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A PAD that was run with the drug amoxicillin. Photo: Barbara Johnston, University of Notre Dame

A team of researchers wants to stop low-quality medicines from reaching patients in developing countries by equipping people on the ground with a simple but powerful tool: a piece of paper.

The Paper Analytical Device, or PAD, is a small card that gives users the ability to test the content of dozens of pharmaceuticals to determine whether a drug contains the correct medicine. The device is described as a “complete lab on a piece of paper.”

The PAD allows chemicals analysis to take place outside of a laboratory setting without any additional equipment or instruments. Only water and a drug sample are needed to conduct a chemical test, eliminating the cost and access barriers that many countries have faced for effectively screening pharmaceuticals.

“What we’re trying to do is level the playing field,” said Marya Lieberman, a professor of chemistry at the University of Notre Dame and the head of research for the PAD project. “Right now when people buy medicines they buy their medicines based mostly on price. We’d like to have the quality of the product come into that equation.”

While estimates vary about the scope of the problem with substandard and falsified pharmaceuticals, a collection of articles published in a special supplement of the American Journal of Tropical Medicine and Hygiene in 2015 described the existence of low-quality medicines as an urgent threat with the potential to compromise decades of successful efforts to combat HIV/AIDS, malaria and tuberculosis.

“The pandemic of falsified and substandard medicines is pervasive and underestimated, particularly in low- and middle-income countries where drug regulatory systems are weak or non-existent,” Jim Herrington, co-editor of the supplement and director of the University of
North Carolina’s Gillings Global Gateway at Chapel Hill, said in a statement.

The World Health Organization, or WHO, describes the existence of such products as an “unacceptable risk to public health that affects every region of the world” and “medicines from all major therapeutic categories.” While WHO says internet connectivity has allowed individuals who manufacture and distribute low-quality medications to access a global marketplace, the organization notes that “it is low- and middle-income countries and those in areas of conflict, or civil unrest, with very weak or non-existent health systems that bear the greatest burden.”

Last year in Kenya, Lieberman said her team found a brand of the antibiotic amoxicillin circulating in which 50 percent of the amoxicillin had been replaced with talcum powder.

“It’s hard to understand when you are living in a well-regulated medical system how chaotic things get in other systems,” Lieberman told Laboratory Equipment.

In that country of more than 48 million, Lieberman said, the supply chains include official government entities, an active private market and non-governmental organizations.

“It’s very hard to monitor all of those sources of medicines. That kind of environment, it makes it really hard for the regulatory agency to keep tabs on what’s actually reaching patients,” said Lieberman. “That’s how we hope the paper test cards will make it easier for regulators to know what’s going on at what’s called the ‘last mile,’ which is how the drug actually reaches the patient.”

Chemicals and paper
There are now scientists, engineers, doctors, reserachers and students from around the world working to help push forward the PAD project, which first started when Toni Barstis, a professor of chemistry and physics at Saint Mary’s College called Lieberman and asked her to collaborate on an effort to adapt chemical tests to paper.

“The idea of putting fabrication and chemistry together was the end all be all for me,” Barstis told Laboratory Equipment. “That’s when I ended up talking with Marya and said, ‘What can we do? Let’s play.’”

The now-patented device that was developed as a result of that initial conversation is created using a heavy paper made of pure cellulose fibers. The paper is imprinted with 12 lanes that contain color-producing reagents that react after a drug is spread across the card and the card is dipped in water.

“Sometimes the lane will give different colors for different products,” Lieberman said. “We have a reagent in Lane B that reacts with primary amines, but the color that forms depends a lot on the rest of the structure of the molecule. We get a lot of information out of doing all these color tests in parallel that lets us sort out a lot of different drugs.”

The PAD currently has the ability to test for about 60 different chemicals, Lieberman said, but the goal is to develop a card that can test as many of the 343 medicines included on the WHO’s essential drug list as possible.

“We hope to make it possible to do regular post-market testing because that’s the only thing that’s going to really help improve the quality of medicines that are reaching patients,” she said.

But finding a way to translate steps that are normally performed in test tubes under a hood in a lab poses some significant challenges.

“There are all these wonderful color tests in the literature that I’d love to put on the card but you have to do them in concentrated nitric acid,” Lieberman said. “That reagent doesn’t survive on the card. It just burns a hole in the paper. We’ve had to develop some workarounds, so there’s some reactions where we can use a substitute acid that’s more stable on the paper.”

Adaptations
Researchers are also working on ways to adapt the PAD so it can be used to detect the quantity of an active pharmaceutical ingredient, or API, in a drug.

Barstis, who recently traveled to Nepal with a group of undergraduate students to conduct PAD research, said they didn’t find outright counterfeit or substituted APIs during that trip. Rather, she said, they found drugs that were “either being stored improperly, so they’re degrading or expired, or there’s a manufacturing issue in terms of quality control where there is not enough of the API or, in some cases, more API ... then should be in that pharmaceutical.”

“We’re trying to adapt the PAD or make another PAD to address that issue,” Barstis said.

They are also investigating the possibility of using these paper-based devices to analyze adulterated milk, detect heavy metal contamination and measure E.coli levels in drinking water. As far as what other tests may be adapted to the PAD in the future, Barstis said “the sky’s the limit. I don’t even want to put a cap on that.”

As researchers work on potential new uses for the PAD, there’s also a simultaneous effort to make the current device even easier to use. That’s the mission of Veripad, a startup company co-founded by Bishoy Ghobryal that is developing a mobile app capable of reading and interpreting a PAD test and generating easy-to-understand results.

Ghobryal said the combination of the PAD and the mobile app “democratizes lab analysis.”

“I see this as currently one of the most accessible, easiest-to-use technologies that brings lab analysis out of the lab,” Ghobryal said. With the app, you can take a photo of a completed PAD test, upload it and get results within seconds.

So, with a piece of paper and a mobile phone you can perform basic chemical analysis, which Ghobryal described as “immensely powerful.”

“You don’t need to be educated. You don’t need to know what’s going on chemically because you have the app,” he said, “and you don’t need to be rich because the app is cheap, because the PAD is cheap. And it’s that combination of factors that really just changes the game here.”

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