The illicit trade of counterfeit drugs is a lucrative, widespread business, and it has a severe impact on developing countries. According to the U.S. Food & Drug Administration, up to 30% of medicines in Asia, Latin America, and sub-Sarahan Africa are counterfeit or substandard.

However, this problem doesn’t just affect low- and middle-income countries. With the rise of online pharmacies — estimated at nearly 40,000 — counterfeit drugs are more common in developed countries as well.

The risks from counterfeit pharmaceuticals are numerous — there are the obvious risks of medications failing to treat a given condition, and severe reactions or even death from a dangerous substance, improper dosage, or a drug interaction. Counterfeit drugs also undermine the public’s trust in healthcare systems, which leads to major health issues (see Figure 1). At a time when misinformation is rampant, it’s vital to provide patients with safe and effective treatments, and that includes combating counterfeit medication and harmful medical products.

Fortunately, researchers are making progress in the development of technologies to stop counterfeiting. Many tactics are being explored to verify that medications are legitimate, from the packaging that protects drugs to the surface and structure of the pills themselves. Some can be observed with the naked eye and others use advanced technologies to scan and validate drugs or packaging. All could provide important breakthroughs in combating fake drugs.

Which drugs are most often counterfeit?

Different therapeutic categories of drugs are counterfeited across the world, but recent research notes that counterfeiters are moving from drugs for non-fatal conditions such as baldness or erectile dysfunction into treatments for life-threatening conditions. For example, drugs like Viagra and Cialis are commonly counterfeited; but now, fraudulent antidepressants and medications for the central nervous system are also increasing. In 2023, the Pharmaceutical Security Institute reported the five major therapeutic categories targeted for counterfeiting (Figure 2):

The anti-infective category includes antibacterials, antivirals, antifungals, and antimalarials. Counterfeit drugs in this category can harm patients with HIV or malaria, and they can lead to antibiotic resistance from inadequate dosages, among other risks.

Technological advances to stop counterfeit drugs

To combat this growing threat, pharmaceutical companies and regulatory authorities are turning to advanced technologies to authenticate medications and deter counterfeiters. One approach is advanced package labeling technologies, such as blockchain, radio frequency identification (RFID), holograms, QR codes, and 2D barcodes.

Several patents have been filed for advanced labeling, such as a process for adding hidden security features to packaging that can be revealed with a laser pointer (US20150183257A1 ), and Nuceria Adesivi S.r.l. patenting the indelible printing of the traceability code for pharmaceutical stickers (EP3130474 A2 [2017]). Companies like Authentix, Inc. and Alp Vision are also working on numerous forms of encrypted printing, holograms, and packaging identifiers.

However, package labeling can be ineffective if drugs are repackaged at any point along the supply chain. As a result, “on-drug labeling” is also being explored to prevent counterfeits from reaching patients. Here are five emerging technologies to stop counterfeits:

• DNA tagging incorporates unique DNA markers into drug formulations. This method is difficult to replicate and easy to verify, making it effective against counterfeiting. However, this technology has drawbacks like requiring costly, specialized equipment. An example of this technology was patented by the University of Southern California, using RFID and DNA taggant authentication systems and methods to prevent counterfeit, gray, and black-market pharmaceutical, medical, and other products (US7710269 B2 [2010]). The company Applied DNA Sciences, Inc., provides molecular tagging and DNA markers for similar operations.‍
• Blind watermarking embeds binary digits (bits) onto the surface of Fused Deposition Modeling (FDM) 3D-printed tablets. The benefit of this process is that it doesn’t impact the appearance, weight, or API content of medications, nor the printing time needed to make the tablets. Further, a computer, FDM 3D printer, and a paper scanner are all that are needed for detection. However, this process only works on straight, flat tablets, and only certain polymers can be used.
• ‍CandyCodes are edible identifiers unique to each pill, tablet, or capsule to which they’re applied. These identifiers are just what their name suggests — they’re nonpareils, the same tiny candy spheres used as decorations on desserts. When applied at random to legitimate drugs during manufacturing, the patterns can then be photographed and stored in a database. A patient would only have to upload a picture from their phone’s camera to the manufacturer’s database to verify that their medications are real.
  
  Since the chances of a random pattern of candy sprinkles being reproduced at random again by a counterfeiter are miniscule, this is a simple, scalable, and relatively inexpensive method to protect drug supplies. The main roadblock to implementing this technology is creating and maintaining a global database of these identifiers and keeping it secure from hacks and data breaches. The firm McNeill-PPC, Inc., explored a similar approach in an earlier patent filing (US20060088585 A1 [2006]) using a microrelief surface, which demonstrates that physical surface modification of individual doses may be a viable technique if data management issues can be addressed.

• Edible Physical Unclonable Functions (ePUFs) also use surface modifications on drugs. In this method, electrospray deposition uses strong electric fields to atomize a liquid suspension onto the surface of drug tablets. For ePUF authentication, researchers used a machine vision approach with the open-source SIFT pattern matching algorithm. The Purdue Research Foundation has also explored this process in a recent patent (WO2021076217 A1 [2021]).
  
  These surface depositions have the benefit of being extremely secure because they can’t be altered or removed. Patients can see them with the naked eye, and a simple phone camera picture can be used to verify that they’re not counterfeit. The main drawback is that automated manufacturing processes are required to achieve higher throughputs, and like CandyCodes, any manufacturer’s database would require management and security.‍
• Hidden imaging with peptide nanodots embeds these nanoparticles in polymer films. By selectively photo-bleaching the nanodots with a focused light source, hidden images or patterns can be created within the films. This approach has several benefits. First, the patterns remain stable, making his technique suitable for long-term storage of information. Peptide nanodots are also biocompatible. However, this method has some limitations in that the polymer films can eventually degrade over time. The limited color palette for nanodots could restrict the complexity of images that can be created, thereby limiting this method’s efficacy. Reading the hidden images also requires specialized equipment that would need to be scaled up and easier to obtain.

What’s at stake

Implementing these and other emerging technologies is more important as the threat from counterfeit pharmaceuticals increases. With the growth in online and mail-order pharmacies, more fake drugs are being sold, sometimes up to 50% of the medicines purchased from these pharmacies. Often operated in regions with lax oversight or regulation, these pill mills are mostly illegal.

Yet, the value of the global counterfeit drug trade is estimated at over $4 billion a year. According to the not-for-profit Pharmaceutical Security Institute, in 2023, there were 6,987 reported counterfeit drug incidents in 142 countries, an increase of 4% from 2022 (see Figure 3). These threats to public health will continue as long as financial incentives exist to sell counterfeit drugs and the internet provides the means to do so, which makes it vital for researchers and pharmaceutical companies to implement innovative ways to thwart counterfeiters.

‍ A multi-faceted approach to prevent counterfeiting

The problem of counterfeit drugs is complex, geographically dispersed, and constantly changing. To meet this threat, the global community needs multiple technologies as well as robust regulatory measures and partnerships. The World Health Organization (WHO) first published guidelines on combatting counterfeit drugs over 25 years ago, and efforts between the WHO, the United States, and other countries are continuing to refine new regulations.

Technologies from advanced package labeling to 3D printing to nanoparticles can make a difference in the fight against counterfeit drugs. With researchers leveraging AI, machine learning, and nanotechnologies, to name only a few, it’s possible that significant progress against the growing counterfeit drug trade is near.