Finding Fakes
Looking at the past, present and future of counterfeit drug screening.
Ravi Kalyanaraman and Varsha Ganesh |
Produced and sold with the intent to deceptively represent origin, authenticity or effectiveness, counterfeit drugs are products that contain no active ingredient, inappropriate quantities of active ingredients or other ingredients that are not found in the genuine product. Estimates suggest that the global counterfeit drug market sits somewhere between US$75 and $200 billion and represents 10–50 percent of all drugs sold in some low-income countries (1).
The first step in authentication testing is to compare the packaging and drug product appearance of the ‘suspicious’ product with the genuine product. However, physical appearance is easily counterfeited, so robust chemical analysis must be used to distinguish between authentic and fake drugs. Needless to say, analytical testing must be both accurate and rapid in this setting.
Traditionally, qualitative and semi-quantitative techniques – for example, disintegration, colorimetry, and thin layer chromatography (TLC) – have been employed to determine if a product is counterfeit (2). Notably, these techniques have been especially useful with regards to taking the ‘lab’ to the field, providing a simple and inexpensive way of determining counterfeits. Global Pharma Health Fund (GPHF)-Minilab still supplies field test kits with simple disintegration, color reaction tests and easy-to-use TLC tests for rapid drug detection and drug potency verification (3).
When it comes to a detailed characterization of counterfeit drugs, gas and liquid chromatographic techniques (GC and LC) are the most prevalent (4). Coupling mass spectrometry (MS) to LC not only assists in authentication but identifies even low concentration of substitute ingredients in a counterfeit. The drawback with such methods is the sample preparation and high lead time required for analysis. To overcome this, direct-ionization MS methods, such as direct analysis in real time (DART) and desorption electrospray ionization (DESI) are being used to eliminate sample preparation (5).
Spectroscopic techniques, such as benchtop FT-Raman and near-infrared spectroscopy (NIRS) possess a distinct advantage over chromatographic techniques in that they are non-destructive and can rapidly characterize the suspect product in seconds – even without the need to remove the drug from its packaging (6). Such portable spectrometers offer a rapid, accurate and specific means of authentication in-field, as they are able to compare the unique spectral signatures or ‘fingerprints’ of the authentic drug product against the suspect. Furthermore, they require little to no training, which means they can be used in the field by law enforcement officials, ensuring immediate identification and take down of counterfeit activities (7).
But what about the surge in the number of protein-based drugs on the market? The extraordinarily high costs associated with biologics make them a lucrative market for counterfeiters – as proved by the recent case of counterfeit Avastin (8). Biologics are, of course, large complex molecules, which makes them hard to characterize and fingerprint. We were part of a team at BMS that was able to show that confocal Raman spectroscopy – coupled with a specialized sample preparation technique called drop coat deposition (DCD) – can be effectively used to fingerprint biopharmaceuticals (9). The technique, coupled with peak fitting, could also be used to determine the secondary structure of the biologics and even offer a way to distinguish between biologics and their generic versions (biosimilars). DCD Raman (DCDR) spectroscopy requires limited sample preparation (deposition of a microliter ‘drop’ of sample followed by solvent evaporation) and yet offers a wealth of structural information (secondary structure can be classified using the Amide I band).
Analytical technology for counterfeit detection has certainly experienced tremendous growth and evolution over time. However, as counterfeiters get smarter and move into the biopharma space, we must arm ourselves with superior authentication techniques. In our view, DCDR spectroscopy is one such tool.
- World Finance, Trade in illegal medicine hits pharmaceutical sector, www.worldfinance.com/home/specialreports-home/trade-in-illegal-medicine-hits-pharmaceutical-sector
- R Mukhopadhyay, “The hunt for counterfeit medicine”, Anal Chem, 79, 2622-2627, (2007)
- The GPHF-Minilab™ Protection Against Counterfeit Medicines, www.gphf.org/en/minilab/
- FM Fernandez et al, “Prevalence and detection of counterfeit pharmaceuticals: a mini review”, Ind Eng Chem Res, 47, 585-590 (2008).
- L Nyadong et al, “Reactive desorption electrospray ionization linear ion trap mass spectrometry of latest-generation counterfeit antimalarials via noncovalent complex formation”, Anal Chem, 79, 2150-2157 (2007).
- Y-P Sacré et al, “Comparison and combination of spectroscopic techniques for the detection of counterfeit medicines”, J Pharm Biomed, 53, 445-453 (2010).
- R Kalyanaraman et al, “COUNTERFEITING: Portable spectrometers for pharmaceutical counterfeit detection”, Am Pharm Rev, 13, 38 (2010).
- M Chauhan et al, “Screening and detecting counterfeit biologics drugs”, BioPharm Asia, 1, 58–64, (2013).
- J Peters et al, “Raman spectral fingerprinting for biologics counterfeit drug detection”, Am Pharm Rev, 19, 46-51, (2016).
Ravi Kalyanaraman, PhD, is an Associate Director at Bristol-Myers Squibb Company in the Global Analytical Technology group within Quality, Global Manufacturing and Supply. He received his PhD from the University of Idaho in 1995 and did his postdoctoral work at the University of Puerto Rico. He served as a faculty member in the department of chemistry at Bemidji State University in Minnesota from 1996 to 2001. He has been with Bristol-Myers Squibb since 2002. His laboratory work in the past with Bristol-Myers Squibb was primarily in developing, validating and transferring chromatographic and MS methods for Quality control laboratories. In the last eight years he has focused on developing new and novel techniques to detect pharmaceutical counterfeits and raw material identification using vibrational spectroscopic techniques, such as Raman, mid-, and near-infrared (NIR). Currently, he leads a team of analytical scientists that are involved in the forensic and manufacturing investigation for products received from product complaints, corporate security and also from various manufacturing sites including third party manufacturing. Also, his laboratory is currently developing new and novel Raman spectral fingerprint techniques for biologics drugs which can be used to screen counterfeit biologics.
Varsha Ganesh is an Associate Scientist at Bristol-Myers Squibb Company in the Global Analytical Technology group with Global Manufacturing and Supply. She received her Masters in Biotechnology from Pennsylvania State University and has been with Bristol-Myers Squibb since 2013. She works on spectral authentication of suspect counterfeits, method development for counterfeit biologics, raw material qualification using vibrational spectroscopic techniques and also on analytical method transfers and analytical robustness initiatives.
