Rapid globalisation and the rise of temperature-sensitive modern drugs have made cold chain management a priority for pharmaceutical companies. Eva-Lotta Persson, research and development supply chain programme manager at AstraZeneca, tells Clinical Trials Insight about the dangers of temperature deviations and the importance of proper risk management.
Organising drug distribution has always been a challenge for the pharmaceutical industry, but over the past few years the process has become considerably more complex. The rise of fragile, temperature-sensitive biologics, the pressure of bringing goods to market as quickly as possible, and the emergence of new markets such as China and India have all dramatically changed the way supply chains are monitored and managed.
Against this backdrop, maintaining the integrity of products and avoiding temperature excursions – deviations from the approved temperature range that a product is exposed to – remains the key focus. If a product, particularly a biologic, is exposed to significant deviations in temperature, it can stop working, potentially rendering a whole batch unusable.
Given the danger this can pose to patient safety, and the reputation and financial well-being of pharmaceutical companies, over the past few years, supply chains have become increasingly regulated through good manufacturing practice (GMP) and good distribution practice (GDP).
“To monitor and track temperature excursions is required, according to GMP and GDP,” says Eva-Lotta Persson, research and development supply chain programme manager at AstraZeneca. “Companies need to prove delivery of quality investigational medicinal products (IMP) to patients, as temperature excursions can result in high levels of degradation, loss of potency and/or altered bioavailability.
“This can be harmful to patients and also provide false results on the efficacy of the IMP being investigated in the clinical programme. Any material that has been subjected to conditions outside the proven stability range must therefore be rejected.”
Keep your cool
What, precisely, do regulators require to avoid this happening? According to Persson, the industry must be able to provide evidence of claims on storage time and temperatures using robust product stability data. “The focus here is often to support long-term storage of the product, either at room-temperature conditions (below 25°C, or below 30°C), refrigerated (2–8°C), or frozen (-25–-15°C),” she says.
“However, data should also be generated to understand whether or not shorter temperature excursions from the approved label range would have a negative impact on quality.
“Cumulative excursions also need to be considered to comply with regulations. For example, if the product is exposed to several smaller excursions, it is important to track and verify that the cumulative time the IMP is stored outside of the approved label range is not exceeding the time verified by stability studies. Some IMP can also be sensitive to cycling between low and high temperatures, which is why limitations on the number of excursions might also be important.”
Costly temperature excursions can occur at any stage in the supply chain from the shipping of bulk drugs from manufacturing site to packaging site, to IMPs that are in the hands of patients. According to Persson, however, the most critical phase is when drugs are shipped from depots to clinical sites.
“These are the shipments that need the most attention,” she says. “Clinical trials are performed worldwide, with different climates, seasons and distances. For some countries, the shipment from the ‘local’ depot will involve transfer over borders and custom clearance. Distribution standards might differ between countries, but for the industry it is really important to keep a global standard for maintaining the quality of products. Shipments to clinical sites are also the transport occurring most frequently. From each depot there might be hundreds, or thousands, of site shipments for a single phase-III study.”
Plane, sailing?
Deciding how to transport these goods is never an easy decision. The two major transportation methods – air and sea freight – carry advantages and disadvantages when it comes to minimising the risk of temperature excursions. By air may be the fastest route to many destinations, but Persson points out some clear drawbacks.
“Shipping large volumes of IMP temperature-controlled can be expensive, due to the limited number of kits held in one container,” she says.
“There are also several instances in which transfers needs to happen. The so-called ‘tarmac-effect’ can often be observed where a box is standing outdoor in the sun or cold (on a loading bay or by the runway) for an extended period of time.”
Sea is well suited to larger depot shipments, Persson says, but adds that checks and balances are required, particularly when shippers depend on dry-ice, or different types of cold packs. “It is important to review validation data,” she says, “so that we can understand how long a time the temperature has been kept at the approved range, and also how susceptible the pack is to external temperature conditions. Validation of a pack needs to factor in external effects and not just be validated in a room temperature environment.”
Persson, who moved into her role as supply chain programme manager in 2011, says that a risk-based distribution strategy, focused on reducing the cost of distribution while maintaining the quality of IMP, is the best approach for clinical trial companies that are dealing with temperature-sensitive goods.
“Most of us have been to a store to buy ice cream,” she offers as an example. “The label on the box clearly states it has to be stored frozen, but no one would bring a freezer into a store in order to take it home. I live in in Sweden, so when I bring ice cream home between October and March, it is sufficient just to cover it in a plastic bag, take it out to my car, and then drive straight home. The quality of the ice cream is satisfactory when I get home and put it in my freezer, where it can remain for a couple of days until it is ready to be consumed.
If it was summer, and the warmer temperatures might mean I bring a cooling bag with ice packs to ensure the ice cream does not thaw. In doing so, I am undertaking a risk-based transportation of the product from the store to my home.”
Persson explains that this approach can be used for shipping IMP “by having a cross-functional review of product quality and distribution routes prior to start of a study”. This means using the most suitable packaging material, depot selection, means of transportation (sea or air freight, trucks and so on) and temperature monitor profile. “It is important to acknowledge that not only active ingredients can be affected,” she notes. “For example, devices that are used to administer the dose, such as syringes or inhalers, might lose functionality if subjected to conditions outside the approved label range.”
Even with a thorough risk management strategy in place, mistakes can occur. In this situation, Persson says learning from errors and working out how to improve is vital. “Part of the distribution strategy should also be a learning review, which involves regularly going back to review excursions and evaluate improvements,” she says. “This can also provide good leverage in discussions with service providers as to where the main issues are identified.”
Controlled doses
While the full strategy Persson outlines might sound complicated, as technology improves, she says, technical solutions will emerge that offer pharmaceutical companies better control over their supply chains. “Shipping materials that are better able to keep products at the right temperature are key,” she says, “especially as more and more treatments move from tablets, or other types of solid formulations, to more sensitive products, such as biologics.”
But choosing which product to procure isn’t easy, and there is often a trade-off between price and quality.
“Look, for example, at temperature monitors,” says Persson. “There are cheap monitors that will only inform you if an alarm’s limit has been exceeded, but there is no download available to understand for how long, or how far from the limit, the breach was. There are other monitors available on the market, which can provide a full trial of the temperature range that a shipment has faced, logging the time and temperature above and/or below the alarm limits.
These temperature monitors will allow a close review of the severity of the excursion and possibly allow for the IMP to be used.
“They also allow a more detailed review of where and when the excursion took place, and provide better data for improving the distribution route or packaging material, but are likely to be at least ten times more expensive than the simplest models.”
With all that in mind, how should companies choose? “For me, it still comes down to understanding what you want the technology to do for you, rather than just adapting your business to new technology,” Persson says. “I think, when exploring new solutions, firms should consider overall cost, simplicity for the user, and environmental sustainability.
“Organisations should be asking if they can reduce waste and minimise emissions and the number of electronic components they use, or reuse material in simple ways.”
Ultimately, whatever new technologies come to market, the goal for cold chain management will remain the same: managing risk, and deploying robust temperature monitoring and stability protocols. As Persson says, “It all comes down to understanding your product with the design of a thorough stability programme to work out how a product will be affected by high and/or low temperatures.”