Ken Kingery: Hello, and welcome to Rate of Change, a podcast from Duke Engineering, dedicated to the ingenious ways that engineers are solving society’s toughest problems. I’m your host for today’s episode, Ken Kingery.
This episode has just about everything you could want in a story. Saving lives and preventing people from contracting a deadly disease? Check. Undergraduates getting a chance to make an impact on the entire world? Check. A deep dive into the tiny notch that helps you open a ketchup packet? Now we’re talking engineering. And as so many collaborations do, this story begins around a water cooler. So let’s jump right in with Bob Malkin, professor of the practice emeritus of biomedical engineering and founder of Duke’s programs Engineering World Health and the Global Public Service Academies.
Bob Malkin: So you know what began when I was at a meeting I was at a scientific meeting and I was standing at the coffee pot. Which was what I do a lot of the time when I’m at a scientific meeting, I find some of the most valuable conversations I have are actually out by the coffee or not in the sessions.
Kingery: It was probably the consortium of global health universities conference, but he’s not completely sure. It was, after all, almost a decade and a half ago. So we’ll cut him some slack.
Malkin: And I met a woman who was working on a project to try to provide single doses of Nevirapine to mothers who were at risk for HIV positive and a risk of delivering their babies at home.
Kingery: When Professor Malkin says “home,” he’s generally referring to low-income countries, especially in East and Southern Africa, where there are more than 20 million people living with HIV as of 2019. That’s almost seven percent of the population in the prime reproductive ages between 15 and 49. And when those people do have children, it’s not a given that they will pass on the infection. If a newborn can receive the right dose of antiviral medications at the right times, the disease can be prevented. Without them, the risk of HIV transmission is as high as 45 percent. But with their proper use, the risk drops to less than five percent. Prevention gives children the best chance at survival, as more than half of HIV-infected children die before age two. And Nevirapine was the first of these drugs to be approved, meaning it had already come off patent and was cheap to come by.
Malkin: And the idea was that Nevirapine was known to prevent the transmission of HIV from the mother to the child. And it was it was effective, but it was also known that all of the standard approaches to delivering the medication were failing. So if you think about your childhood, your Mom probably gave you medication in a spoon, perhaps in a, I don’t know, a dropper, maybe a…
Kingery: Spoon full of sugar?
Malkin: Yeah, yeah. Nevirapine’s already pretty sweet so, probably wouldn’t want to add sugar. But it turns out, all of these standard methods destroy the medication. So the effort was failing, and moms who are delivering in home—which is actually quite common even today in Africa, for example, and in other places as well—they had nothing. And their kids were at high risk of becoming HIV positive. So USAID, the United States Government, funded a project to try to determine a way to provide single-dose Nevirapine to babies. And that project was failing. By the time I was talking to this woman at the coffee pot, she and her team had worked on it for seven years and everything failed.
Kingery: Professor Malkin didn’t know why exactly their efforts were failing, but he had some ideas. Perhaps something about evaporation or the way the medication was being handled was destroying it. And, crucially, they were all testable.
Malkin: So I brought it back to Duke and there was a student Michael Spohn, who was a mechanical engineering student and looking for an independent study project. And Michael and I both thought, you know it take take a little bit of time to set up, maybe a month or two to set up a really good experiment to shut these processes down, and then we can take a look at data. Turned out it was more like a year and a half to set up the experiment, so we can be very confident that, you know, we knew what we were doing. But Michael set up to experiment. He shut down evaporation, he shut down the loss of preservatives…and neither of those hypotheses were correct. It became clear very quickly—once we had the data was actually pretty obvious what the problem actually was—and in fact I would say within about a minute of having the data and determining what actually was the problem, we were able to design the Pratt Pouch—at least that sketch of the design of the Pratt Pouch, and a solution to the problem.
Kingery: The problem, believe it or not, had more to do with how paint dries than any sort of complicated biochemical reaction.
Malkin: The problem had to do with volume-to-volume ratio, or the similar problem, the analogy that I like to use which many people are familiar with is the surface-to-volume ratio. So if you, for example, go to Home Depot or any kind of store and buy yourself a gallon of paint it will come as a liquid. As soon as you spread that on your wall, it will become a solid. The reason or a reason that it makes that transition from a liquid to a solid is you’re going from a can, which has a relatively small surface area with a large volume, to the wall, where you have a relatively large surface area for a small volume. And the paint then undergoes a transition when you change that surface-to-volume ratio. That’s what was happening to the medication. Slightly more complicated, but that’s what was happening into the medications. The medication was actually exposed to a change when it was removed from the bottle into this packaging—syringe, cup, spoon or whatever—that change in shape, if you will, or storage conditions, was causing the medication to precipitate or causing the medication to change from a liquid to a solid.
Kingery: Professor Malkin explained that in a typical health care setting, the medication would be taken directly from the bottle and provided immediately to the baby in the hospital. Or in other words, the paint was immediately applied to the wall from the can. But in some places in Africa, where women travel long distances for even routine health checkups and usually give birth at home, doctors were trying to give this medication weeks or even months before it was going to be used.
So after three semesters of undergraduate student Michael Spohn working to discover the problem, he then turned to working on a solution with Professor Malkin. In short, they had to design some sort of container that would keep the paint in liquid form even after it left the original container. And whatever the solution was, it had to be biologically inert, free from contamination, easy to use, and cheap enough to deploy on a large scale.
Malkin: So you know we both were familiar with packaging like what you get when you go to a fast food restaurant. They have ketchup or there’s many other actually things—there’s salad dressing and there’s these other packages that you’ve probably seen yourself, where you tear it open in a corner and pour it out. The critical thing about some of those packages, is that they have at least three layers and typically they’re going to be five layers. The first layer is this plastic, which actually contacts the contents. There’s an adhesive layer. Then there’s an aluminum foil layer, which prevents water from getting out and oxygen and light from getting in. And then most typically there’s going to be another layer as a plastic layer over that which doesn’t matter too much that’s mostly to protect the aluminum foil, which is quite thin. Just a mill or even less, I think it’s it might only be eight microns thick. And then we actually put some markings on the outside so moms have some clues about how to use the device. So this is a pretty well developed technology. And it’s specifically aimed at this problem—controlling what access the contents have to the plastic but also exposure to oxygen, air, and light, and things like that. So we immediately suspected that this packaging would work in this case. There are available packaging for food—which is usually what is used actually for pharmaceuticals is food packaging—that and, as I mentioned, like salad dressing ketchup, mayonnaise, mustard – actually mustard is not in these packages
Kingery: The reason for this, by the way, remains a mystery to me.
Malkin: But other things which are packaged like that. So this was a readily available technology. And, importantly for us, it is a technology that is relatively easily implemented. In other words you don’t need a huge manufacturing facility to fill and seal these packages. So we envisioned very quickly, after only a few months of additional research, that we could actually set up a plant quickly—in Africa or wherever—to fill and seal these with the right amount of material.
Kingery: So there you have it. A simple, elegant solution that was immediately able to be implemented and save lives. Except, of course, life is rarely that easy.
Malkin: Though you and I might be quite familiar with ketchup or mayonnaise or salad dressing in one of these packages, that doesn’t mean someone who is delivering their baby at home in Africa is. So we had a question, you know, could moms really do this? And then there’s still was also a question of could the empty the contents because we’re one of the dose to be accurate. So we wanted babies to get the right amount. So the mom had to be able to tear it open while holding the baby, dribble the contents into the mouth, while emptying the entire pouch into the mouth of the baby. So there were you know some challenge—and that’s all in addition to accomplishing the main goal, which was to actually store the medication successfully. So we had these three big questions which still needed to be answered, about the design.
Kingery: So at this point, the project is already almost two years into its life. The problem has been identified, and has a potential solution. Now comes the not-so-simple process of engineering a fool-proof system that meets all of the rigorous medical standards that come with packaging, storing and delivering life-saving mediation. And that took about another five years of rigorous engineering.
Malkin: So there are five layers in the basic pouch, and all five of them, I think we changed. So we probably tried 20 or 30 permutations.
The outer coating, we changed. It turns out that the outer plastic affects tearing and how easily the moms can tear the pouch.
Also there’s typically a notch, which you may not think much about. But that notch and the shape of that notch varies between different materials. So we needed to find a material that really preserved the medication really well, but was really easy for the moms to tear open, which are conflicting objectives.
There are many different sealing technologies. And so we went through three or four different sealing technologies, as well as two or three different filling technologies for the pharmacist to fill.
Kingery: And then there was the problem of the ink.
Malkin: We wanted to print on the outside, instructions to the mom. So the cheapest way to do that is to take a roll of the original material—which comes in these huge rolls—and my meaning many feet across and several feet in diameter. Thousands of pounds these roles weight. They stick them on a machine, they run at a high speed, and they print all of the outside packaging printing on the outside. Then they reroll the package and send it off to a different machine to cut and seal the three sides. Well, at the moment when they reroll that roll, the outside of one pouch touches the inside of the next pouch. That means that the ink that you use to print has to be compatible with the medication you’re going to later store inside the pouch. The first iteration, that wasn’t true, we used a randomly selected ink and of course it destroyed the medication. None of us realized that they rerolled the roll before putting it on the next machine to cut and seal the pouches. So yes, very specific. It took a long time to get every one of these processes from the shape of the notch to printing the instructions.
Kingery: To design the best Pratt Pouch possible, the team’s decisions needed to be driven by actual data from actual women. Which meant they needed help. They got volunteer moms to try to use the packets to deliver the medication to dolls as practice…and eventually to real babies in Africa…which actually resulted in quite a few failures early on. That led to a redesign in the labeling instructions.
Malkin: To even the shape of the pouch itself, so that moms could one-handed squeeze the pouch and empty the contents. Turns out that if it’s wider and shorter, or longer and thinner, moms are more or less successful at emptying all the contents into the baby’s mouth. Different than, for example, emptying the contents onto a hamburger, where it doesn’t matter very much with the empty all the contents, and the hamburger is not squirming in your lap.
Kingery: Right, sure, I don’t think I ever get all the ketchup out of any of those packets so…
Malkin: But it matters. Dosing matters for this medication. So it’s not like ketchup, where you could just open up another pouch, squeeze some more ketchup on your french fries. Here you want the baby to get exactly the right dose. So this emptying percentage is a really important number for us.
Kingery: 5000 opened pouches were analyzed on a microscopic scale to determine how exactly the packets were getting opened. For example, how much tear force was used, how long was the tear and how many failures to tear occurred. Later on in the process, when trials had moved from dolls to live babies, blood samples were taken from babies’ heels to determine if the medication was indeed getting into their bloodstream correctly. High-performance liquid chromatography tests made sure that the medication was in fact still intact a year after being packaged.
And besides collaborating with healthcare workers in Africa or industrial companies for the more complicated tests, almost all of this was still being led by a string of bright, enterprising Duke undergraduates.
Malkin: There were maybe some graduate students involved as well, especially later in the process when we got into field trials. So actually going to these places and collecting the data. But, yeah, I mean I had undergraduates year after year who would pick up the project.
Kingery: But engineering problems weren’t the only challenges that needed to be overcome. While the drug itself was approved in every country they wanted to use it in, the packaging was new. And every country in the world has its own equivalent of the FDA that needs to provide approvals.
Malkin: And this varied from Zambia, for example, which took about four hours to get approval. So between us requesting approval and its availability in the market took about four hours. And at the other extreme is Tanzania, which took three years to get approval for distribution of the Pratt Pouch on the Tanzanian market.
Kingery: Despite all the challenges over more than a decade’s worth of work, the Pratt Pouch program is now up and running in Ecuador and Uganda with the help of grants from sources like the National Institutes of Health and USAID. Tens of thousands of babies have received antivirals. In Kampala, Uganda, semi-custom equipment assembled by Duke graduates are capable of reaching more than 10,000 infants each year. And for all they know, that’s just the tip of the iceberg.
Malkin: However, keep in mind the technology is completely open source. We very early on decided not to use any sort of intellectual property protection. All of the designs, all of the usage, the labeling—everything is open source. So anyone can actually go on to our site, download all the data, download all the designs, order themselves up some pouches and start getting them approved in their country for use and distributing them. So in fact they’re there can be and could be many places using them that I wouldn’t know about.
Kingery: As for the programs they do know about, Professor Malkin’s goal is to reach at least 80 percent of HIV –positive moms in Ecuador and Uganda. He also has his sights set on setting up new programs in additional countries. But as have all things planned for the past couple of years, the pandemic has brought them to a virtual standstill.
Malkin: Normally we are very active in expanding use of the pouch in trying new variations with it, to make sure that they are or are not compatible, like antibiotics, for example, TB meds. However, almost all of that work has stopped right now. The way that we have driven the project from the beginning is undergraduates at Duke, and we do have an undergraduate working on the program right now, but the majority of that was field work. Most of the work was going into the field traveling. And right now that’s just not possible for the undergraduates at Duke. Once this situation resolves and, you know, I assume we are going to all get back to kind of a normal life. I don’t exactly k now when but, once we do, I fully assume that we’re going to get back to having the students travel, getting field data once we’re able to gather data in the field, then we can also go back to writing grants and really supporting the operation fully.
Kingery: But as any good engineer knows, almost all problem have a solution if you’re willing to put in the time and effort required to find it.
Malkin: Absolutely, so we will not you know sort of rest, if you will, on this project, because there are still millions of mothers delivering their babies, who are HIV positive. Those babies at risk of themselves becoming HIV positive and the moms aren’t getting access to the medication problem is quite severe right now, because of coven, but it is going to. Continue we our goal is to see that every mom is able to medicate their kid and prevent the kid from being HIV positive, so we have a long way to go, there is no really end in sight to this problem and, as I said, that’s only one issue, there are also issues with TV men’s for children, there are issues with antibiotics for children, so there are a lot of access issues that the pouch may be able to solve.
Kingery: That’s the show for today. I hope you’ve enjoyed hearing about how just one conversation around a coffee stand with the right people can inspire a string of undergraduate engineers to change the world. If you want to learn more about Professor Malkin’s work and the Pratt Pouch, you can keep up with their progress at pratt.duke.edu. And if you want to hear more inspiring stories such as this one, I encourage you to subscribe to this podcast.
Thanks for listening.