Copycat Chemistry: Uncovering Counterfeit Drugs

The US Food and Drug Administration (FDA) defines counterfeit medicine as a fake medicine that is contaminated, contains the wrong or no active ingredient, or contains the right active ingredient at the wrong dose (1). These “knock-offs” have caused significant harm to public health, and though many steps have been taken to deter fraudsters, fake pharmaceuticals remain a serious issue in both developing countries and the Western world. In fact, the Pharmaceutical Security Institute reported 5,081 crime incidents in 2019 – an all-time high – and the COVID-19 pandemic has only exacerbated the problem (2). Earlier this year, Interpol’s annual Operation Pangea reported an increase of around 18 percent in seizures of unauthorized antiviral medication, and more than 100 percent increase in seizures of unauthorized chloroquine (3) – a direct response to the coronavirus outbreak.

It is clear that counterfeiters will stop at nothing to make a profit, so what can be done to combat fraudulent pharmaceuticals? There are a number of measures in place around the world to detect counterfeits, including track and trace packaging, blockchain technology, and monitoring of online pharmacies. But with the global market for counterfeit medicines continuing to expand, it will become increasingly difficult to keep our supply chains safe. Here, we discuss the growing need for sophisticated chemical analysis of the drugs themselves, and our approach to telling the real products from the fakes.  

Identifying a fake

The analytical methods used to detect counterfeits vary widely in the equipment, training, and preparation involved. For more detailed characterization needs, NMR, GC, HPLC, and MS are the more popular techniques, but they demand more extensive training and preparation of samples. On the other hand, spectroscopic techniques offer a faster and less labor-intensive route to counterfeit identification. Some of the more popular techniques include Raman, near-infrared spectroscopy (NIR), and mid-infrared spectroscopy (MIR). In addition, having access to energy dispersive X-ray (EDX) and UV-Vis spectroscopy is useful when additional information is needed on a specific product; for example, to uncover provenance or link multiple cases together.

Typically, there is a progression of techniques that any counterfeit screening lab will run through to confirm or deny the authenticity of a product. Each and every case is different but, as a general rule, our team will start with a morphological examination of the sample, which involves examining the size, shape, and color of the suspect product, and looking for any inscriptions or engravings. We often use microscopy in this work, so we can take high-resolution images of the samples if we need to – especially if we start to see any evidence of foreign matter, or visual clues indicating inauthentic manufacturing processes or materials.

We’ll then move on to a more detailed analysis of the sample. We usually rely on spectroscopic techniques – primarily because spectroscopy provides very specific data for what we consider to be a minimal investment of time and resources. In contrast to chromatography, where you spend maybe 90 percent of the time preparing and running your samples, and 10 percent interpreting the data, with spectroscopy it’s almost the reverse. Moreover, it is non-destructive in nature – a key benefit when you’re working with a limited amount of sample, which can be used as evidence in court proceedings. 

Raman spectroscopy is our go-to technique, but the same principle applies across all our vibrational spectroscopic approaches. Suspect drugs are scanned using a laser, which results in a change in the energy state of the scattered light by the different chemical functional groups present in the suspect product. The resulting spectral fingerprint can then be compared against the fingerprints of known drugs. Notably, our lab ensures that spectral fingerprints are consistent across different batches of the same Bristol Myers Squibb product – we measure the degree of fingerprint variation across batches, validating with products from other manufacturers. In this way, we can ensure that fingerprints are unique for each and every type of medicine we produce.

Knowing your limits

Our approach to counterfeit detection depends on the product we are testing and the limitations of certain techniques. For example, highly colored samples are problematic for Raman spectroscopy – with the more powerful lasers of a benchtop instrument, you can end up burning your sample. With limitations in mind, it’s also important to have a complete toolbox of complementary techniques at your disposal. This way, you can piece different data together to get a complete picture of a drug.

One of our major limitations, until about 4 years ago, was the inability to routinely analyze biologics spectroscopically because of their size and complexity – and their low concentration in the aqueous solutions in which they are often formulated. That meant running more traditional, labor-intensive tests using MS or NMR that also consume the precious sample. To overcome the problem, our team at Bristol Myers Squibb developed a benchtop method for Raman analysis of biologics, using a special sample preparation technique called drop coat deposition (DCD) [See sidebar]. So far, the method has enabled us to stay ahead of biologics counterfeiters.
 

Smarter, faster, more productive

The bad news is that counterfeiters are getting smarter and they are learning from their mistakes; over the years, we’ve seen counterfeit products get better in quality. As this continues, it’s going to become harder for us to tell the difference between authentic and fake drugs. All manufacturers must continue to keep pace with emerging trends by employing the most cutting-edge technology in their counterfeit screening labs.

We’re not only on the hunt for the latest technology, but we are also increasingly looking into portable technology. In fact, we’re currently working on a handheld version for our biologics analysis using a portable Raman spectrometer. Miniaturization boosts flexibility and coverage by enabling any time, any place testing – but it does tend to come with a trade-off in terms of performance. That said, we’ve typically found that the benefits outweigh any drawbacks; for example, portable instrumentation allows us to roll out analytical technology in manufacturing sites across the world, and even in the hands of non-scientists, which improves efficiency and empowers the user.

As well as miniaturization, we also see an increasing need for user-friendliness. As counterfeiters get more sophisticated and widespread, it’s inevitable that we’re going to have to increase testing, which means more people outside of the lab environment conducting analyses. Whether it’s the patient, the pharmacist, or someone else along the supply chain – these tools must be accessible to those without professional training. The software and sensor might increase in sophistication, but the usability must be streamlined and simple.

It’s true that counterfeiters are getting increasingly intelligent in their approach. At some point, they will likely find a way to fool our packaging and tracking authentication systems. But being able to get the exact same chemical composition as a regulated product? Unlikely – and that’s why counterfeit analysis labs need to stay ahead of the game.