patient and pharmacist assess the
identity and potential authenticity of the drug product especially when
combined with dosage design parameters including shape, logo, and
imprint code.

Pearlescent color coated pills can be rendered via a bi-layer coating
process. Because the color subcoat system is sandwiched between the
tablet and the pearlescent top coating, it would be extremely difficult
for a counterfeiter to identify the color specifications for the subcoat
and the pearlescent top coating, and thereby create an exact counterfeit
product from a visual perspective.

An additional identification feature which adds further complexity to
counterfeit reproduction is the pearlescent color shifting surface of
the tablet. Much like a hologram, the color shifting coating can be
combined with other taggant authentication technology on the solid
dosage to maximize both tablet identification and authentication. The
color shifting pearlescent visual effect can be replicated on the
package which creates another challenge to the counterfeiter during
counterfeit repackaging and counterfeit "salting".

Combined with uniquely designed tablet shapes and size, the combined
pearlescent- shaped tablet adds significantly greater difficulty to
counterfeit replication. Unique shapes would require special tablet core
tooling to create a counterfeit product. Although tooling copies might
possibly be made via a manufacturing process called investment casting
(for example), the counterfeiter would need to take this step which is
not necessary when standard oval, round and capsule shaped tablets are
designed into the innovator drugs.

By combining color pearlescent shifting coatings with tablet shape and
imprint code, product identification is strong to the patient as well as
the healthcare industry.

2.  **Continued: Please provide limitations for identification,
    validation, track and trace, or authentication**

***Micro-taggant Technology Comments***

There are no limitations related to identification, validation or
authentication. Track and Trace interoperability will be dependent upon
the standards set by FDA.

***Chemical Taggant Technology Comments***

The determination of authenticity is destructive to the solid dosage.

***Visual Identification Technology Comments***

Pearlescent color and color shifting film coatings do not authenticate
or provide track and trace or validation of the product. However, they
do provide a good tool to help patients and Health Care providers
identify potential counterfeits before they are taken so that they can
then be authenticated.

2.  **Continued: Please provide costs of implementation and use;**

***Micro-taggant Technology Comments***

Micro-taggants can be applied to film coated pills for nominally one
cent per tablet in the manufacturing process (Nominally a \$1.00
increase in manufacturing cost for 100 tablets). [Example, 100 tablets
selling at \$10/tablet would have a selling price of \$1000. Adding the
cost of the on-dosage anti-counterfeitng taggants, the selling price
would increase to nominally \$1001.00.]{.underline}

Micro-taggants can be applied to tablets with existing pharmaceutical
manufacturing facility film coating equipment. [No additional capital
investment is required to add micro-taggants to the film coated
tablet]{.underline}.

[The inclusion of micro-tags into film coated tablets has no impact
(positive or negative) on productivity (manufacturing production
rates).]{.underline}

***Chemical Taggant Technology Comments***

Chemical taggants can be applied to film coated pills for nominally one
cent per tablet in the manufacturing process. (Nominally a \$1.00
increase in manufacturing cost for 100 tablets). [Example, 100 tablets
selling at \$10/tablet would have a selling price of \$1000. Adding the
cost of the on-dosage anti-counterfeitng taggants, the selling price
would increase to nominally \$1001.00.]{.underline}

Chemical taggants can be applied to tablets with existing pharmaceutical
manufacturing facility film coating equipment. [No additional capital
investment is required to add chemical taggants to the film coated
tablet]{.underline}.

[The inclusion of chemical tags into film coated tablets has no impact
(positive or negative) on productivity (manufacturing production
rates).]{.underline}

***Visual Identification Technology Comments***

Pearlescent color coatings can be applied to film coated pills for
nominally 1/10th of a cent per tablet in the manufacturing process
(Nominally a dime increase in manufacturing cost for 100 tablets).
[Example, 100 tablets selling at \$10/tablet would have a selling price
of \$1000. Adding the cost of on-dosage identification technology, the
selling price would increase to nominally \$1000.10.]{.underline}

Pearlescent film coatings can be applied to tablets with existing
pharmaceutical manufacturing facility film coating equipment. [No
additional capital investment is required to add pearlescent coatings to
the film coated tablet]{.underline}.

2.  **Continued: Please provide benefits to the public health;**

**Benefits to the Public Health Comments**

***Counterfeit Prescription Drug Prevention:*** Pharmaceutical
counterfeiting is a global problem affecting the health and lives of
people around the world. Counterfeit drugs present a global financial
burden as well as a health and safety burden, currently projected to
approach \$75 billion (U.S. Dollars) in lost pharmaceutical sales
revenues by 2010. In 2006, 3.4 billion prescriptions were dispensed in
the U.S. If only 1% of those drugs were counterfeit (current estimate of
counterfeit drugs within the United States is just under 1%), 34 million
U.S. prescriptions would be affected. Globally, the WHO estimates that
10% of the global drug supply is counterfeit.

***Medication Error Prevention:*** The National Institute of Medicine
reported in 1999 that medical mistakes kill between 44,000 and 98,000
Americans each year. In 2006, the Institute reported that medication
errors are among the most common medical errors harming at least 1.5
million patients every year. The medical cost impact of these medication
errors is estimated to be a minimum of \$3.5 billion a year.

***Micro-taggant Technology Comments***

Micro-taggant technology can serve a dual purpose in serving the public
regarding the availability of safe drugs. The first benefit is in
protecting the public against counterfeit drugs. The second benefit is
in protecting the public against medication errors:

*Counterfeit Drug Protection*

-   On-dosage micro-tag technology, if matched with on-package indicia
    can provide a "self-authenticating" process for a pharmacist to
    match drug information on the package with the drug information
    contained in the micro-taggant indicia contained on the surface of
    the solid dosage. The advantage of this on-package and on-dosage
    link is that the information can be changed by the pharmaceutical
    manufacturer "at-will" to provide a moving target authenticating
    system.

-   On-dosage micro-tag technology can be simply applied to the solid
    dosage to provide a covert authenticator. Due to the secure supply
    chain and trade secret manufacturing process of one manufacturer in
    the United States, it is unlikely that a counterfeiter would be able
    to manufacture the microtag indicia.

-   On-dosage micro-taggants are being developed to enable bar code
    scanning of microscopic bar codes included in the micro-taggant
    indicia present on the film coating of tablets. These microscopic
    bar codes would be invisible to the human eye. This on-dosage
    micro-taggant technology is envisioned to not only be interoperable
    with ePedigree Track and Trace systems for anti-counterfeiting
    applications, but also provide an automated tablet
    counter/identification/authentication system to complement the
    triple check systems already in place in pharmacies. This would
    provide an automated system to reduce medication errors as well as
    authenticate and count tablets during the dispensing process. The
    system could also reduce the workload of the pharmacist during
    prescription dispensing.

-   These quick identification and authentication systems are covertly
    applied to the dosage form, and can provide Customs Border
    Protection with efficient field determinations of a product's
    authenticity or counterfeit status since the micro-taggants can be
    read using a relatively inexpensive reader that could be used in the
    field.

*Medication Error Prevention*

-   The development of the on-dosage 2D bar coded micro-tag interface
    with bar code scanning devices in pharmacies would enable a fast
    method to potentially identify, count (as well as authenticate)
    pills. This would enable the bar coded microtagged solid dosage to
    be interoperable with ePrescribing systems thereby aiding in the
    dispensing process to reduce medication error due to human error.

***Chemical Taggant Technology Comments***

*Counterfeit Drug Protection*

-   On-dosage chemical taggant technology can be simply applied to the
    solid dosage to provide a covert authenticator. Due to the secure
    supply chain and trade secret manufacturing process of one
    manufacturer in the United States, it is unlikely that a
    counterfeiter would be able to identify and manufacture the chemical
    taggant specified for the drug. Low concentrations make detection by
    conventional means difficult, reducing the likelihood of detection
    and identification by the counterfeiter.

-   These quick identification and authentication systems are covertly
    applied to the dosage form, and can provide Customs Border
    Protection with efficient field determinations of a product's
    authenticity or counterfeit status.

***Visual Identification Technology Comments***

*Medication Error Prevention*

-   Several pharmacy chains require tablet shape, color and imprint
    information on prescription labels. Unique color, shape and imprint
    code tablet design would aid in differentiating medications, and
    reduce human error during dispensing or administration of drugs.

**2. Continued: Please provide feasibility for widespread use**

***Micro-taggant Technology Comments***

On-dosage micro-taggant technology can comply with global regulatory
requirements. It is a technology that is very economical and can be
applied by pharmaceutical manufacturers worldwide. Each product can be
uniquely identified, and there is no limitation to the combinations of
indicia available for product applications. Pharmaceutical companies
worldwide can use the micro-tags in existing manufacturing facilities.
No process changes are necessary. On-dosage micro-taggant technology can
verify authenticity of solid dosages in 3^rd^ world countries where
there may be no network database available. The system does not require
sophisticated equipment or the internet to function with complete
reliability 24/7/365 anywhere in the world.

***Chemical Taggant Technology Comments***

On-dosage chemical taggant technology meets global regulatory compliance
requirements. It is a technology that is very economical and can be
applied by pharmaceutical manufacturers worldwide. Each product can be
uniquely identified, and the chemical identification cannot be reverse
analyzed by counterfeiters. Pharmaceutical companies worldwide can use
the chemical tags in existing manufacturing facilities. No process
changes are necessary. On-dosage chemical taggant technology can verify
authenticity of solid dosages in 3^rd^ world countries.

***Visual Identification Technology Comments***

Pearlescent color film coating systems are FDA and EU compliant and can
be applied by pharmaceutical manufacturers in existing film coating
equipment. Prescription drugs employing pearlescent film coating systems
have been developed and are currently pending FDA approval.

2.  **Continued: Please provide utility for e-pedigree**

***Micro-taggant Technology Comments***

On-dosage micro-taggant technology can be linked with on-package bar
code identification and RFID identification in a parent-child
relationship. In this way information-centric micro-taggants can provide
ePedigree and Track and Trace linkage from the manufacturer to the
pharmacy at the point of dispensing. The use of information-centric
micro-taggants would enable a patient to maintain privacy through the
dispensing process since the micro-tag would be covert beyond the
pharmacy.

***Chemical Taggant Technology Comments***

On-Dosage chemical taggant technology would not have direct utility for
ePedigree applications

***Visual Identification Technology Comments***

Pearlescent Color coating technology would not have direct utility for
ePedigree applications

3.  **Is the technology interoperable with other technologies? If so,
    describe.**

***Micro-taggant Technology Comments***

On-dosage information-centric micro-taggant technology is anticipated to
be interoperable with electronic track and trace e-pedigree
technologies. It is also interoperable with packaging security
technology.

***Chemical Taggant Technology Comments***

On-dosage chemical taggant technology is interoperable with packaging
security technology.

***Visual Identification Technology Comments***

Pearlescent color and color shifting (hologram) technology is
interoperable with packaging security technology.

> **4. What standards are necessary for supply chain use of the specific
> technology? What is the status of development of such standards?**

***Micro-taggant Technology Comments***

The standards necessary for supply chain use of on-dosage micro-taggant
technology include:

-   Optical or electronic magnification device (estimate \$200 equipment
    cost per device) to read the micro-tag and authenticate the drug.
    Bar code scanning with magnification would enable electronic
    interoperability with bar code and RFID electronic Track and Trace
    systems

-   Status of Development: Optical and electronic magnification devices
    are commercially available. Bar code scanning is in development, and
    anticipated to be commercial in 2008/2009. It is also anticipated
    that these systems will be interoperable with bar code
    anti-counterfeiting systems currently being developed in Europe.

***Chemical Taggant Technology Comments***

-   A proprietary test kit (resembling a pregnancy test kit) would be
    required to authenticate a solid dose drug

-   Status of Development: The system is completely commercial, and is
    being applied to several Rx drugs in the United States

***Visual Identification Technology Comments***

-   Not Applicable

> Status of Development: No standards required since this is a visual
> identification system for human perception which relies on a
> comparison to previously used dosage forms. Benefits could result if
> FDA would include a high resolution picture of the approved dosage
> form and a detailed description of the various overt design features
> in drug approval documentation and any databases that are maintained
> which could be made available to the public so that patients and
> health care providers could check what the standard color, color
> shift, logo image, shape and size should look like.