UV Laser Marking to Combat Drug Counterfeiting

The FDA defines counterfeits as fake or falsified medicines that “may be harmful to your health because while being passed off as authentic, may contain the wrong ingredients, contain too much, too little or no active ingredient at all or contain other harmful ingredients.”¹

Combating drug counterfeiting can be roughly divided into technological segments including quality control, serialization, track-and-trace and authentication, and regulatory affairs such as legal frameworks, international cooperation, public awareness, and others. This paper outlines a method of drug authentication by UV laser marking solid dosage forms.

Most technological advances in anti-counterfeit efforts relate to tamper-proof packaging, track-and-trace labeling, and corresponding database management systems. However, these approaches are not very effective if the drugs are repackaged in multiple distribution centers scattered around the world. For example, RxNorth.com² — a Canadian internet pharmacy that delivered drugs made in China using an elaborate route from Hong Kong to the UAE to the UK, the Bahamas, back to the UK, and finally to consumers in the USA — pleaded guilty to conspiracy to commit mail fraud in 2012.³ Today, according to the FDA, there are roughly 35,000 active online pharmacies, and only 5% follow US pharmacy practice standards.⁴

From this perspective, authentication on the level of individual tablets and/or capsules can be a game changer. Ideally, a scanning device would analyze a tablet, determine API and other excipients, compare with tabulated values, and greenlight if there is a match. A comprehensive review of the methods used for this purpose is given in reference ⁵Deviceses based on high-performance liquid chromatography, FTIR, NIR, or Raman spectroscopy can easily detect fraud, but they can hardly fit in consumer pockets (both literally and figuratively) and cannot be used for every tablet in question. Marking individual tablets with a unique and easily identifiable code seems more practical. That, for example, can be a QR code with a factory lot serial number easily traceable to the source. A consumer could then validate the medicine by scanning the code with a regular smartphone application and accessing a corresponding database. The database, of course, should be encrypted to prevent unauthorized access but that is likely a quite manageable “software” problem. The real “hardware” problem is marking equipment since traditional ink-based offset and/or ink-jet technologies do not have the resolution required to make a readable 2D code on a small tablet surface. Even if they had it the print would not be durable enough to survive the long journey from manufacturer to consumer. This is where UV laser technology comes into the picture. UV laser irradiation can produce legible printing on a tablet surface either by selectively removing material from the very top layer without damaging the surrounding area (micro-etching or ablation) or by changing the color of UV-sensitive excipient distributed within the top layer (marking).

K. Ludasi, et al.⁶ have analyzed the applicability of UV laser ablation for 2D coding of pharmaceuticals. As expected, they found that the resulting etching depth, surface roughness, and, consequently, the marking appearance depend on the coating composition since every excipient might react differently. For example, a naturally pigmented surface can be etched uniformly while one doped with Titanium Dioxide (TiO₂) cannot. Alternatively, for a successful UV laser marking only one photosensitive component must be present. For example, the presence of TiO₂ in the coating is a necessary — and in most cases sufficient — marking condition independently of other excipients in the formulation. The first system for the pharmaceutical industry based on this principle was developed by Tri-Star Technologies in 2002.⁷ A detailed description of UV laser marking of tablets and capsules containing TiO₂ is given in reference 8.

An obvious advantage of laser marking versus laser etching is that the applied laser fluence (the amount of total laser energy incident on a unit area of material surface) required to change color is much lower than to remove material. Therefore, only a specific excipient gets affected by UV radiation leaving the rest of the materials intact. Another advantage is marking durability. Because of limited pigment concentration, color-changing particles are distributed through the material volume with relatively large distances between each other, like balls scattered on a pool table, except for having the same color. That makes the tablet surface partially transparent to the laser beam allowing color change in the deeper layers. The marking “under the skin” is naturally protected by the skin from the environment and is impossible to alter without significant surface degradation detectable by the naked eye.

For example, gelatin films are transparent to UV light while yellow color additive strongly absorbs it and changes to grayish brownish. Figure 1a is an oversimplified illustration of the phenomenon in space and time. An incident laser beam propagates through the top slice of material (a monolayer with a thickness comparable to the average pigment size), interacts with yellow pigments losing a fraction of its energy by turning them brown, and moves further down through the next layers until most of the laser pulse energy dissipates (D-layer). That usually happens within the top 50-100 layers, restricting marking depth to about 50um which is far below the thickness of a gelatin shell, and preventing laser radiation from reaching the API inside. The process is quite short in time as well since laser pulse duration does not exceed 50ns.

Figure 1b shows an actual cross-section of gelatin film used in soft gel production marked in a dot matrix manner. Note that the extension of the marking (dark) areas under the surface does not exceed 50um while the film thickness is about 800um. In contrast to gelatin film the coating thickness for many solid tablets is below 100um,⁹ however, the laser beam does not reach the API under the coating either. Here the marking depth is restricted to just a few layers since the pigment concentration is much higher. Typical gelatin shell formulation has about 1% of TiO₂ ¹⁰ while typical Colorcon coatings for solid dosage forms have 20-30%.¹¹

Figure 2 presents 2D codes imprinted by UV laser on tablets with coatings containing Titanium Dioxide and/or Yellow Iron Oxide. Despite the limited area and high density of the pattern, the marking resolution makes the code easily readable using a regular smartphone application. Depending on the code size and complexity, tablet surface properties, and other features, an advanced laser marking system can process 10 to 100 tablets per second which is a common production rate in the pharmaceutical industry. In general, printing the same code, referring, for example, to a lot number, on all tablets in the batch should enable traceability of each tablet by the consumer. In addition, unlike pad printing, laser technology allows changing the print on the fly. This opens the door to serialization since each tablet in the batch can be marked differently.

UV laser marking technology is easily scalable from a small R&D system printing one tablet at a time to high-rate manufacturing. Low-volume inexpensive tablet printers not bigger than a regular desktop computer can be placed at points of sale such as pharmacies, clinics, etc. This would allow a unique identification of each tablet at the time it is dispensed, adding another layer of security to prevent drug counterfeiting and overdose. For example, imprinting personal identity information such as names, licenses, and/or prescription numbers enables tracing pharmaceuticals back to patients, prescribing physicians, dispensing pharmacists, etc. Figure 3 shows a photo with the picture ID of the author and a generic fingerprint pattern printed on the tablets.

Biometric information such as fingerprints or picture IDs can also be marked and used to verify both a prescription and a patient. In a multi-person household, medications can easily get mixed up. The picture on the pill gives an instant clue as to whom it belongs. Paramedics responding to possible overdose cases can determine if the drugs found on the patient were prescribed to the patient by simply looking at the picture. Scanning the QR code on the other side can offer instant access to lifesaving information about the drug. Law enforcement officers can ascertain if the person in possession was indeed prescribed the medication, and if not, further investigation can be done to help fight drug abuse in the system.

Of course, imprinting personal information on pills can be controversial, requires cooperation on all levels including federal and state authorities, drug manufacturers, pharmacies, and end users, and won’t happen overnight. The purpose of this article, however, is to illustrate technical capabilities that are readily available and can be used to combat drug counterfeiting today. The CDC has reported that more than 93,000 people died of an overdose in the US in 2020.¹² Clearly, time is of the essence.

References

1. https://www.fda.gov/drugs/buying-using-medicine-safely/ counterfeit-medicine
2. https://www.justice.gov/opa/pr/canadian-citizen-pleads-guilty-scheme-defraud-consumers-purchasing-pharmaceuticals-online
3. https://globalinitiative.net/wp-content/uploads/2017/12/IRACM-Counterfeit-Medicines-and-Criminal-Organizations-Oct-2013.pdf
4. https://www.fda.gov/drugs/besaferx-your-source-online-pharmacy-information/besaferx-frequently-asked-questions-faqs
5. Zhang H, et al. Materials and Technologies to Combat Counterfeiting of Pharmaceuticals: Current and Future Problem Tackling. Adv Mater. 2020, 32. https://doi.org/10.1002/ adma.201905486.
6. Ludasi et al. Comparison of conventionally and naturally colored coatings marked by laser technology for unique 2D coding of pharmaceuticals. International Journal of Pharmaceutics. 2019, 570. https://doi.org/10.1016/j.ijpharm.2019.118665
7. I. Murokh. Laser Marking Discrete Consumable Articles. US patent 6,429,889 B1, 2002. https://patentimages.storage.googleapis. com/34/e3/a9/17463d55bc10b4/US6429889.pdf
8. I. Murokh. https://www.tabletscapsules.com/3641-Technical[1]Articles/593320-Tablet-and-Capsule-Marking-Direct-UV-Laser-Marking-of-Tablets-and-Capsules/
9. S. Sacher et.al, Feasibility of In-line monitoring of critical coating quality attributes via OCT: Thickness, variability, film homogeneity, and roughness. International Journal of Pharmaceutics: X, Volume 3, 2021. https://www.sciencedirect.com/science/article/pii/ S2590156720300293?via%3Dihub
10. A. Naharros-Molinero et. al. Shell Formulation in Soft Gelatin Capsules: Design and Characterization. Advanced Healthcare Materials: Volume 13, Issue 1. https://onlinelibrary.wiley.com/ doi/10.1002/adhm.202302250
11. https://www.colorcon.com/resource-center/colorcon-academy/ webinars/titanium-dioxide-e171-regulatory-status-and-technical-solutions
12. https://www.dea.gov/sites/default/fi les/2021-09/DEA_Fact_Sheet-Counterfeit_Pills.pdf.

Author Details

Igor Murokh, PhD Senior Scientist- Tri-Star Technologies

Publication Details