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On-dose authentication: Walking softly, prepared to stick
 
Peter M.O. Wong, TruTag Technologies
 
While the exact size of the problem is unknown, counterfeit drug products harm patients and pharmaceutical manufacturers. This article discusses why on-dose authentication (ODA) is a superior anti-counterfeiting and diversion-detection approach and how it can defray costs in other business areas.
 
Adulterated and unsafe drugs have threatened public safety since before President Theodore Roosevelt signed the Pure Food and Drug Act into law in 1906. Today, the distribution of counterfeit and/or uncontrolled medicines is an enormous problem, measured in the tens of billions of dollars [1]. The exact size of the problem is not known because of the illicit nature of the activity, but counterfeiting continues to attract sophisticated criminal organizations. Making fakes, after all, is a lucrative business for criminals. For drug manufacturers, however, counterfeiting—including adulteration and illegal diversion—reduces revenue, increases costs, exposes them to liability, and damages brand reputations. But most important, fake drug products put patients' lives at risk.
 
And counterfeiting is not the only risk to patients' safety. With today's complex global supply chain, quality control can be a challenge. In 2014, GlaxoSmithKline received inquiries from consumers in seven states claiming to have discovered non-Alli weight-loss pills inside bottles that had been sealed. The company issued a voluntary recall pulling the popular Alli pill from store shelves in 40,000 retail outlets across the USA and Puerto Rico over concerns about possible package tampering. A range of tablets and capsules of various shapes and colors were reported to be found inside bottles. Additionally, some bottles inside the outer carton were missing labels and had tamper-evident seals that were not authentic. ODA tools could have helped investigators and quality professionals to determine quickly the provenance of the improperly packaged products and remedy the problems.
 
A virulent affliction
The demand for prescription drug products is strong, particularly for narcotic pain medications, life-saving pharmaceuticals, and so-called lifestyle drugs, such as those for treating erectile dysfunction. All of those drug products can cost patients a lot of money, depending on their health insurance plans, and many people thus seek less expensive options. For those without a valid prescription, internet pharmacies that peddle cheap, no-questions-asked drugs are alluring. They're usually also unreliable [3]. In less-developed countries, where supply chain security is weak, counterfeits may account for as much as 25 percent of the pharmaceuticals in the market [4]. Furthermore, price differences across geographic markets create arbitrage opportunities for people to exploit.
 
Plus, the laws against pharmaceutical counterfeiting and diversion carry relatively light criminal penalties. Therefore, distributing legitimate-looking erectile-dysfunction pills and antidepressants entails minimal risk compared to other illicit activities, such as manufacturing methamphetamine or trafficking in cocaine or heroin. Pharmaceuticals are high-value items that are easy to transport, often simple to mimic in appearance, and until recently, impossible to trace at the dosage level.
 
The appeal of ODA
Pharmaceutical manufacturers have long battled the counterfeiting problem with a variety of measures: holograms, specialty inks, tamper-evident seals, and more recently, radio-frequency identification tags. Repeatedly, counterfeiters have persisted in spoofing these package-level security measures.
 
Besides, authentic packaging does not guarantee authentic medicine. That's one of the biggest shortcomings of current e-pedigree and track-and-trace legislation. The focus is on the provenance of the package, which doesn't allow you to verify whether the medicine inside is legitimate or counterfeit.
 
Thus, innovative brand owners are turning to ODA methods that mark or tag individual unit doses at the batch level, allowing you to distinguish between real and fake drug products. In addition to marking the individual tablet or capsule and bridging the gap in the pedigree chain, ODA offers brand owners the opportunity to extend its sophisticated tracking technology to other areas of their businesses. That's an important consideration because regulatory obligations, such as risk evaluation and mitigation strategies (REMS) and e-pedigree, require manufacturers to exercise more control over their supply chain. ODA can help do that as part of a multilayered system that secures and tracks pharmaceuticals, which helps manufacturers protect the essence of their brand: the quality of the medicine itself.
 
FDA support for innovation
A 2011 FDA Guidance for Industry provided a pathway for regulatory compliance when using an ODA system containing physical-chemical identifiers (PCIDs) at the dosage level [5]. The FDA has also noted its responsibility to "harness the latest advances in science and technology to improve the health and well-being of American consumers" [6]. That obligation includes "strengthen[ing] the safety and integrity of the global supply chain" for foods and drugs, one of the FDA's four strategic priorities.
 
Furthermore, in the Guidance the FDA emphasized one of its signature programs, the Analytical Tool Initiative, which focuses on identifying rapid analytical tools and putting them in the hands of field investigators and scientists. In fact, in 2010 the FDA trained field investigators how to use a counterfeit detection device and a toxic-elements detection device to find and combat counterfeit drug products. As the FDA gains experience with these tracking and authenticating technologies, the agency, lawmakers, consumers, and other stakeholders will expect pharmaceutical manufacturers to make greater use of them. Additionally, the FDA will use its new technical expertise to promulgate other strategic priorities: stronger compliance and enforcement.
 
Assessing ODA systems
imageThe FDA Guidance on PCIDs has also prompted brand owners to take a fresh look at innovative ODA methods. Implementing a strategic ODA system requires planning, commitment, and a significant investment of time, money, and other resources. The ideal ODA system would address immediate needs and allow scale-up over the long term to justify the investment. To address immediate needs, look for an ODA system that demonstrates reliability, implements easily, and offers strong security.
 
Fundamental questions include:
  • Can the ODA system integrate easily into my existing manufacturing process and information technology framework (photos)?
  • Does the ODA system allow automated authentication?
  • How much training or expertise does the ODA system require?
  • What kind of extraneous equipment does the ODA system require for use?
  • To what extent does the ODA system rely on outside service providers?
  • What regulatory hurdles might the ODA system impose that could delay or jeopardize drug product approvals?
  • Do the security features of the ODA system truly defend against counterfeiters and unauthorized diverters?
Furthermore, a robust ODA system should be equipped to evolve with the end-user's needs. Does it offer security features that can advance over time to meet an increasingly formidable and sophisticated enemy? Because the capabilities of counterfeiters will continue to progress, ODA defenses must as well. For example, compare the security system of current Blu-Ray DVDs, which allows manufacturers to renew and adjust security measures, to the one used with earlier DVDs. The early system had one security lock that could not be repaired, once broken, and the secret key was thus available to everyone thereafter.
 
The ODA system should also scale up across the enterprise as a business tool to defray the costs of implementation and maintenance and to adapt to industry changes. The ODA system you select should offer a sound return on investment over the long term.
 
While you may implement an ODA system to address counterfeiting and secure your product, think about how the system could also serve a variety of departments and multiple applications, allowing you to cut costs or reduce risks. Those abilities alone could justify the cost of the entire ODA system. Examples include evaluating questionable product returns, reducing mistakes in sample handling, complying with REMS, and managing clinical trials.
 
Securing product. Product security teams can use handheld readers to authenticate products immediately or confirm them as frauds in the field. On-the-spot detection allows brand owners to identify leaks in their global supply chain.
 
Returns monitoring. Spot-checks of returned product can determine whether the tablets in the returned containers correspond to the merchandise's documentation. Any discrepancy would allow you to reject a return and withhold refunds until you receive correct documentation. Returns are not a small problem. According to the Healthcare Distribution Management Association, US pharmaceutical manufacturers receive returns for refunds of as much as 2 percent of products [7]. For blockbuster products, refund errors could total tens of millions of dollars.
 
Quality control and sample handling. When workers take samples during manufacturing, on-dose taggants or markers indicate the lot from which the samples came. You can investigate quality incidents more effectively.
 
REMS compliance. The FDA's focus on REMS obliges manufacturers to demonstrate control over the use and distribution of their products [8]. That can be a costly exercise, but penalties for products that don't comply with REMS begin at $250,000 for the first offense. An ODA system might be especially valuable in cases where the FDA mandates controlled distribution of a product. In fact, debate is occurring right now about whether the FDA should impose greater control over Schedule II narcotics. But even products requiring basic REMS may benefit from an ODA system because it would demonstrate brand owners' concern for patients' well-being and offer a powerful management tool for compliance and planning.
 
Clinical trials. In blinded clinical trials in which the placebo and comparator appear identical to the investigated drug product, a covert ODA system provides dosage-level tracking of the many small batches used in a trial. A clinical research organization can use an automated ODA system to check and reconfirm the provenance of products in a blister pack without revealing the information to blinded patients or administrators. The importance of this dosage-level authentication increases as brand owners outsource clinical trials, including sending them offshore.
 
Types of ODA systems
The key is finding an ODA system that can support all of those functions. Several approaches are available on the market, including ones that use:
  • Botanical DNA, which can hold vast amounts of information as a forensic marker;
  • Small fluctuations in the amount or ratio of key ingredients to differentiate between products or lots;
  • Taggants of GRAS materials that bear symbols visible only through a microscope;
  • Nano-size lithography or etching of the surfaces of tablets or capsules that special equipment at authentication centers identifies and interprets;
  • Forensic markers at the core of a drug product that are recovered upon dissolution to confirm authenticity; and
  • Unique flavorings and/or pearlescent or other specialized coatings that are difficult to mimic.
Micro-tags
imageThe technology that my company offers uses micro-tags of inert, edible, pure silica, a GRAS ingredient that pharmaceutical companies have used in foods and drug products for decades [9]. The micro-tags are encoded with unique spectral signatures chosen from a library of millions (photos). That allows great flexibility in on-dose and on-package labeling. The micro-tag can reveal the lot number, authorized country of sale, customer's name, shipment data, and dosage strength as well as other information. It's also possible to link the labels of the micro-tags with a packaging-based serialization and enterprise resource planning system to connect the dosage information with data related to the bottle, pack, carton, case, or crate.
 
You can apply the micro-tags in a standard pan coating operation to cover a single tablet with multiple covert and secure spectral bar codes. The brand owner can then implement the ODA system throughout the company, as described above. Readers on a bench top in the field or at a manufacturing site analyze the micro-tags. The randomized features of the micro-tags can also allow you to add even stronger security measures over time.
 
Conclusion
When evaluating ODA systems, investigate not only how they protect your brand but also how they improve your business. Former FDA Commissioner Margaret Hamburg paraphrased Theodore Roosevelt in discussing the counterfeiting problem: "In a moment of decision, the best thing you can do is the right thing. The worst thing you can do is nothing."
 
That describes today's reality. Companies that do nothing stand to lose the most. In the face of evolving challenges and new opportunities, opt for action and examine how implementing an effective ODA system can provide immediate and sustained benefits.
 
References
  1. "Counterfeit drug count is tough to swallow." Carl Bialik, The Wall Street Journal, Sept 11, 2010.
  2. "GlaxoSmithKline recalls Alli" (Press Release). GlaxoSmithKline, March 27, 2014.
  3. World Health Organization fact sheet 275, January 2010.
  4. Testimony of FDA's acting associate commissioner for policy and planning before the Subcommittee on Criminal Justice, Drug Policy, and Human Resources, House Committee on Government Reform. November 1, 2005.
  5. Guidance for Industry: Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting, issued by the FDA in October 2011.
  6. Strategic Priorities 2011-2015: Responding to the Public Health Challenges of the 21st Century. FDA draft, September 29, 2010.
  7. HDMA Factbook 2009-2010. Healthcare Distribution Management Association.
  8. Guidance for Industry: Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications. FDA draft, September 2009.
  9. TruTags from TruTag Technologies, Kapolei, HI.

Peter M. O. Wong is chief operating officer at TruTag Technologies in Emeryville, CA. Wong has worked with integrated information technology companies for more than 20 years in Silicon Valley.

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