OR WAIT 15 SECS
Agnes Shanley is senior editor of Pharmaceutical Technology.
While more companies are embracing taggants, researchers are developing new technologies that will be extremely difficult to reproduce.
Counterfeit pharmaceuticals continue to threaten public health and safety. The International Criminal Police Organization (Interpol) estimates that counterfeit drugs cause more than one million deaths per year (1). While governments explore fundamental solutions to the problem, pharmaceutical manufacturers are fighting this threat to their customers and brands through serialization and the use of anticounterfeiting technology.
Several years ago, for example, Eli Lilly invested $110 million on serialization and anticounterfeiting measures such as color-shifting inks and distinctive tablet shapes and colors, for its widely copied Cialis, Cymbalta, and Zyprexa brands (2,3).
Merck KGaA is using pigments in its Security-M labels, which are added to product packaging, allowing products to be identified and authenticated. It also offers CheckMyMeds, an app for patients that lets them verify barcodes on medications before taking them (4).
Counterfeiters, however, continue to improve their packaging and “manufacturing,” too, so the fight against them shows no signs of abating. The search is on for technologies that counterfeiters cannot hack. This article describes the scope of the problem and highlights some research in areas that could be applied to personalized medicines as well as analytic testing and forensics. In 2017, the Pharmaceutical Security Institute (PSI) documented a rise in drug diversion incidents around the world, including diversion of medicines provided under compassionate use or “named patient” programs and purportedly from trusted countries, says PSI director Tom Kubic. In addition, in 2017 more counterfeit pharmaceuticals were able to reach the legitimate supply chain in Europe, Kubic says. Tablets and capsules remain the most widely imitated dosage form.
Policing efforts claimed some victories, most notably Operation Pangea VIII in 2017, which involved Interpol, the World Customs Organization (WCO) and customs and security forces in more than 115 countries, and FDA. The effort resulted in the seizure of more than $81-million-worth of counterfeit medicines and medical devices and the shutdown of 2400 illegal websites in 2017 (5).
A final, formal report on Pangea VII is still being drafted, Kubic says, noting that Pangea included counterfeit medical devices for the first time in 2017. “Interpol’s successful coordination of the global enforcement effort against illicit medicines, such as the Pangea operations, illustrates its ability to overcome significant challenges. Its partnership with WCO serves as an exemplary model of cooperation, and they deserve credit for helping to protect the safety and well-being of patients around the world,” says Kubic.
According to PSI data from 2016, posted directly on the organization’s website, www.psi-inc.org, 3147 cases of pharmaceutical counterfeiting, theft, and diversion were reported, up 5% from 3002 in 2015, and 2177 in 2014. Of these incidents, 520 resulted in either raids or customs seizures. However, seizures fell by 45% between 2015 and 2016, according to PSI data. In 2016, 38% of seizures occurred at commercial facilities, but 46% were noncommercial.
The five most frequently counterfeited therapies were genito-urinary medications, anti-infectives, central nervous system treatments, hormones, and cytostatic drugs, according to PSI. In addition, 1258 people were arrested for counterfeiting and diversion, down 9% from 2015, according to PSI data.
In the United States, meanwhile, the opioid addiction crisis has brought increased levels of counterfeit opioids, especially fentanyl, into the supply chain, blurring distinctions between illegal street drugs and counterfeit pharmaceuticals. Fentanyl follows the historical tradition of a legitimate therapeutic eventually becoming a street drug. This first happened with Merck’s morphine, then with heroin, which Bayer introduced as a synthetic and (so the company thought) non-addictive treatment for opium addicts.
The pattern was later seen with Purdue Pharma’s oxycodone, and has repeated with fentanyl, a synthetic pain reliever originally developed under a Janssen patent, that is 50 to 100 times more potent than morphine (6).
The PSI has noted a shift in counterfeit fentanyl manufacturing to the US, and an increase in illicit imports of equipment such as tablet presses as well as other formulating ingredients into the US. In 2016, customs officers seized 440 pounds of fentanyl, up from two pounds in 2013, also seizing increased volumes of its precursors N-Phenethyl-4-piperidinone (NPP) and N-phenyl-1-(2-phenylethyl)-4-piperidinamine (ANPP).
In addition, customs confiscated 58 pill pressing and tableting machines in 2016, up from 24 in 2014 (7).But, on the government level, some believe that light penalties fail to deter counterfeiters, and argue that too much of the responsibility for preventing product diversion and counterfeiting has shifted to the manufacturer.
Legislation such as the EU Falsified Medicines Directive (FMD) and the US Drug Supply Chain Security Act (DSCSA) require that manufacturers identify pharmaceuticals at the unit package level, as a first step to establishing full product traceability within the supply chain, to prevent pharmaceutical counterfeiting. However, the cost and effort required is considerable.
As Price Waterhouse Cooper (PwC) analysts have noted, compliance with the FMD alone has already cost manufacturers 500 million euros (2). A PwC survey of 38 senior pharma executives in 2017 found that most were satisfied with their companies’ supply chain integrity protection methods, yet acknowledged that extra steps would be needed to protect product from counterfeiting (2), suggesting the need for more incentives to invest in the required technologies.
Today, one year before the FMD deadline and nearing the extended DSCSA deadline, a number of manufacturers and their contract partners have not even begun serialization efforts. Efforts such as the Open SCS working group are underway to simplify and reduce the IT costs for serialization and traceability efforts (8).
In the end, more collaboration will be needed between governments, law enforcement agencies, and manufacturers. Some governments don’t treat counterfeiting as a national healthcare issue but instead believe that the industry needs to solve and pay for the solution, notes Charlie Gifford, technical director of the Open-SCS working group. “Merely implementing a data-collection system will not be enough. The data must be used and organizations set up to follow up on counterfeiting incidents. In addition, laws need to reduce the incentive for counterfeiting by exacting harsher penalties,” he says.
Anticounterfeiting is challenging because it needs to be approached from three different perspectives and lines of attack--from the point of view of the manufacturer, distributors and healthcare providers, and the patient, says Jay Kennedy, assistant professor with the University of Michigan’s Center for Anticounterfeiting and Product Protection (CAPP).
More education is needed for healthcare providers, Kennedy says, to ensure that they do not buy medications from unauthorized sources. But education is most crucial for consumers, and the lure of lower costs is hard to counter when addressing online pharmaceuticals. In addition, quick response (QR) codes and the other technologies that are being used for anticounterfeiting can be daunting for some consumer groups, including senior citizens.
Technology already exists to improve manufacturers’ response to counterfeiters. Taggants, packaging and bottle designs, inks, and labeling are all being improved. In the taggants area, TruTag’s platform was selected for use in nutraceuticals and health products by the Daily Wellness Company. Products will be tagged to enable their detection and authentication throughout the supply chain. The company has also partnered with Sumitomo Corp. of America, which is investing in its technology, to develop its platform for various applications, including those in pharmaceutical manufacturing (9).
Applied DNA Technologies, meanwhile, has expanded its global operations with a new test lab in India. The company has also been selected by TheraCann International Benchmarks to develop its SigNature molecular tracking system for use in the tracking and tracing of legal cannabis for medical use (10).
In 2017, the plastics manufacturer Clariant introduced Plastiward, a system that uses covert taggants developed by SICPA SA, to provide an integrated plastic-based anticounterfeiting technology that can be used in pharmaceutical packaging or placed within a medical device. The taggant is incorporated either as a masterbatch form or as a finished polymer compound. Through the supply chain, the tagged product could be detected and authenticated using a monitoring system developed by SIPCA (11).
New approaches are also in the works that will be nearly impossible to duplicate, says Kennedy. Many of these will be especially useful for personalized medicine. He points to a new DNA tagging system (12) now in the early conceptual stage, which is being developed by University of Michigan professor Evangelyn Alocilja. In this approach, a strand of DNA would be attached to a product and a sequence would be coated with a material that would allow it to be seen with a light emitting diode.
The strand would allow users to identify product information, manufacturing data, and chain-of-custody information on that product, and would cost less than a penny per item.
At the University of Copenhagen and Finland’s Abo Akedemi University, researchers are looking into the use of ink jet printing to make edible dosage forms in a QR code that the patient would simply ingest. APIs would be placed in the ink in the pattern of the code, and dosage form would look like a code on a substrate. Not only could this approach lend itself to point-of-use manufacturing, but it could prevent product diversion, tampering, and counterfeiting (13).
Other advances are focusing on analytical measurements to aid in the forensic detection of counterfeit pharmaceuticals within the supply chain. One effort is focusing specifically on measuring surface gloss, using diffractive optical element-based sensors to inspect the surface porosity of flat, two-phase tablets.
Researchers used lab-based and handheld gloss meters as well as an optical profilometer to study the surfaces of commercially available tablets, contrasting measurements from authentic and counterfeit antimalarial tablets. Gloss values and surface roughness measurements between the two groups were substantially different, suggesting that the method could be used for quick inspection and field screening of fake tablets (14).
At Sao Paulo State University in Brazil, researchers are evaluating the use of matrix-assisted laser desorption and ionization (MALDI) mass spectrometry to detect counterfeit dosage forms of all types. Researchers report that the technique simplifies analysis, speeds detection, and minimizes sample preparation (15).
1. N. Southwick, “Counterfeit Drugs Kill 1 Million People Annually: Interpol,” insightcime.org, October 4, 2013.
2. PriceWaterhouse Cooper, “Fighting Counterfeit Pharmaceuticals: New Defenses for an Understated and Growing Menace, pwc.com, June 29, 2017.
3. J. Swiatek, “Eli Lilly Intensifies Efforts to Stop Fake Pharmaceuticals,” indystar.com, April 6, 2014.
4. Merck KGaA website, Report on Anticounterfeiting, 2016.
5. H. Sklamberg et al., “A Global Fight Against Dangerous Counterfeits and Unapproved Medical Products,” FDAvoice.com, June 30, 2015.
6. S. Bhatia and D. Turock, “Chemical Engineers Respond to the Addiction Crisis,” Chemical Engineering Progress,” November 2017.
7. Dept. of Homeland Security, “Stopping the Shipment of Synthetic Opioids: Written Testimony of CBP Acting Executive Assistant Commissioner for Operations Support,” dhs.gov, May 25, 2017.
8. A. Shanley, BioPharm International, 31(1), 2018, 48-59, 51.
9. Press Release, “Trutag Technologies and Sumitomo Corp. of America Form Global Strategic Partnership,” December 4, 2017.
10. Press Release, “Applied DNA Sciences Awarded Multi-Year Contract,” adnas.com, January 25, 2018.
11. Clariant, “Clariant and SIPCA Plastiward Anticounterfeiting System Featured at Pharmapack Europe 2017,” Press Release, January 2017, clariant.com.
12. C. Graminich and J. Wilson, “Emerging Challenges and Progress: A Report on the ACAPP Center Brand Protection Summit,” University of Michigan, 2017.
13. M. Edinger et al., International Journal of Pharmaceutics, 536(2018), 138-145.
14. P. Bawuah et al., Journal of the European Optical Society, Rapid Publications, 13(18), June 2017.
15. J. Bronzel et al., Journal of Mass Spectrometry, 52 (6), 752-758 (2017).
Vol. 42, No. 2
When referring to this article, please cite as A. Shanley, “Anticounterfeiting: In Search of the Unhackable,” Pharmaceutical Technology 42 (2) 2018.