The vaccine market is growing. Despite some well-documented challenges – not least the threat posed by ‘anti-vaxxers’ – its revenues climbed to $25.5 billion in 2014 and there is plenty of scope for optimism that the market will remain in good shape.
Inoculation programmes are known to present a logistical headache, however. The products are highly sensitive and will naturally biodegrade over time, meaning proper storage and transportation procedures are essential. In particular, storing them outside of a suitable temperature range can cause irreversible loss of potency.
"The FDA requires some type of verification that you used procedures to ensure that your product maintains temperature as indicated on the label," says John Conway, head of customer service and distribution at Novartis Vaccines and Diagnostics. "Vaccines must maintain a correctly refrigerated state."
This is not just about keeping in line with the regulators. From the manufacturer’s perspective, vaccines are complicated to develop, production costs are high and margins are slim. Factor in the relatively modest shipment sizes, and it is clear to see that wastage is not an option.
Worse still, if a product turns out to have been stored incorrectly during transit, it may be necessary to revaccinate everyone who received that batch. Not only is this costly for the manufacturer, it also may reduce public confidence in vaccinations and lower the herd immunity.
According to the US Centers for Disease Control and Prevention, it is better not to vaccinate at all than to administer a dose that has been mishandled.
Storing up problems
Maintaining good distribution practice is therefore just as important as production. As explained on a World Health Organization release: "It’s not just about developing safe and effective vaccines. It’s about getting vaccines to the right place, at the right time, in the right condition, and that means delivery systems that are as advanced and innovative as the vaccines they support."
Taken out of context, the manufacturers’ requirements generally sound quite simple. Like most biological pharmaceuticals, the majority of vaccines need to be stored at 2-8°C, with a desired average of 5°C.
Any temperature excursions may damage the vaccine, especially if it is left out too long, or slips out of the appropriate range a number of times.
Importantly, these vaccines must never be frozen. When this happens, constituent proteins are denatured, emulsions become unstable and vials can crack. This can lead to lowered potency and a heightened risk of side-effects.
While there is nothing groundbreaking about the idea of avoiding extremes of hot and cold, how you go about it is a different story. A vaccine may travel thousands of miles in its journey from manufacturer to provider, with the climate varying hugely from one region to the next. The task becomes maintaining temperature consistency, even as conditions outside change.
"We might package a product leaving Louisville this morning, where it’s 7°C, and it’s delivered tomorrow in Arizona where it’s 27°C," explains Conway. "Ten years ago, people would say we will look at what the temperature of the destination is and we’ll pack it according to that, so if it’s a warm destination you’d pack it with more ice bricks.
"But if it sits in the UPS hub in Louisville for a couple of hours, and then you put it on an aeroplane at 35,000ft, it will be too cold. So how do you maintain the temperature across different temperature zones?"
Cool runnings
Generally speaking, vaccines must be stored in specialised refrigerators or cold boxes, and the temperature inside should be monitored at all times with a digital maximum-minimum thermometer. This will identify when the temperature strays out of the recommended range. Some of the newer devices are alarmed, making it easy to address any problems as and when they arise, while others provide a visual notification to the shipping personnel.
In Conway’s case, he addressed the quandary with a spot of creative thinking, ascertaining exactly what temperature variations his shipments would face before determining how to pack them.
"I developed what’s called a thermal profile," he explains. "I did a few thousand test shipments in which I didn’t ship the product, I just shipped a temperature monitoring device. I took a box and punched some holes in it, so the monitor would record the ambient temperature the box would be exposed to, and it took a reading every 30 seconds or so.
"I shipped these for next-day delivery during the summer and at winter, all across the United States. So I had hundreds of thousands of data points, and from that I developed a profile of what my package would be exposed to and how the ambient temperature was affecting my product. I then built an insulated box using insulation and gel bricks to counteract these effects."
Conway’s cold boxes are not infallible – after all, temperatures may still fluctuate unpredictably beyond the scope of the thermal profile. His team therefore performs additional monitoring with a chemical indicator that is triggered when the temperature dips below 2°C, or rises above 8°C.
Additionally, because these boxes have been tailor made for Novartis, they are useful only for shipments that start at Louisville, and move around the US. Still, it is easy to see how similarly configured cold boxes might function in a range of different scenarios.
"If you tried to cover a wider range of places your boxes would get heavier, you’d have to add more bricks to them, or you’d need to have a bunch of types of packaging and I didn’t want to do that," says Conway.
"But once you got past the initial cost of all the design work, however, it proved to be very beneficial financially. And we could give our customers a package that we knew was validated: we knew that when they got it, it was going to be at the right temperature range."
Remote control
Vaccine programmes in developing countries require even more intensive monitoring strategies. If a shipment has arrived to a remote village in India, from a manufacturing facility in North America, for example, it is likely the temperature difference will be extreme. Unfortunately, they may face additional complications in the form of unreliable electricity connections and weak transportation infrastructure.
Here, the typical solution would be vaccine vial monitors (small stickers that register cumulative heat exposure). These were first developed in the 1980s, and are currently available for all vaccines used in developing country immunisation programmes. UNICEF and WHO estimate that they save around $14 million a year through preventing the discard of usable vaccines.
In countries such as the US, the main area of contention is not so much the cold chain itself, as what happens when the product finally arrives at its destination. In 2012, a government report revealed that some free vaccines for children were being improperly stored.
Of the providers studied, 76% had stored vaccines at incorrect temperatures for at least five hours during the two-week period assessed, which meant the vaccines in question were liable to be less effective.
"We don’t think this report makes us question whether our vaccines are safe or not, but we take the results very seriously and plan to work with the states and local paediatricians’ offices to make sure they’re stored safely," said Dr Anne Schuchat, director of the National Center for Immunisation and Respiratory diseases at CDC, at the time.
No compromises
Evidently, it is important to keep the vaccine in good condition all the way from the manufacturer’s facility to the point of administration. After all, if there’s a weak link in the cold chain, that product will be compromised, and it doesn’t matter where that link is.
"I started in this business 17 years ago, and at that time the FDA just wanted to know how the product was manufactured and what it was like at the point of manufacture," recalls Conway. "And then they started looking at what happened between the manufacturing facility and the distribution facility, so we have really concentrated on that.
"Now they want to see what that last mile looks like, and whether or not it will have an impact on your product. They’re also looking at the actual vaccination clinic and asking how the product is being stored. I think that’s where we’ll be in the next ten years, and I’m not sure where it’s going to go, but it should be interesting."
One thing is clear: while vaccines can save lives, developing the products is only half the story. They must also be stored and transported with an inordinate degree of diligence, and treated with immense care.
