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PTSM: Pharmaceutical Technology Sourcing and Management
Covert and layered approaches to combat drug counterfeiting and illegal diversion strive to stay ahead of criminal enterprises.
Although they receive less press than illegal drug trafficking, pharmaceutical diversion and counterfeiting remain huge, growing, and largely undocumented, problems (Sidebar). A report by the World Economic Forum, released in 2011, found that fake drugs have a $200-billion-per-year impact on the world’s drug manufacturers (1). The business costs of illegally diverted drugs may be several times higher than that, says Kent Mansfield, president of TruTag Technologies, which has developed an on-dose covert security solution that is now in pilot and trial programs with pharmaceutical manufacturers and film coating providers.
“The companies we work with don’t tend to separate counterfeiting and diversion. They may have different teams working on each problem, but they don’t split out the numbers. Instead, they’ll typically say ‘This [problem] is costing me X million,’” says Jim Sinisgalli, director of marketing development at Systech International, LLC. “Generally, if a client has a good understanding of the extent of a product’s illegal diversion, they can better assess and address the entire [security] problem,” says James Lee, Systech’s vice-president of product management.
Recently, researchers have called for better labels to distinguish between all the possible forms of counterfeiting and diversion (2). Both counterfeit and diverted drugs hurt the public, when, for example, people abuse and become addicted to drugs intended for legitimate therapeutic uses, or take products that have expired or been improperly stored or labeled, says Mansfield. Both worlds collided recently in investigations into the death of the musician, Prince, which some reports linked to diverted opioid pain killer as well as a counterfeit generic drug (3).
Serialization and track-and-trace efforts promise to give manufacturers more control than ever in preventing illegal diversion, and they can help in anticounterfeiting efforts, but, by themselves, are not enough to prevent counterfeiting. Covert and overt brand protection technologies are also needed. All solutions must work in concert to achieve the three goals of protection, detection, and prosecution, says Shabbir Dahod, CEO of TraceLink, whose cloud-based platform is being used in many pharmaceutical serialization and traceability programs. “Security is a continuous battle, and, no matter what we do, criminal organizations are using sophisticated methods. We must continually raise the bar,” he says.
One of the vulnerabilities of overt, visible anticounterfeiting technologies for pharmaceuticals is that they are packaging-based, and easily duplicated. Criminals have become adept at mimicking not only logos, but color-shifting inks, and holographs. As a result, the use of each of these technologies tends to be short-lived before tweaks and updates are needed.
“Overt technologies are only good for a certain period of time until counterfeiters figure them out. They can only be expected to last so long, and they tend to be expensive,” says Lee, who sees the need for a layered approach to preventing both counterfeiting and diversion.
“If a company is relying on a hologram to demonstrate authenticity, then both the supply chain inspector and/or the consumer need to know what the real hologram looks like, so that they can effectively spot the difference between a fake and an authentic one. These days, this [differentiation] is becoming much more difficult to do,” says Mansfield.
He recalls situations in the past where drug companies were using scratch-off codes that could be authenticated by texting the revealed numeric code to a security database or calling the number through a special hotline. Within six months, he says, fakes were discovered where either a false hotline phone number was used, or a single authentic number was duplicated multiple times. “In the latter cases, counterfeiters copied one real code for use with multiple fake packages, knowing full well that only a small percentage of consumers were actually participating in the program,” says Mansfield.
Although overt technologies remain important and are being improved, a number of anticounterfeiting techniques are focusing on covert, invisible approaches. One way of doing this is by incorporating taggants, tiny markers that identify the product, into its formulation.
This approach has become more attractive to pharmaceutical companies since 2011, when FDA published its final guidance on physical chemical identification markers (4). The guidance mandates that the material already be an approved ingredient that is generally recognized as safe (GRAS) and present in extremely small amounts in the overall formulation. Providing that all requirements have been met, all that manufacturers need to do is to complete dissolution testing to ensure the release profile or stability of the drug is not affected, and to report use of the material on their annual report to FDA for the product, says Mansfield.
A number of companies are working on taggants that would be added directly to the drug to allow for product authentication. So far, these taggants only work on pills, and some can also be used on labels or packaging, while research is evaluating their use in other dosage forms in the future.
Applied DNA Sciences, for instance, uses a plant-based DNA marker that can be embedded in the pill’s coating or packaging. Micro-Tracers, which has sold tracers for use in coding animal drugs for more than 55 years, has taken a different approach. Utilizing technology from the semiconductor industry, the company offers SECURtracers, edible particles 50-150 microns in size that can be embedded into pills, capsules, and labels. Each particle is comprised of GRAS chemically inactive materials, fluoresces under UV black light, and contains lettering 10-20 microns in size.
To confirm authenticity, pills or packaging can be viewed under a simple, inexpensive microscope to read the lettering on the tracer particles. The process requires less than 30 seconds and can provide such information as manufacturing company name, lot number, production date, and expiration information.
If tracer particles are included within pills or capsules, the dosage forms would be ground to powder, and the particles isolated magnetically before being read under a microscope. Particle design is customizable, with x and y dimensions of 50 microns or larger in size. Letters can be etched in sizes as small as 2 microns wide and 10 microns long.
Also working on taggants is TruTag, whose On-Dose authentication solution for oral solid-dosage forms grew out of US Army medical research from 2009-2011, and work by the company’s Chief Science Officer Michael O’Neill. It features three key elements:
The solution allows for verification directly from the dosage form and would complement serialization and track-and-trace technologies. TruTag has run more than 100 pilot tests, evaluating the technology with multiple APIs via a broad number of common pharmaceutical film coatings, as well as in blends. In addition, the taggants’ impact on stability, dissolution, and efficacy have been verified, says Mansfield, who expects full-scale commercialization later this year.
TruTag has been working on film coating application testing, using various active ingredient solid-dose products, with multiple pharmaceutical manufacturers. The company is also involved in technical collaboration with leading pharma film-coating suppliers and is about to publicly release the results of these studies to industry. Additionally, the contract research and manufacturing company, WuXi Apptec, has invested in the company and is promoting the on-dose technology.
Systech International, LLC, which is actively involved in serialization and track-and-trace efforts, has also developed a covert security technology, Unisecure, which clients are evaluating and using as a second layer of protection.
The technology uses machine vision to derive unique fragments from machine-generated universal product codes (UPCs), based on imperfections caused by the paper, the printer, or other conditions. “No two labels are exactly the same,” says Lee. Mike Saborski, a vision software specialist at Systech, was able to find a way to leverage the unique imperfections inherent in any installation to come up with identifiers for each product.
Unisecure is being added as an additional layer above serialization, Lee says, with the ultimate goal to add traceability as well. “If you have two identical serial numbers, you cannot distinguish between them, but if you look at the signature fragments for each, you’ll see differences between the two. This way, when you scan the UPC code for tracking and authentication history, you know it’s the right item in the right market,” he says.
Using the technology does not require any special equipment, just a standard camera mounted on a production line, Lee says. Users capture the image and device fingerprint for each product, and then move on to the next.
One pharma company that had already serialized has added Unisecure as a second brand-protection layer. After pilot testing the combined approach in April 2016, the firm now plans to deploy it on serialized lines for high-cost drugs, Lee says. Another company is evaluating it for a mix of different products, both pharmaceuticals and consumer products, he adds.
Systech, half of whose business is in Europe and the US, has been expanding in Asia. A few years ago, the company set up an office in China, and in September 2016, it launched an office in India.
While developers continue to improve brand-protection technologies, pharmaceutical manufacturers and their partners are making progress on serialization and traceability efforts, now mandated in much of the world. “Since January 2016, we’ve seen a ten-fold increase in the number of contract manufacturers embarking on serialization programs,” says Dahod.
In general, he says, the technology required for brand-protection already exists. “The challenge will be integrating it into one single source to disseminate information that can be easily accessed.”
1. K. Van der Elst and N. Davies, Editors, Global Risks 2011, Sixth Edition, World Economic Forum.
2. G. Buckley and L. Gostin, Editors, Countering the Problem of Falsified and Substandard Drugs, Institute of Medicine of the National Academies (National Academies Press, Washington, D.C., 2016).
3. Associated Press Minneapolis, “Counterfeit Pills Found at Prince’s Home Contain Powerful Opioid Fentanyl,” August 21, 2016, theguardian.com.
4. FDA, Guidance for Industry, Incorporating Physical and Chemical Identifiers in Solid Oral Dosage Form Drug Products for Anticounterfeiting (October 2011).