Pharmaceutical companies increasingly outsource their peripheral activities to focus on core activities but there is one area where outsourcing has long been the norm and that is logistics. Especially with international supply chains, the practical and technical complexities of shipments have almost always been managed by third-party logistics providers (3PLs) who coordinate the activities of all the players involved. There is some risk involved in handing over any product to a 3PL, and most industries maintain a certain level of inventory in case product is delayed, lost or damaged in transit. However, that approach can be problematic for pharmaceuticals because of tightening regulations (e.g. Good Distribution Practice), increasing criticality of life-saving medicines, and the time and temperature sensitivity of many pharmaceuticals. Nowhere is that truer than in air transport where a shipment may have to pass through the hands of twenty or more organizations to complete its journey, leaving the pharmaceutical shipper in the uncomfortable position of having to put highly valuable medicines into the hands of unknown operators, to be handled in an unpredictable environment, for an uncertain time period.
The simple fact is that to load cargo into an aircraft, that cargo must be transported outside and exposed to whatever weather conditions prevail at the airport at that moment. This ‘tarmac time’ may be as short as a few minutes, but can be up to several hours depending on the airport, the cold-chain facilities available, and the varied needs of the airlines, ground handling agents, airport security agencies, customs and the 3PLs handling the shipment. In addition, the exposure conditions on the tarmac vary with geography, season and time of day. The International Air Transport Association (IATA) has produced Temperature Control Regulations (TCR)1 specifically for the handling of pharmaceutical products, and in addition have set up the Center of Excellence for Independent Validators (CEIV) certification system to ensure best practice is applied and spread as widely as possible in the air freight industry. However, the TCR make it clear that while it is the duty of the different parties in the air-freight logistics chain to understand the risks and minimize them where possible, it is nevertheless the shipper’s responsibility to package the goods to withstand those risks without being damaged. And this is where pharmaceutical companies have the most involvement in the logistics process, working with their 3PLs to specify the thermal protection system to be used, and to validate that it really delivers adequate protection on the specified routes and carriers.
Now let’s think scientifically about what happens to a pallet of goods protected by a passive thermal protection system when it goes out onto the tarmac to be loaded into an aircraft. The protection might just be carton boxes, or it could be more sophisticated insulated boxes. Alternatively, the whole pallet may be covered by a thermal blanket, or by panels of rigid insulation assembled around it, or the entire pallet may be placed inside a passive thermal shipping container. In all cases, heat must be conducted through the thermal protection before the temperature inside can change, and the bigger the temperature gradient through the thickness of the packaging, the more heat will flow and the faster the temperature of the goods will be affected.
So, let’s say your Controlled Room Temperature (CRT) shipment is moved out of a certified pharma facility at 20°C, at an airport where the local weather station reports a temperature of 20°C. Does that mean you have nothing to worry about? I think most experienced logistics quality managers would still worry. The outside air temperature may be 20°C, but if the sky is clear, the sun’s rays can quickly heat the surface of the load far above that temperature. Most of us have direct experience of this at the beach, where the air temperature may be pleasant, but the sand is too hot to walk on with bare feet. Cargo waiting to be loaded into an aircraft can behave just like the sand, and the hotter the outer surface of the load, the faster heat will flow to the cooler interior. We have done tests which show that even in mild ambient temperatures, the sun can heat the outer surface of cargo to 60°C, or even above 70°C, creating a significant driving force to push heat into the product inside.
Of course, a good packaging engineer will have selected packaging made from insulating materials which are tightly closed to minimize intrusion of warm air, and which have a high thermal resistance (R-value) to reduce the flow of heat. The bigger the R-value, the slower heat will flow, and the more tarmac time you have before an excursion occurs.
Now, here’s where the first problem can arise in specifying thermal packaging systems. Most packaging manufacturers (and many logistics validation specialists) specify systems using data obtained in thermal chambers. This is convenient because in theory, if standard test conditions are used, it allows straightforward comparisons to be made. However, thermal chambers use heated air to create hot conditions, so the outer surface of anything in the chamber will never exceed the set point, nor will the floor attain the high temperatures tarmac can reach. There is no sun inside a thermal chamber (nor any effective way to simulate it) so a key aspect of real-world exposure is not reproduced in thermal chamber testing.
The consequences of this can be illustrated with a simple experiment.2,3 We took identical pallets of simulated product (100 kg) at nominally 20°C, protected with different insulating systems, and then put them in a thermal chamber at 40°C to record how the temperature of the simulated product increased over time. Looking at the graph below, System 1 performed better than System 2, with a slower temperature rise and taking longer to reach 30°C. This was expected, because System 1 had a higher R-value than System 2.
So now let’s compare this thermal chamber result with a real-world situation. We brought the same pallets back to room temperature and then put them outside in the sun at midday. We couldn’t arrange for the weather to give us exactly 40°C that day, so the ambient conditions were not quite that severe, but 35°C was still rather hot.
Two things are immediately evident. First, even though the outside air was a not quite so hot in the real-world test, the load temperatures rose faster than in the thermal chamber. That is the solar effect, heating up the outer surface rapidly and driving heat into the load faster. Secondly, the two systems seem to have different susceptibilities to the solar effect. Look at the time taken to reach 30°C. System 1 held out for little over two hours in the thermal chamber, but in the real-world test it failed after only one hour. On the other hand, System 2 did slightly better in the real-world test than in the thermal chamber, out-performing System 1, even though it has a lower R-value.
So, what’s going on here? Well, another important property of thermal packaging is reflectivity. If radiant energy just bounces off the surface rather than being absorbed, that surface stays cooler and the temperature gradient pushing heat inwards is reduced. But to look at this in more detail, we must be clear about what kind of energy we need to reflect and how that reflectivity should be measured. It may be surprising, but out on the tarmac, heat is not usually the biggest problem. It feels like there is a lot of heat rising from the tarmac, but if you take a radiometer and point it upwards at the sky, you can easily measure over 1000 W/m2 in solar radiation streaming down from the sun. That’s a lot of power hitting every square meter of surface, and it’s what makes the tarmac heat up in the first place, just like the sand on the beach. However, the kind of radiation coming from the sun and from the ground is different. Warm tarmac emits long wavelength, far- infrared which we colloquially refer to as ‘heat’. But the surface of the sun is ‘white hot’so its emissions peak in short wavelength, visible light and near-infrared. It doesn’t matter whether light, near-infrared or far- infrared hits your pallets though. If it is absorbed, it becomes heat and increases the temperature.
Now, a lot of thermal packaging systems use aluminized, metallic films or aluminum foil to ‘reflect the heat’. These products are frequently adapted from the building industry, where they are installed inside roofs and walls to reflect long wavelength, far-infrared radiation and improve the energy efficiency of the building. Out on the tarmac, we can expect them to reflect the far-infrared coming up from the ground, but what about the bigger threat from solar radiation? Some manufacturers quote reflectivity values as high as 97% in their product literature, but they rarely give any details of how, or over what spectral range this is measured. Some reference ASTM standard E1980,4 which defines how to calculate the relative tendency of different building materials to heat up in the sun, so it sounds reasonable to use it for thermal packaging. However, ASTM E1980 actually defines a ‘solar reflectance index’ as a scale with boundaries set by high and low solar reflectivity. But the high reflectivity standard only reflects 80% of solar radiation. So the fact that a thermal packaging system has a 97% solar reflectance index does not mean that it reflects 97% of the sun’s energy; in fact, its true reflectivity is unlikely to be above 80%.
We measured the solar reflectance of several aluminized thermal packaging systems using another ASTM method, E903,5 which is generally viewed as the most accurate way to make this type of measurement. Sure enough, in the range where solar energy peaks, we got numbers around 80%. That might not sound so bad, but it means these aluminized materials are soaking up about 20% of the sun’s energy, which all goes into heating up the cargo. A metallic surface may appear very ‘reflective’ to the eye, but appearances can be deceptive.
Now let’s go back to the thermal packaging systems we compared earlier. System 1 used multiple layers of bubble wrap and metallized film to achieve a high R-value and it did well in a thermal chamber but poorly in the sun. System 2 had a lower R-value but performed much better out on the tarmac and the reason is that its surface has a very high reflectivity in the critical range where the sun’s radiation peaks. Measured by ASTM E903, it’s solar reflectance is above 90%. It has a brilliant white, matte surface; white because it reflects light uniformly across the visible spectrum so has no preferred ‘color’, and matte because the light is reflected diffusely so it doesn’t form any image when it hits your eye.
So, what are the consequences of relying on thermal chamber results to select thermal packaging systems? On the one hand, you might see a high number of unexpected excursions, which will require corrective action/preventative action and additional work to release product to market, or may even lead to product loss. And if excursions are few, that probably means the specified packaging has a higher R-value than necessary, which also adds cost. Understanding solar reflectance may allow shippers to reduce the R-value requirement, use less bulky thermal packaging systems, and that means:
- The thermal packaging system may be cheaper,
- Shipping and storage costs for the thermal packaging system are lower,
- Labor costs to install it are reduced,
- Warehouse efficiency is increased,
- Freight costs may be lower as less bulk is added to the shipment.
Now there’s one more thing I want to say about how the sun affects pharmaceutical shipments on the tarmac. Ever heard of the greenhouse effect? In a greenhouse, sunlight streams in and is absorbed by everything inside, and that absorbed energy warms everything up. When the contents of the greenhouse radiate that energy, it is as infra- red which is blocked by the glass and trapped inside the greenhouse. That’s why the temperature inside ends up warmer than outside, which is great for plants but you wouldn’t want to put temperature sensitive medicines in a greenhouse! Unfortunately, that’s exactly what happens when stretch wrap or poly-film is wrapped around the outside of pallets. These films behave much like glass, letting light in but then trapping heat and creating a local greenhouse effect. Even white films can cause this problem because they still let a lot of light through, and don’t have great reflectivity either. I have seen pallets of pharmaceutical products at certified cold-chain warehouses, carefully protected with thick, expensive thermal packaging but with the whole pallet then wrapped from top to bottom in stretch-film. Or insulated pallets packed together on an airline ULD have plastic sheeting thrown over the whole load because the airline, ground handling agent or airport requires the film for rain protection or security reasons. And the shipper who has outsourced the logistics to a 3PL may not even be aware that this is happening. I don’t doubt the thermal packaging systems have been validated on those routes, but I can’t help wondering whether the shippers could have used less complex and costly insulation systems if the load wasn’t then being transported to the aircraft in what is effectively a solar heated oven!
So, in summary, whether it is in the specification and testing of packaging materials or in the details of how product is handled thorough the cold chain, it is important that pharmaceutical companies engage with all the parties involved to understand the technical and practical details at each step. And the effect of the sun is one of the most important technical details. If we can do that well, working together we have a better chance to find more cost-effective ways to deliver medicines safely to the patient.
References
- Temperature Control Regulations (TCR) 6th Edition, 2018 – International Air Transport Association.
- “Cargo cover performance under real environmental conditions”; Brabbs, S; PDA Cold & Supply Chain Logistics Conference, Amsterdam 2016.
- White Paper – “How the properties of cargo covers affect their performance in real exposure conditions”; April 2017; Brabbs, S; Cherukupalli, S; Knorr, L M; Weimerskirch, A; E.I. du Pont de Nemours and Company.
- ASTM E1980 – 11 “Standard Practice for Calculating Solar Reflectance Index of Horizontal and Low-Sloped Opaque Surfaces”; ASTM International; Book of Standards 04.04.
- ASTM E903 – 12 “Standard Test Method for Solar Absorptance, Reflectance, and Transmittance of Materials Using Integrating Spheres”; ASTM International; Book of Standards 12.02.
A PhD chemist with 30 years’ experience in R&D, and cited as an inventor on numerous patents, Steve is currently Global Application Technology Leader for Transport Protection at DuPont. He has been working in pharmaceutical cold-chain developments for several years and is a member of the IATA Time & Temperature Working Group.