Abstract
The development and commercialization of high-quality handheld spectrometers has enabled the use of a new set of tools for rapid, remote, and real-time anti-counterfeiting measures—blurring the previous distinction between covert and forensic protections by making spectral identification a reality in the field. Emerging regulatory requirements for serialization have not eliminated the need for authentication. It is now possible to screen products and packaging instantly, on-site, without any wet chemistry or chemists. Better authentication methods make it possible to test more efficiently, and target security resources to catching and deterring counterfeiters, ultimately protecting patients. In this article, we provide several examples of near-infrared spectroscopy (NIRS) techniques developed and commercialized for authentication and counterfeit detection for commercial pharmaceutical packaging.
Introduction
Brand protection is a strategic imperative for every pharmaceutical manufacturer, packager, and distributor. Maintaining supply chain integrity and keeping patients safe presents perhaps the greatest challenge to companies in the drug marketplace, including branded, generic, and over-the-counter products. Expensive products, including the newer biologics, present a major lure to counterfeiters and diverters, given the extraordinary illicit profit opportunities from even a handful of successfully marketed fakes. But the problem extends across price ranges: the target is one of opportunity, and highvolume/ lower cost products are also vulnerable. Brand protection measures are essential, and there is a growing consensus that standalone instant authentication is a key element of a comprehensive anti-counterfeiting strategy.
The development of small, highly accurate, and affordable spectroscopic devices has made worldwide authentication by non-experts a real possibility. One way to take advantage of these devices is to create taggant recipes that can be detected spectroscopically. The taggant is not a single substance (which might be more vulnerable both to reverse-engineering and to its own supply disruptions). Instead, it is a chemical code, which is more versatile in that it offers combinatoric possibilities yielding innumerable options. More to the point, spectrometers for field use by non-specialists give yes/no, match/no-match answers without providing any evidence of the underlying algorithms or computations.
Covert chemical taggants provide a weapon in the fight against fake medicine by enabling authentication throughout the supply chain. Until now the use of covert taggants in anticounterfeiting has involved rare or crafted molecules paired with highly complicated and cumbersome detection techniques. This approach is based upon the assumption that if the anti-counterfeiting measures employed are sufficiently complicated and expensive, the protections they offer will remain beyond the reach of those attempting to replicate them. Today that assumption appears faulty. The level of technical ability demonstrated by counterfeiters has risen dramatically in recent years and shows no sign of abating. Fakes can no longer be identified by misspellings on packaging. Many illicit manufacturers have moved beyond the “quick score” and now aim to sell mock versions that are good enough to garner repeat customers. These sophisticated operations are capable of producing something akin to a generic copy of a legitimate product—but with no cGMP procedures: no quality control, no clean rooms, no accountability. In addition, these same counterfeiters have become impressively skilled at mimicking a wide array of packaging-based brand protection measures by deploying their own holograms, their own UV ink, and their own fluorophore taggants. Simply elevating the complexity and expense of a brand protection measure is no longer a reliable obstacle to duplication.
The approach described here addresses protection needs across the marketplace without the need to escalate costs and complexity. This spectroscopy-based brand protection returns the anti-counterfeiting advantage to legitimate manufacturers, packagers, and distributors using inexpensive, instantly verifiable chemical taggants. The system relies on a set of commodity chemicals arrayed in a code. The code is employed to tag products and packaging so that these items can be quickly and easily authenticated in the field without disclosing the underlying components of the coding scheme. The system is compatible with many types of drug packaging including paperboard and labels, borosilicate glass vials, polypropylene caps and bottles, syringes, shrink wrap, lacquer, aluminum shells, and plastic vial buttons. Code-based spectroscopic tagging can create a vast array of unique chemical codes, many of which may be applied to the surface of or embedded directly into the packaging.
The work described here uses commodity chemical compounds shown to meet rigorous specifications for spreading capacity, color fastness, temperature, humidity, and many other user requirements dictated by regulatory, as well as manufacturer, needs. The ability of UV-cured commodity chemicals to apply and adhere to a wide range of materials and remain undetectable in the visible spectral region is a key enabler of the technology. The NIR region of the electromagnetic spectrum has been shown to be useful for distinguishing specific regions of absorption of compounds not present in an authentic substrate.1 Likewise, the use of taggants purposely used to label a substrate can be used for authentication. This property is what makes the selected compounds particularly effective as covert taggants: the potential counterfeiter is unaware of their presence, and does not even know to search for them. They are undetectable to the naked eye, but detectable to the spectrometer.
We describe a brand protection system employing a 3-step process: develop suitable formulation(s) from commodity chemicals, apply the selected formulation, and verify that chemical code contained in the applied formulation exhibits the desired spectral absorption attributes.
Methods
This experiment demonstrated the efficacy of the chemical tagging process on paperboard using techniques similar to those previously validated with plastic stick-on labels, parenteral vials, and steel electronic components. Application was performed by mixing the taggants into materials used in paperboard manufacture. Note that other spectroscopies may be used, such as midinfrared or Raman, but in this work we report specifically on the application of diffuse reflectance NIR to detect applied taggants.
The authors use chemicals generally recognized as safe (GRAS) for pharmaceutical applications.
Results
The results of this work show that there are specific and easily discernible differences between untagged and tagged packaging and products when seen in the near-infrared spectrum (780 nm to 2500 nm). However, these differences were entirely undetectable to the naked eye in the visible spectrum (400 nm to 800 nm). These differences between tagged and untagged subjects are evidenced in the resultant formulation spectra by the presence of specific absorption bands in the NIR region. These absorption bands are not present in untagged packaging and products, thereby demonstrating the utility of the methods for discriminating between packaging and products that have taggant material versus those that do not.
Benefits
No Reverse Engineering. The most effective anti-counterfeiting solutions deny security personnel access to the coding employed to protect the product being examined. That is, brand protection best practice is to separate what is needed to detect counterfeits from what is needed to create counterfeits. Spectroscopy is ideal here: a handheld spectrometer can provide an instant “Yes/No, Green/Red, Match/No-match” answer. For the advanced user, it can provide spectral and chemometric data. Nevertheless, a counterfeiter with a good spectrometer and software will not be able to make the connection from a spectrometer reading—“(1429, 0.2) (1640, 0.3) (1803, 0.17)”—to the covert taggant code that produced it. NIR spectra are comprised of broad and overlapping overtone and combination bands arising from the primary mid-infrared bands. This fact, coupled with the additional process steps taken to add or coat the product with said taggant, confounds the NIR spectra even further. The tagged product spectrum that now contains information about both the chemical taggant as well as the physical changes that gave rise to it results in a unique pattern that is specific only to that package. Furthermore, the technique can be massively scaled. That is, additional taggants may be added, increasing the number of wavelengths. By doing so, yet another variation can be introduced. Another dimension is added when the concentrations of each of the taggants are varied, such that the absorption function of the bands introduces variation in the spectrum.
Scales Well, Green. The anti-counterfeiting approach described here uses non-toxic commodity chemicals as taggants, and commercial off-the-shelf spectrometers as field detectors. Because this solution avoids proprietary techniques, molecules, and instruments, it can be scaled quickly.
Combinatoric Smarts. The combination of commodity (inexpensive) chemicals to create a taggant code provides a solution that is inherently cost-effective. Yet combinatoric possibilities of these compounds offer packagers and manufacturers the choice of innumerable secure codes.
Commodity Chemicals. By employing inexpensive commodity chemicals as taggants, the cost of this brand protection technology scales well, making it available to generics and over-the-counter drugs.
Testing at Multiple Points. Most manufacturers do not worry about counterfeits during the production process. However, the growth of contract manufacturing and other outsourcing suggests that it is prudent to verify materials at various points in the supply chain.
There are several handoffs in the process of getting the product from the manufacturer, through packagers and distributors and finally to the patient, and each of them provides an opportunity for counterfeiting and diversion. If quality is not confirmed near the consumer, quality may not be delivered. The feasibility of field testing is demonstrated by the work described here. The testing should be a full profile, not a single-ingredient test that could be adulterated. Counterfeiters are increasingly savvy and single-ingredient taggants and tests can be spoofed, as the pharmaceutical scandals with diethylene glycol, melamine, and heparin remind us. The most secure method in the long run is testing at or near the point of dispensing via spectroscopic analysis. Field spectroscopy offers robust protection for its ease of operation, speed, and low cost, and delivers a rapid, non-invasive, non-destructive, and portable chemical analysis.
Hardware. Relevant hardware developments include the emergence of highly capable pocket-size spectrometers from companies such as Texas Instruments and JDS Uniphase, as described by Coates.2
Experiment 1
Coating for Paperboard
- Covert taggant mix applied on paperboard at 4 concentrations: 5%, 15%, 20%, and 30%
- Taggant had to meet color specification
- Taggant had to meet texture specification
- Taggant had to meet GRAS specification
Detectability is the key characteristic of the commodity chemicals proposed for use as taggants, but they have other distinguishing features as well: they can be spread out into thin films, they adhere well, their viscosity is appropriate, and they cure quickly. When considered together, these properties make the tagging solution flexible and costeffective for brand protection.
Spectral Results
The spectra in Figure 1A show specific differences between tagged and untagged paperboard, with the red showing anticounterfeiting taggant, clearly differentiated from the untagged paperboard shown in black.
Figure 1. Spectral differences between tagged and un-tagged paperboard.Experiment 2
Coating For Pharmaceutical Aluminum Vial Tops
- Covert taggant mix applied on aluminum shells at 3 levels of thickness: 3 mil, 5 mil, and 10 mil
- Taggant had to meet colorfast specification
- Taggant had to meet autoclaving specification
- Taggant had to meet irradiation specification
- Several UV cured taggants 3met specifications
Figure 2. NIR spectrum of untagged, tagged, autoclaved, and irradiated aluminum vial shells (Red).
Figure 2 shows the NIR spectrum of untagged, tagged, autoclaved, and irradiated aluminum vial shells (red). The taggant absorption bands can be seen as distinct features and are discernibly different from the spectrum of the respective untagged aluminum shells (black). NIR spectroscopy was used to distinguish the presence or absence of taggants from their substrates. Additional factors include the properties of the chemicals to be spread out into thin films, their adhesive properties, their viscosity, and their UV curing properties.
Conclusions
Commodity chemicals can be used for the purpose of formulating taggants for coating packaging and product components. The formulations must exhibit a range of properties that are required for the explicit purpose of remaining undetected in the visible spectrum but exhibit specific absorption bands in the NIR spectrum that allow detection when an NIR spectrometer is used to locate the presence of specific absorption bands arising only from the formulated coating material.
The covert nature of the taggants makes it hard for counterfeiters to detect their presence, much less copy them. The use of hand-held instruments for field authentication makes it easier to test more, protect more, and better target prevention, security, and forensic resources.
References
- Burns DA, Ciurczak EW, eds. Handbook of Near-lnfrared Analysis, Third Edition. Boca Raton London New York: CRC Press, Taylor & Francis Group; 2008.
- Coates J. A review of new small-scale technologies for near infrared measurements. Am Pharm Rev. 2014;17(4):74-78.
Author Biography
Gary E. Ritchie is Director of Scientific Affairs for InfraTrac, Inc., located in Silver Spring, MD. Gary is an internationally recognized expert in pharmaceutical analysis, regulatory compliance, laboratory management, design quality, and process analytical technology (PAT) using spectroscopic methods including near-infrared and multivariate analysis. Gary has 19 years of industry experience with increasing responsibility, 5 years of policy experience, and ongoing consulting experience in the pharmaceutical and biopharmaceutical industry. He was Scientific Fellow for Process Analytical Technology with the United States Pharmacopeia (USP) and Liaison to the General Chapters, Pharmaceutical Waters and Statistics Expert Committees from 2003 through 2008. As a USP in-house expert on the FDA Process Analytical Technology and Quality by Design Initiative, he was responsible for over 30 Pharmacopeial chapter revisions that incorporated and reflected the revisions by the FDA on the 21st Century cGMP Initiatives. He also led collaborations on several FDA, USP, and industry projects that resulted in several Pharmacopeial standards. Gary has more than 25 peer-reviewed papers and book chapter contributions, 5 issued patents, and numerous industry journal articles, and has been invited to give many conference and symposia presentations worldwide. He was President of The Council for Near-Infrared Spectroscopy (2012–2014). Gary holds a Master's of Science and Bachelor of Arts degrees in Biology from the University of Bridgeport.