Exposing Counterfeit Drugs

Ravi Kalyanaraman, Ph.D.’s journey into the shadowy world of counterfeit pharmaceuticals began unexpectedly. As the Director for Forensics and Innovative Technology (FIT) at Bristol Myers Squibb, his primary focus was ensuring the quality and safety of his company's legitimate products. But an intriguing challenge from his management, years ago, changed his career trajectory and opened his eyes to a pervasive, dangerous problem.

"My background is in spectroscopy," Kalyanaraman explained, with a quiet confidence in his voice. "I'm actually a Raman spectroscopist by training." He recalled the initial surprise when asked to apply his expertise to counterfeits. "At the time, I really thought, you know, only Gucci bags and Rolex watches are being counterfeited. I never thought that pharmaceutical products would be counterfeited."

Accepting the challenge, he began integrating sophisticated spectroscopic tools into the lab, not just to authenticate Bristol Myers Squibb products, but to actively detect counterfeits. He became the Scientific Director of FIT.

The scope of the counterfeiting problem, Kalyanaraman stressed, is far broader than many realize. "Pretty much every product has been counterfeited," he stated. While blockbuster drugs like Viagra famously made headlines years ago for being heavily faked, the reality is that counterfeiters are driven purely by profit, targeting anything that yields a quick return. "It's really the money that stands behind this," he emphasized.

More recently, Kalyanaraman's team has seen a disturbing shift towards counterfeit biologics, particularly cancer-curing drugs. "If they can simply put water in a vial and then sell that as a biologics drug, that's easy for them," he explained. 

"It's very easy to counterfeit biologics because often the product itself is just a clear liquid in a vial. So all they got to do is take a vial, put even just water or saline, and then just put a label on it that kind of looks similar to our label, and then just sell them."

This alarming trend has escalated in the last five years.

The implications of these fakes are dire, particularly for patients battling life-threatening conditions. "A lot of these biologics are cancer-fighting drugs," Kalyanaraman warned.

"So the patients are basically not getting treated. And unfortunately, a lot of these patients are at the very late stage in their cancer."

The insidious nature of the crime means that even when a patient dies, it’s often impossible to discern if it was due to the progression of their illness or the lack of effective medication.

"It's a very difficult challenge for us. And that's one of the main reasons why we need to have a very strong and robust program like what we have in BMS to rapidly screen counterfeit biologics."

So, how do Kalyanaraman and his team fight back? The process begins with acquiring suspect drugs, often facilitated by a robust security department within Bristol Myers Squibb, or even, alarmingly, from patients themselves who experience unexpected adverse reactions or a lack of therapeutic effect. These samples, often sourced globally, primarily from outside the U.S., are then sent to Kalyanaraman's lab.

His team has developed spectral scan a rapid screening technology leveraging a HORIBA confocal Raman spectrometer, specifically the XploRA™ Plus unit. At the heart of this innovation is a technique called drop-coat deposition for the sample.

"All we need is a microliter of your sample, so we don't even need the whole vial. So all we need is a very small drop," Kalyanaraman detailed. This tiny drop is placed on a hydrophobic plate with a shiny stainless-steel bottom. When the liquid evaporates, it creates a "coffee ring effect," concentrating the active ingredient at the ring's edge.

"We go and use the Raman laser from the HORIBA instrument, and we would probe only the coffee ring to see if there is active ingredient in the product," Kalyanaraman explained. "And sure enough, if it's a counterfeit drug, you're not going to see any active ingredient. In fact, some of these counterfeit drugs, you won't even see the coffee ring effect." This powerful method has been in use since 2017.

Kalyanaraman highlighted the significant advantages of their chosen methods, primarily microscopy and spectroscopy. "The biggest, biggest advantage of spectroscopy is it's very rapid. So it takes only a couple of minutes to collect the Raman spectrum," he noted.

Microscopy, on the other hand, is used for examining packaging components, scrutinizing printing and physical forms. Crucially, both techniques are non-destructive.

"If it's a counterfeit drug, the sample is evidence," Kalyanaraman emphasized. "So you don't destroy the evidence." This is a key differentiator from traditional methods like HPLC or mass spectrometry, which consume the sample.

However, spectroscopy isn't a silver bullet.

"Sometimes spectroscopy may not be the only technique or may not be the right technique to give the correct answer that we are looking for," Kalyanaraman admitted. In such cases, the investigation expands to include HPLC with mass spectrometry for confirmation.

The battle is constant, as counterfeiters are becoming increasingly sophisticated. "Some of these counterfeiters are very, very smart," Kalyanaraman observed. He recalled a chilling instance where a counterfeit drug for the same medical indication actually contained an active ingredient – but it was an over the counter, generic version, not the proprietary Bristol Myers Squibb compound. "The counterfeit product itself, the packaging component almost looks authentic these days," he added, crediting improved and more accessible printing technology.

"We have to stay one step ahead of them," Kalyanaraman declared.

To achieve this, his team has invested in hyperspectral imaging. This technology collects thousands of spectral outputs, pixel by pixel, in the visible and near-infrared regions of the electromagnetic spectrum. 

"The software itself can go and look for subtle differences between pixel and pixel spectra and really come up with a way to confirm that it is our product," he detailed.

This applies not only to the chemical composition of the drug but also to the physical components of the packaging, scrutinizing the printing inks and pigments that the counterfeiters now cleverly mimic. "Visually, if you look at it, you can find or you cannot say the difference between an authentic and a counterfeit, but the hyperspectral imaging will do the job for us."

The work isn't just about scientific detection; it has a significant regulatory dimension. "Within [the] U.S., there is a requirement," Kalyanaraman stated. "If a company finds a counterfeit drug within their legitimate supply chain, and if we confirm that it's a counterfeit drug, we have to notify the FDA within 24 hours." This formal process involves completing specific forms and applies even if the product was not originally sourced from the U.S. but found within its borders. Bristol Myers Squibb's reach is global, meaning they must be concerned about the entire worldwide supply chain.

Kalyanaraman also shared some "unusual" findings: from vials of pure water or saline sold as expensive biologics, to the inclusion of generic active ingredients for the correct indication. He recounted a striking case from a few years ago, near the U.S.-Mexico border, where a high-volume Bristol Myers Squibb product was counterfeited with astonishing accuracy in its packaging. People would cross the border seeking lower-priced medication, only to discover, upon testing, that the tablets were merely aspirin. "So there are a variety of, you know, different counterfeits we have seen," he summarized.

Looking ahead, Artificial Intelligence (AI) is poised to revolutionize counterfeit drug detection even further.

"When you are collecting, you know, hundreds and hundreds, actually thousands of spectra, within a span of a minute, how are you going to analyze [it] without a machine learning algorithm and software?" Kalyanaraman asked rhetorically. His team has recently invested in this area. Beyond spectral data, AI will also be applied to the vast libraries of images of authentic and counterfeit products the lab has accumulated. "The AI is going to help us, for sure it will... See, things that you can't [see] with our human eye or even with our hyperspectral images."

Beyond technology, Kalyanaraman believes passionately in the power of education and outreach.

"How little information they have about counterfeit drugs," he remarked, referring to people outside, and even sometimes within, the pharmaceutical industry. He travels globally to raise awareness, emphasizing that this fight requires collective effort. While organizations like the Pharmaceutical Security Institute foster information sharing among pharma companies, the broader public needs to be informed.

Despite the concerted efforts of regulators and pharmaceutical companies, Kalyanaraman admits the counterfeiters currently have an edge. "I want to say the regulator in pharma, but unfortunately, it's the counterfeiters," he conceded. The sheer scale of the problem—billions of dollars in counterfeited products worldwide, particularly outside the U.S.—makes it incredibly challenging to police and regulatory agencies. He cited a recent U.S. case involving Biktarvy,^® an HIV drug, counterfeited to the tune of $250 million. "It's very scary," he acknowledged. While law enforcement ultimately intervened, it highlights how even robust regulatory systems can be breached by "a few bad people" within the legitimate supply chain.

Kalyanaraman's work is a testament to the ongoing vigilance required to protect public health from a cunning and relentless enemy. Armed with cutting-edge spectroscopy and the promise of AI, he and his team continue their critical mission, one chemical fingerprint at a time.