Perspectives On In-Dose Anticounterfeiting And Point-Of-Dispensing Testing

By Shannon Flank, Ph. D., and Gary Ritchie

Drug counterfeiting continues to grow, with an estimated global cost of $200 billion annually. Multilayer solutions are needed, including lightweight, patient-friendly protections in the dosage form itself. Drugs can look alike, sound alike, and may actually have many of the same ingredients. Discriminating real versus fake (or diverted or adulterated) drugs based on packaging differences alone may not be sufficient to protect the patient. Outsourcing, repackaging, and a global supply chain further complicate the task.

Savvy counterfeiters routinely defeat protective measures in six to nine months. Some manufacturers have increased their efforts by educating their supply chain customers and patients on enhanced visual inspection of packaging and product; capacity building with law enforcement, regulatory authorities, NGOs (nongovernmental organization), and ad hoc groups; surveillance; corporate forensic capabilities; along with increased pharmacovigilance.

Follow The Money
What is faked?  It’s all about money, of course. Blockbuster drugs are vulnerable. Expensive products are counterfeited, including HIV/AIDS and cancer drugs. Shortages and panics provide openings for counterfeiters, since strapped suppliers are eager to get product and, as a result, grow less vigilant about its sources. Embarrassment-related drugs are purchased surreptitiously, including via Internet (Alli, Cialis, Levitra, Propecia, Viagra), as are pain, anxiety, and sleep preparations (although diversion tends to be the more significant problem for controlled substances). Counterfeiters sell drugs for cholesterol, osteoporosis, acid reflux, blood pressure, growth hormone, hyperactivity, etc., and they even go after toothpaste, shampoo, toilet paper, perfume, vitamins, and of course cosmetics. Particularly in developing countries, just about every drug is vulnerable. If all the fakes were placebo-level sugar pills, the sick would suffer, but the effects would be limited. Unfortunately, the consequences are worse. Some of the fakes are actually poisonous or contain ingredients that can cause harm. Many contain subtherapeutic doses of active ingredients and contribute to drug resistance, a particular concern with malaria and tuberculosis drugs and antibiotics. Not only are the patients who take the counterfeits harmed, but the entire public health effort is compromised, breeding superbugs in the pursuit of profits. Counterfeiting is lucrative — far more lucrative than trafficking in illegal drugs and with far lower penalties. Increasingly, the next target is the product with fewer or weaker anticounterfeiting measures, and wise companies are making plans to place some forms of protection on every one of their products. This, in turn, puts new pressure on technology suppliers; measures must be found that are easy to roll out for multiple products and inexpensive enough to use on generics and other products with lower margins.

The Risk Plan
Companies can leverage their investment in brand protection for an improved return on investment. Possible areas of leverage include satisfying FDA concerns, lowering insurance costs, improving the efficiency of forensic investigations, and improving quality by exploiting the design space to design in anticounterfeiting measures and reduce waste.

The FDA now requires a risk plan for certain types of drugs. Increasingly, this REMS (risk evaluation and mitigation strategies) is expected to include information on protecting the public against counterfeiting and diversion, now considered part of pharmacovigilance. As a European Pfizer executive recently noted, “Lack of efficacy is a reportable event.”  That is, a drug that fails to heal may be a counterfeit and should not be ignored.

Well-planned use of brand protection measures can lower risk, perhaps to the point of paying a lower insurance premium. Strong asset tracking, such as sensor-based solutions, can favorably affect insurance rates.

The hope is that anticounterfeiting measures will succeed in deterring counterfeiting completely. If fakes do show up, quick investigation and prosecution can limit the damage. Product protection that makes it possible to track down the supplier can save money in investigation, and especially by limiting the scope of any recalls. Better, some methods make use of forensic information to predict the next problem, providing a head start in thwarting it.

Finished products are not the only problem. Hovione’s Guy Villax called the threat of falsified APIs an “iceberg.”  In the era of global supply chains, problems can arise long before you put your product into a package for sale and festoon it with protections. If product traceability is to be a weapon against counterfeit and diverted drugs, the process could involve referencing upstream API sources.

Beyond Package Protections
The FDA recommended in-dose protection in a draft guidance document released in July 2009. Acknowledging that packaging does not always accompany the drug itself and that even the most sophisticated printing measures can be faked, the FDA is moving toward suggesting solutions inside each dose. These tend to be covert, mostly because they are too small to see. Among the issues: in-dose tagging should be GRAS (generally recognized as safe), hypo-allergenic, secret — but then how can you be sure they are safe?  If it is not secret, how can the counterfeiters be kept from copying it?  What about liquids, gels, and powders?

Taggant-free approaches are attractive. It is useful for a manufacturer or law enforcement official to be able to look for some sort of in-product or on-product verification. Inserting taggants, however, has certain disadvantages. Creating a special taggant, particularly at nanoscale, can be expensive. Adding it to a drug requires approval (initially for the safety of the substance itself as GRAS and then in each formulation). If counterfeiters know about it, they can try to copy it. So, there is an incentive to keep it secret. Consumers, however, are nervous about undisclosed pharmaceutical ingredients, worrying about allergies. Anyone who knows anything about the taggant is vulnerable to bribery, blackmail, and theft — and then the whole tagging scheme can break down. For all of these reasons, there is growing interest in dose-level protections that are taggant-free.

Most of the in-dose protections focus on tablets and capsules, offering a nanotag of some sort, an element in the coating, special ink, or microprint. Increasingly, particularly in the case of biologics, the drug is not a solid dose form, but a liquid (or a powder or gel). Obviously, ink is not useful in those cases, and coatings are irrelevant.

More analytical devices are becoming available as portables and even as handhelds. There are even handheld mass spectrometers available. Now that the laboratory is mobile, the next challenge is to make decision making mobile. The field user should be able to make an informed decision based on the output of the instrument. Better yet, a nonscientist field user should be able to screen substances, evaluate risks, even analyze a counterfeiter’s range and plans. In this way, the new instruments can empower not only manufacturers’ investigators, but also customs and police officials, so investigations can proceed quickly.

Could a savvy counterfeiter reverse-engineer a drug’s formulation from its spectral signature? It is highly unlikely, particularly in the case of near-infrared (NIR) spectroscopy, which records a signature not only of the API and excipients and their amounts, but also of such physical properties as particle size. However, the use of NIR-CI (near-infrared chemical imaging) does present opportunities heretofore not possible with NIR spectroscopy alone. NIR-CI gives both qualitative and quantitative physical-chemical and spatial distribution information of pharmaceutical ingredients present in a solid dosage drug formulation. Currently, it is used to discern homogeneity/heterogeneity properties of solid drug formulations, which affect the dissolution performance or dissolving properties of solid drug formulations in the intestines. In the unlikely case that a counterfeiter managed to use NIR-CI spectra to create a spectrally matched copy, that copy would be both precise and clean, pretty much cGMP — and you wouldn’t mind taking it yourself. For companies plagued by close, generic-like copies or by diversion, spectroscopy can be supplemented with additional fingerprinting or tagging options.

The challenges of anticounterfeiting continue to grow, but the goal remains clear: Protect brands and patients with efficient, cost-effective approaches that empower the whole supply chain without complex infrastructure.

About The Authors
Dr. Sharon Flank is CEO of InfraTrac. She founded the company in 2006 to provide in-product anticounterfeiting solutions for pharmaceuticals and other regulated substances. Her management expertise reaches back to 1981, managing scientists, academics, and software engineers. She received her Ph.D. from Harvard and her A.B. from Cornell.

Gary Ritchie is director of scientific affairs for InfraTrac. He is the former scientific fellow for process analytical technology (PAT) for United States Pharmacopeia, Documentary Standards Division. His multidisciplinary expertise includes current good manufacturing practices, all facets of FDA product and process regulatory compliance documentation, validation, and data submission.