How do you overcome the challenges of the very end of the clinical supply chain and ensure temperature is maintained through to destination? Julian Piallat, R&D global distribution manager at Sanofi, speaks to Abi Miller about maintaining the correct shipment temperature once a product has reached an investigational site, or even a patient’s home.
The ‘last mile’ of the clinical supply chain is perhaps the hardest to get right. The conclusion of logistics, where the shipment reaches its destination, presents a wide array of challenges that may outfox the unprepared. Even if the transportation process has gone without a hitch, the point of changeover is harder to control. Once the product arrives – at a hospital, doctor’s office, or investigational site – there is a chance it will be damaged or spoiled. After all, if the site personnel aren’t conversant with storage protocols, all the care you have taken in transit can be wasted.
All pharmaceuticals must be handled with caution, of course, but the treatment of temperature-sensitive products is becoming a particularly hot issue for the pharmaceuticals industry.
While, in the past, ‘temperature-sensitive’ may have referred narrowly to vaccines, insulin and a few biotech products, more recently the definition has broadened to include anything with a temperature specification. Today’s GxP regulations require every consignment to be stored and handled under exactly the right conditions.
As Nicholas Basta, editor-in-chief of Pharmaceutical Commerce, explained in 2014: “There is a small but growing trend for shipping ambient-temperature products in a monitored, controlled manner, which is a departure from past practices. Recent good distribution practice (GDP) guidelines, which the industry is gradually adopting, require control even of room-temperature products, which is essentially everything that is not refrigerated or frozen. With each passing year, the oversight of pharmaceutical and biologics shipping is getting tighter.”
What is more, the number of biologics products has increased. Now featuring heavily in the clinical trials pipeline, these drugs are highly sensitive, and the vast majority of them require cold chain. For the most part, they need to be stored at 2–8°C, with any temperature excursions likely to cause an irreversible loss of potency.
Being lax with these products isn’t an option. Because shipment sizes are typically small and highly expensive, pharma companies can’t afford to keep sending out new batches. This has led to a surge in logistics spending: according to Pharmaceutical Commerce’s Biopharma Cold Chain Sourcebook, pharma cold chain logistics will be worth $16.7 billion by 2020, a growth of 52% since 2014.
Take control
Last mile issues, then, are becoming more salient than ever. As Julian Piallat, R&D global distribution manager at Sanofi, explains, the sponsor itself has limited input once the product has been passed on. “It is critical to train people who are not cold chain specialists, to make sure they have the right equipment and right control system to ensure the storage of the product at the appropriate conditions,” he says.
“Awareness of the challenge is not enough: the main point is really to ensure that the products are stored in the best conditions at site, as soon as they have been delivered by the carrier.”
Sanofi focuses closely on logistics. As of October 2016, its R&D pipeline contained 43 pharmaceutical new molecular entities and vaccine candidates in clinical development. Around 70% of these are biologics, with 40% being monoclonal antibodies. In April 2016, it invested €300 million to expand its biologics site in Belgium.
Most of the company’s cold products, says Piallat, require a temperature range of 2–8°C, which must be sustained over a shipping time of at least four days.
“Prior to reaching the last mile, the products used for Sanofi clinical trials go through a strong supply chain, from the production workshop to the patient through investigational sites,” he says.
“This flow goes through – owned or not – distribution centres that are able to manage this cold chain with the appropriate equipment and processes.
“Over the last year, a partnership with a thermal packaging supplier has improved the company’s cold delivery to the investigational sites. Moreover, to ensure products continue to be protected once delivered to the patient at site, Sanofi must provide insulated bags to bring its products into the fridge of the patient – this is the ‘last mile’– at the right temperature on the way back home, to get the same efficiency on this last mile than on the part of the flow it is directly managing.”
Reaching this point wasn’t easy. Sanofi needed to acquire the know-how, as well as the optimal thermal packaging, for shipping drugs. It eventually settled on a phase-change material (PCM), as opposed to something water-based. PCM materials are designed to melt or solidify at certain temperatures, releasing or absorbing heat in the process.
“There is no need to adjust the combination of packs over the seasons, as the temperature protection of 2–8°C is ensured from our warehouse to the fridge of the investigational site,” says Piallat. “But the main challenges remain at the investigational site.”
With regards to these sites, Piallat says sponsors have several options. The first is to lend the investigators whatever equipment they need, and to provide the appropriate training. The advantages with this are obvious – you have a site you can trust to finish the job you’ve started – but it does require a greater investment of time and resources. What is more, you may need to be more stringent in your selection of investigational sites, in order to ensure the process will be respected.
Another option is to monitor the fridge temperature at the investigational site with a basic recorder. Throughout this process, the temperature is recorded every day by the investigator teams and is checked by the sponsor during site monitoring. Site personnel must be trained in how to handle the temperature loggers in order to ensure they are sending out correct data.
“This can be implemented easily and the investment required is limited,” explains Piallat.
A more high-tech version of this process involves connecting the investigator’s fridge to the sponsor’s cloud through a recorder, enabling the sponsor to see what is going on directly. If you pay attention to the hype surrounding the internet of things, this kind of thing might seem to hold great potential – and certainly, RFID (radio frequency identification)-enabled fridges have been used for a while to help hospitals manage their inventory. While this approach may come in useful in the future, it is not currently under consideration by Sanofi.
“Sanofi performed a pilot study with RFID, and the results were not in line with its objectives,” says Piallat.
A fourth option is to ship products directly to the patient’s home, using a ‘direct-to-patient’ (DtP) model. This is attractive for a number of reasons, not least the improvement in the patient’s experience, and greater patient retention.
Remain consistent
It also means temperature integrity is easier to assure – the medicine is likely to be administered there and then, rather than being kept on an investigator site in indeterminate conditions. Unfortunately, implementing this technique can prove complex from a regulatory or data privacy point of view, meaning it is not yet within the capabilities of every sponsor or logistics provider.
Piallat says that Sanofi’s overall processes remain consistent, no matter where the shipment is heading.
“There is no impact in term of supplying process, such as the same thermal parcel, same carrier, same on-process control,” he says. “The only difference is the delivery day or time, as a physician in their office can’t receive a shipment every day like a major hospital could. There are also legal constraints and specificities in some countries.”
Whatever approach a sponsor chooses, certain aspects of the process are non-negotiable. For instance, it is important to add a temperature monitoring device to each parcel, to control temperature right up until the point of changeover. Upon arrival, any variation or anomaly will be identified immediately.
It’s also crucial to put successful planning and communication strategies in place, helping to minimise error.
“For all these processes or options discussed, where we can always improve is through better communications, and training of the staff at the pointof delivery, as they have to fully understand the storage requirements,” explains Piallat. “Of course, we also need to ensure that the recipients have the right equipment. Communication is certainly key to success: this must, of course, be tailored, and may be different for big hospitals, retail pharmacists or town physicians.”
Given the complex demands of today’s clinical trials, cold chain is likely to remain a hot topic for a while, and nowhere are its challenges more pressing than in the all-important last mile. However, with a well thought-through strategy in place, sponsors can rest easy that their logistics providers won’t fall at the final hurdle.