Hot mess: clinical supply temperature control

Temperature control is essential for all sorts of commodities, but, in the case of pharmaceuticals, the slightest shift from hot to cold, or vice versa, can render investigational medicinal products (IMPs) entirely ineffective or even toxic. All sorts of situations can cause these mistakes: errors made in transit and storage, often rooted in simple human error, can lead to products being rejected or, more dangerously, used, raising serious safety concerns for patients.

With more than 36 years of industrial pharmaceutical experience under his belt, James Krupa, director of clinical supplies at Shire, knows a fair bit about these issues. Often, he argues, the most common cause of temperature fluctuation during distribution and storage is basic human error: a team member not taking enough care to make sure monitoring systems are correctly set up, for one.

“For distribution, whether it is from depot to depot or depot to clinical site, the most common cause of temperature fluctuation would be the incorrect placement of the temperature device within the container, as well as not remembering to turn it on,” he says.

As small as these mistakes may seem, the consequences can be significant. Problems can be costly, if the IMP needs to be replaced; time-sensitive, if a patient is at the site and waiting to be dispensed the IMP; and resource-intensive, as it would be necessary to determine whether the IMP is still usable.

“You usually need quality assurance, scientists and clinical supplies to determine if the IMP can still be used based on documented time-out-ofenvironment (TOE) stability data as a function of temperature and cumulative time,” says Krupa. “This information must then be communicated by clinical operations to the clinical site.

“A lot of temperature excursions are reported right before a patient is to be dispensed an IMP. This demonstrates to me that the sites and companies are not doing a good enough job of monitoring the temperature.”

And these unfortunate accidents are so common that some pharmaceutical companies are now hiring professionals to specifically deal with these kinds of issues: ‘temperature excursion specialists’ are popping up with increasing frequency in the clinical supplies field because of the volume of excursions that are encountered.

The harm that these kinds of errors can cause should not be underestimated. While statistics aren’t available to give a better indication as to the losses that poor temperature management incur, those in the pharmaceutical industry are unequivocal on the importance of monitoring. A report by Darren Wedding, senior vice-president of operations for Zuellig Pharma, one of Asia’s leading healthcare services providers, lays it out in unambiguous terms.

“The efficacy of today’s higher-value and structurally complex drugs can be destroyed through a single cold-chain break,” he stated in the report. “The integrity of controlled room-temperature products can be impacted through inconsistent environmental conditions during distribution, while a weak link in the management of temperaturesensitive clinical trial materials can impact study outcomes and lead to extremely costly delays in bringing new products to market.”

“These challenges, as well as the globalisation of supply chains and increased regulatory scrutiny, which can reach across borders, make temperature management throughout the pharmaceutical industry more important than ever before.”

Common problems

Speaking to Krupa, it seems that a lack of information is, generally, the cause of a lot of IMP temperature fluctuation accidents.

“It could also be a result of improper placement, and insufficient number of ice packs and cold packs according to the detailed instructions for the container during distribution,” he says.

In the case of phase-change materials, panels may not have been properly preconditioned in a refrigerator or freezer to reach the correct temperature for the package to ship in the tight temperature range that has been requested.

It’s not usually storage at depots that’s the problem, according to Krupa; they generally adhere to current best practice, as well as employing validated temperature systems that constantly monitor the temperature in the facility with preset alarms – systems commonly known as BAS (building automation system).

“Storage at clinical sites is more of a challenge, regardless of temperature required,” Krupa says. “The identifiable cause can be poor circulation or ventilation of the room or chamber housing the IMP, especially if filled to overcapacity [for example, IMP stored on the floor or stacked to the ceiling of the chamber].

“Clinical sites have sometimes not turned off the temperature monitor when they have opened and inspected the contents to acknowledge receipt of the IMP.”

Chambers themselves are usually not constructed for GMP or medical purposes to maintain a tight temperature range. Mistakes can also be made through other basic technical errors. In fact, a common cause of temperature excursion is that a refrigeration unit goes out over the weekend and is not reported promptly. Lack of training at clinical sites, a high turnover of products and not monitoring temperature on at least a daily basis can also contribute to this problem, according to Krupa.

But what kind of real-time monitoring systems can be used to keep an eye on this, and which sharing strategies are the most effective? For one thing, investment in new monitoring technologies can make a big difference. For example, GPS temperature monitors that can detect temperature excursions when IMPs are in transit and programmed to keep them within the desired temperature range are worthwhile, says Krupa.

“Some companies also have a small medical-grade refrigerator that they purchase or rent, which can be used to store IMPs at 2–8°C at the clinical site or in a patient’s home,” he continues. “The refrigerator is equipped with a computer/LCD that controls access and tracks temperature profiles. Temperature data is transmitted through wireless cellular and can also trigger temperature-excursion email alerts.”

For keeping costs down, it doesn’t even have to be this advanced. Forewarned is forearmed, after all, and having a company’s clinical operations team thoroughly check out a clinical site’s capability for maintenance of proper storage before the qualification visit can make a big difference.

“This is done by the clinical site filling out a survey on how they will maintain proper IMP storage,” says Krupa. “This shows that the company is very serious about enrolling sites that can adequately demonstrate [their capacity to] store the IMP under specified conditions. If it’s an existing site, check their history of proper temperature storage.”

The criteria can be defined in a standard operating procedure, and training at the site on how to properly store IMPs and what to do if a temperature excursion is identified can be carried out.

Better monitoring

Best practice can also be affected by circumstances, and clinical trial professionals often need to tailor their monitoring systems for different needs. For depot-to-depot shipments, for example, Krupa recommends GPS temperature monitoring because the amount of IMPs being distributed is large and, as a result, the risk is significant.

“For direct-to-patient (DTP), again, you would want GPS temperature monitoring using a medical-grade refrigerator at a patient’s home,” he says. “For clinical sites, GPS would be ideal. However, this may not be practical because of the costs.”

But, as time progresses, clinical sites will be much more adept at maintaining temperature with the right chambers and equipment for two simple reasons: because the industry and global regulators demand it, and the technology will have significantly reduced the chances of errors being made.

“Technology will be such that temperature excursions will be reported in real time and alert all pertinent parties to mitigate IMP wastage and maximise use,” Krupa says. “This will be a culture change for a lot of sites.”

We might not even have to wait for a culture change. A few years ago, the EU updated its Good Distribution Practice (GDP) Guidelines to include new recommendations regarding temperature management for IMPs in transit, and the new rules have had a knock-on effect across the broader industry. With the potential losses that can be incurred through inadequate temperature management and monitoring, it’s surprising it’s taken so long.