DNA Molecular Taggants: A Hidden Key to Pharmaceutical Patient Safety

The pharmaceutical industry has always been at the forefront of safety practices given the potentially dire consequences of a breach in product purity. Still, counterfeit drug products remain a growing problem¹. Technologies that enable drug counterfeiting, adulteration, and diversion are becoming more accessible, accurate, and affordable, and online buying offers anonymous worldwide distribution. As it becomes easier to replicate the look and feel of a popular tablet or capsule and mimic the graphics and serialization on a package, the stakes have never been higher.

The US Drug Supply Chain Security Act, the EU Falsified Medicines Directive, and other regional initiatives have created a groundswell of industry focus on authentication and traceability of packaging for solid oral dosage forms (SODFs). In contrast, there has been relatively little discussion about technologies for authenticating and tracing the SODFs themselves. 

In 2011, the FDA issued a guidance for industry titled, “Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting”². The guidance primarily focuses on dosage-form identification and defines a physical-chemical identifier (PCID) as “a substance or combination of substances possessing a unique physical or chemical property that unequivocally identifies and authenticates a drug product or dosage form.” Examples of PCID substances include “inks, pigments, flavors, and molecular taggants.” 

A molecular taggant is a unique microscopic material added to a product in small concentrations that can be detected for traceability purposes—essentially a molecular barcode. A recent development in PCID technology is the use of DNA as a molecular taggant. DNA molecular taggants can help pharmaceutical companies address the counterfeit drug problem by providing a means to identify and trace both SODFs and packaging throughout the supply chain. 

Why DNA? 

DNA molecular taggants function the same way as standard digital barcodes but with far richer authentication capabilities. A traditional black-and-white-striped barcode uses the digital language of the binary system (ones and zeros) to form letters, numbers, and characters in accordance with standard symbologies. DNA, on the other hand, uses four molecular bases—adenine (A), guanine (G), cytosine (C), and thymine (T)—in combination to form unique sequences. To give an example of DNA’s coding capacity, the human genome (haploid) uses 3 billion base pairs to encode 4^(3 billion) bits of information— equal to approximately 1 gigabyte of digital code³. 

Just as different sequences of human DNA can be used to identify a unique individual, a DNA molecular taggant added to a drug product’s active pharmaceutical ingredient (API), fillers, coatings, inks, and/or shells can be used to authenticate and trace that particular product. The DNA molecular tags used in pharmaceutical products are orders of magnitude smaller than the human genome, typically less than 200 base pairs in length. In most cases, this PCID identifier is used like a car license plate, referring to a database that contains much more contextual information about the product, such as the owner, manufacturing facility, year of manufacture, or other relevant data. 

DNA molecular taggants offer several benefits over other PCIDs. DNA is a common molecule that is highly resolvable. While pharmaceutical applications may use only trace amounts of DNA (approximately 10-16 parts DNA per part SODF excipient), devices either in a lab or in the field can use polymerase chain reaction (PCR) processing to amplify a 1-molecule sample from an SODF or packaging to millions of molecules and analyze the sample within 30 to 45 minutes. This same PCR technology can cost-effectively produce DNA at the scale required to support widespread adoption of DNA molecular taggants by the pharmaceutical industry. 

A proven technology DNA molecular taggant technology has been proven in a range of other supply-chain applications, including: 

• more than 830,000 microcircuits for the US Defense Logistics Agency to provide counterfeit risk mitigation in critical supply chains; 
• 200 million pounds of cotton at nine gins in the US and Australia that supply more than 1,000 retail stores, with purity testing proven through to finished goods; 
• 20 million pounds of polyester and recycled polyester masterbatch, tested through to finished home and auto goods fabric to prove claims of authenticity and sustainability; 
• • 60,000 metric tons of fertilizer in Belgium, with detection of tagging and blending performed at the product’s destination in Africa; 
• • cash-staining dye in more than 40,000 ATMs/cash degradation devices and asset marking solutions, providing supporting evidence in UK and EU courts in the convictions of 117 criminals to more than 550 sentence years; 
• 60,000 luxury automobiles upon importation to Sweden, providing linkage to vehicle identification numbers and helping to solve several crimes, including one that involved criminals operating from Sweden, Lithuania, and China sellinstolen parts as new. 

DNA molecular taggants are formulated to be compatible with their host carriers and protected against environmental or process conditions but extractible for authentication purposes. In many industrial applications, DNA authentication occurs after the taggants have been subjected to chemical processing or harsh solvents or cured in a military-grade epoxy. By comparison, SODF ingredients need to be digestible, so pharmaceutical DNA molecular taggants use less-resilient, more-accessible matrices such as film coatings, food-grade inks and shellacs, and hydroxypropyl methylcellulose (HPMC) capsules. 

Many industries and companies use DNA as an information carrier, including life sciences and healthcare, law enforcement forensics, data storage technology companies, and even national data archive organizations. This focus means that significant funding is being put into DNA technology, resulting in a proliferation of smaller, faster, less expensive, and more mobile authentication methods, which may result in more widespread use of DNA molecular taggants for pharmaceutical authentication in the future. 

Safety 

DNA molecular taggants are essentially a new use for an ancient substance. The short, unmodified DNA sequences used are biochemically generated using large-molecuscale PCR processes and are chemically indistinguishable from the DNA in humans, plants, animals, food, or bacteria. Consequently, after routine pharmaceutical purification, the resulting molecular taggant is chemically identical to the DNA complement of food. 

Although synthesized from standard DNA building blocks, DNA molecular taggants are designed to be simple product identifiers with small sequence structures and no biological function or information coding. As a result, the taggants have no capacity for gene function and are more stable with respect to extreme heat, UV light, and absolute dryness than standard DNA. 

A well-known third-party food and drug safety consulting firm assesses DNA molecular taggants as Generally Recognized as Safe (GRAS) “through experience based on common use in food prior to January 1, 1958” per 21 CFR 170.30⁴. The FDA’s “Statement of Policy—Food Derived from New Plant Varieties” (57 FR 22984, May 29, 1992) offers the agency’s view that [DNA] nucleic acids omnipresent in food are presumed to be GRAS, and by following FDA guidance related to the introduction of other nucleic acid material, no serious question of GRAS status would be expected⁵. 

In the area of orally delivered vaccines and other orally delivered biologics, the FDA and World Health Organization (WHO) have determined that intact genesized human DNA may be safely included in oral dosage formulations at levels as high as 100 micrograms per dose^{6, 7}. In the FDA guidance, the agency notes that this allowance is conservative and that if the DNA were applied as fragments that were smaller than gene size (much less than 500 base pairs, for example), then the 100-microgram standard would be seen as even more conservative than it is for long, functional human DNA. The DNA concentrations required for molecular taggant applications for both pharmaceutical SODFs and packaging are orders of magnitude less than the FDA and WHO guidance. 

Using DNA molecular taggants for tablets, capsules, and packaging 

As previously described, DNA molecular taggants can be added to the coating, ink printing, or ingredients of a tablet or capsule, providing traceability. The feasibility of this technology has been demonstrated through collaborations between taggant suppliers and some of the industry’s largest companies, with further investment toward commercialization underway. 

For packaging, the DNA taggant can differentiate a real product from a fake by covert addition to the ink used to print barcodes or to the varnish on the package. For example, Videojet Technologies offers a continuous inkjet molecular ink solution to pharmaceutical, biotech, and medical-device companies. Linking the identifiers of the SODF and the package together and incorporating this information and subsequent authentication transactions to a digital record provides a strong archive for proactive and reactive audits. 

Imagine a scenario in which a company would like to use DNA molecular taggants to allow authentication of both the dosage ingredients and the packaging for an SODF product. After a formulation and validation period with the specific application and ingredient, the molecular taggant would arrive at the company’s manufacturing facility in small vials in liquid or powder form. Following the manufacturer’s instructions, the company would add the taggant during its standard production process, by mixing it into the tablet coating powder, capsule shell shellac, SODF ink, or packaging ink or varnish. 

Companies can now buy standard industry inkjet equipment for printing variable date/lot code serialization information with secure ink pre-tagged with their specific DNA molecular taggant identifier. Pre-tagged ink is available in black or clear, allowing for covert serialization that can be illuminated with UV light. No production process changes are required. To use the taggant in varnish or flexographic ink on the package, the company would mix the taggant into the carrier prior to printing. 

Upon completing a batch, the company tests the product using a portable DNA authentication device as part of standard QC protocols to verify that the right taggant has been applied at the right concentration to ensure subsequent supply-chain authentications. The authentication process requires only a trace of product and provides results in less than an hour. 

For future authentications in the supply chain, the taggant is extracted using either a water swab of the surface or by completely dissolving the coating or entire SODF in water and running the material on the authentication device. Proactive supply chain testing can detect and deter adulteration, diversion, or other risks immediately. Reactive testing involves investigating a problem after it occurs and the damage has already been done. 

As with any product, companies must observe strict security protocols to further deter nefarious actions. These should include the use of tamper-evident packaging, chain-of-custody management, and other measures for storing and transporting both the taggant and the resulting product. 

Drug product authenticity and traceability are critical for patient safety. The pharmaceutical industry has already begun using DNA molecular tagging in film coatings and capsule shells and is exploring DNA molecular tagging as one of many solutions to help fight drug counterfeiting— both inside and outside the box. 

References 

1. Peter Behner, Marie-Lyn Hecht, and Fabian Wahl, “Fighting counterfeit pharmaceuticals: New defenses for an underestimated—and growing—menace,” June 29, 2017, https://www.strategyand.pwc.com/reports/counter feit-pharmaceuticals. 

2. US FDA Center for Drug Evaluation and Research (CDER), “Guidance for Industry: Incorporation of Physical Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting,” October 2011, https://www.fda.gov/downloads/drugs/guidances/ ucm171575.pdf. 

3. Mike DeHaan, “Comparing the Genetic Code of DNA to Binary Code,” August 25, 2015, https://www. decodedscience.org/comparing-genetic-code-dna-bina ry-code/55476. 

4. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/ cfCFR/CFRSearch.cfm?fr=170.30. 5. https://www.fda.gov/Food/GuidanceRegulation/ GuidanceDocumentsRegulatoryInformation/ Biotechnology/ucm096095.htm. 6. US FDA, “Guidance for Industry: Characterization and Qualification of Cell Substrates and Other Biological Materials used in the Production of Viral 

Vaccines for Infectious Disease Indications,” February 2010, http:// www.fda.gov/downloads/biologicsbloodvaccines/ guidancecomplianceregulatoryinformation/guidances/ vaccines/ucm202439.pdf.