Drug counterfeiting continues to increase and likewise, its global threat to patient safety continues to rise. The World Health Organization (WHO) estimates that one million deaths occur from counterfeit malaria drugs every year.  And while the United States drug supply is one of the safest in the world, it is not immune to these concerns.  It is important for pharmaceutical manufacturers to understand not just the different types of threats they face but also the tools and technologies available today to prevent counterfeit drugs from entering the supply chain.

Once a drug leaves its manufacturer it is left wide open to be adulterated, completely faked, diluted, relabeled, and repackaged or manufactured without authorization.  While the counterfeit is often physically indistinguishable from the genuine product, most of the time the counterfeit does not provide the intended therapeutic value. 

In order for a manufacturer to the reach complete product security, it’s important to understand the different types of drug supply chain security threats:

• Theft:  stolen from the legitimate distribution network

• Geographic:  transported illegitimately into another country’s distribution network

• Counterfeit:  unauthorized product introduced into the legitimate distribution network

• Contract:  unauthorized sale of a product based upon contractual restrictions

• Fraud:  fictitious sale of a product in order to claim financial benefits

Vulnerabilities in the Supply Chain

Trying to pinpoint exactly where the vulnerabilities lie is next to impossible. While the US, Europe and other countries with well-developed supply chains are not immune to the risks described earlier, their supply chains are relatively secure. Occasionally counterfeit products are introduced through unscrupulous wholesalers (a weakness in the U.S. system) or through re-packagers involved in the legal parallel trade system in Europe; however, the greatest weakness in these countries is the introduction of counterfeits through so-called internet ‘pharmacies’. For instance, a study conducted in 2007 by the European Alliance for Access to Safe Medicines (EAASM) concluded that 62 percent of drugs ordered from internet pharmacies not requiring prescriptions were counterfeit.

In the developing world, there are many weak points in the supply chain, each of which leaves patients particularly vulnerable. In these regions, there is often insufficient oversight by regulatory authorities of local manufacturers that while not producing outright counterfeits, may be producing substandard products. For example, inspection at ports of entry is resource-constrained and as a result frequently limited to visual inspection only. Additionally, many countries do not have a well-developed process for filing drug applications, such that the regulatory authorities may have no information about a particular product or brand that is distributed in the country. Finally, products are often sold in single doses outside of their traditional packaging and, to make matters worse, the transaction takes place in unauthorized points of sale such as market stands. All these factors create a market where consumers are very vulnerable to unscrupulous counterfeiters who see an opportunity to make money easily with very little risk.

Technologies to Combat Counterfeits

To date, the pharmaceutical industry’s primary defense to counterfeiting is to create more sophisticated packaging that makes imitation more difficult, like bar coding and RFID.  However, counterfeiters are increasingly sophisticated themselves and this approach only secures the packaging and not the product itself. There are several analytical techniques that can be used to verify the product, but these all require the use of trained chemists in a laboratory, which precludes effective monitoring of products in the supply chain on a meaningful scale. While a few companies have introduced products using techniques such as thin layer chromatography (TLC) or near infrared (NIR), one analytical technique that has gained significant traction in the fight against counterfeits is Raman spectroscopy. 

Following are further details on each of these techniques, highlighting the pros and cons of each solution:

RFID/ePedigree

California was the first state to instate an electronic pedigree (e-Pedigree) law, which was going to be required for January 1, 2010; however, it was pushed back to 2015.  This law would require every product that enters the market (in California) to be serialized (through RFID tagging or another track and trace method). Some states have followed since, but the deadlines continue to be pushed back as manufacturers need more time to allocate funds and man power to ensure compliance.

Electronic pedigrees provide a comprehensive set of tools to bear on securing the legitimate supply chain. Product information such as NDC, lot number, and expiration date are gathered from the original manufacturing process and then securely linked to extensive transaction detail about the changes of possession that a drug undergoes from manufacture to final dispensation. If serialized products are shipped, these serial numbers are also incorporated into the pedigree. As a result, the e-Pedigree secures the chain of custody, preventing phony transactions and products from getting into or remaining in the legitimate supply chain. This is beneficial because electronic pedigree systems can detect counterfeited and diverted products by identifying forged pedigrees as they are received and analyzing transaction trails to identify suspicious patterns.

The downside—and this is common to any technology—is that RFID is extremely costly from an operational standpoint – it requires additional man power and has some technology hurdles to overcome before it can be more broadly applied. For example, each individual pallet or package requires an individual RFID chip which, despite decreasing costs, still generally cost between 7-15 cents.  There are also unsettled questions about whether the RF energy used to read the tags may impact sensitive biologics.  Lastly, like any packaging technology, one main limitation is that it does not secure the product itself, making it largely irrelevant in markets where the product is sold without its original packaging.

Thin Layer Chromatography

Thin Layer Chromatography, or TLC, is a relatively low-tech solution involving traditional wet chemistry tests.  These are relatively inexpensive to conduct and are good at determining whether a particular product has the appropriate amounts of the active ingredient.  The Global Pharma Health Fund (initiated and funded by Merck in Darmstadt, Germany) has developed a kit called the Minilab. The Minilab is basically a portable lab that fits in two suitcases and weighs 100 kg and includes materials necessary to perform TLC (as well as dissolution and color reactions) and ascertain the quality of 52 common drugs.  The Minilab is particularly useful in areas with very limited resources, and has been deployed in 70 countries in the world.  However, it does require users to be trained in chemistry, can only test the 52 products it is designed for, and due to its size and weight, is not well suited to on-the-spot testing of drugs in the field. 

NIR and Raman Spectroscopy

NIR spectroscopy in the laboratory and portable Raman spectroscopy in the field make a lot of sense to evaluate together.  Both are beneficial to manufacturers as they test the validity of the actual drug.

NIR is a well-known spectroscopic technique used in laboratories around the world.  It probes overtones of fundamental vibrations of molecules, generating spectra with large, broad bands.  While these spectra are uniquely suited for certain applications, for anti-counterfeiting they necessitate some data pre-treatment which requires users to possess advanced spectroscopy knowledge.  Furthermore, because NIR is less selective than other forms of vibrational spectroscopy, it is susceptible in the field where environmental factors like temperature or humidity can lead to false positives with authentic products. 

Raman spectroscopy is less well-known but has been a game-changer in the industry since becoming available as a portable, handheld instrument. Basically, unlike NIR, Raman spectroscopy looks at light that changes in wavelength when a sample is illuminated with photons; so in this case a laser beam illuminates the sample at a very narrow wavelength and highlights the few photons that come back with a shift in wavelength known as the “Raman Effect.” It is a relatively weak effect that until the advent of semiconductor lasers was quite difficult to pick up and required very large instruments. Now with high-power output, low-power consumption lasers, manufacturers can get the specificity of Raman in a handheld instrument.

NIR versus Raman

• Raman spectrum delivers a graph of very sharp, fine peaks as compared to the large rounded curves that you get from the NIR.

• Both NIR and Raman are able to test through packaging (via, bottles and/or blister packs). The challenge with NIR is that you end up having effects that come from the packaging such as changes in package quality or supplier, which get picked up and can lead to false positives or false negatives.  This doesn’t happen when using Raman.

• The biggest difference is not so much which technology is more accurate, because both work well and are effective. The difference has to do with the efficiency with which you apply each technology. With NIR, several samples if not dozens of samples are needed in order to create an appropriate test method and then that needs to be validated on the instrument. Then, these samples are constantly monitored over the season as small changes in that particular material may occur due to seasonal variations, such as humidity, or small differences in particle size. These changes all affect the results produced by NIR. With Raman, only a single sample is needed and it’s analyzed once, no matter the season, and the method is built. This method can then be exported to as many instruments as you want, anywhere in the world. For example, if a method is built in Indianapolis and exported to a plant in Singapore or Argentina, there’s no need to retest the method. Raman allows manufacturers to test accurately and with far less cost of managing these methods, which often require several full time employees.

 The ideal solution for ensuring the integrity of the supply chain is to use various means of tracking and authentication from the earliest point in the supply chain all the way until the consumer.  This means that the verification of raw materials used in manufacturing of drugs is also important.  Regulatory authorities like the FDA and standards-setting bodies like United States Pharmacopeia or the European Pharmacopeia mandate certain protocols for testing the identity of incoming raw materials used in pharmaceutical manufacturing.  However, in most countries only a statistical sample of all materials needs to be tested.  The advent of new technology like portable Raman spectrometers allows manufacturers to easily verify the authenticity of all their incoming raw materials easily and cost effectively, which would be cost prohibitive if it had to be done in the laboratories.  This has led the majority of the world’s top pharmaceutical manufacturers to adopt portable Raman spectrometers as an integral part of their quality control at the point of receipt of raw materials during manufacturing. In doing so they further ensure the quality and safety of the drugs that eventually reach consumers.

Conclusion

With the many threats flooding the drug supply chain globally, it is important for drug manufacturers, contract packagers, wholesalers, repackagers/kitters, warehouses, pharmacies, hospitals and clinics to know that there are technologies available to help prevent harm to its customers.  Because the vulnerabilities in the supply chain are widespread, it’s impossible to completely eradicate counterfeits from the pharmaceutical supply chain. However, the most effective approach is to employ several layers of the best technologies available in combination, including Raman for dosage-form analysis as well as RFID for security measures built into packaging. This will build a pervasive, protective shield for all products by providing deep visibility into the movement of a drug as well as a chemical analysis for each drug as it moves throughout the supply chain, thus directly combating diversion by providing maximum protection from counterfeit drugs.