Ahead of the game – risk management in clinical trial supply chains

The rapid globalisation of the pharmaceuticals market, the heavy time and cost burdens of R&D, the trials process and bringing a drug to market, coupled to the increasing complexity, temperature-sensitivity and fragility of many modern drugs (especially biopharmaceutical products) are making cold chain management a priority for pharmaceutical companies.

Any temperature excursions can prove detrimental to the shipment of a drug, especially when it comes to temperature-sensitive products, whether they are at a clinical trial stage or approved for commercial production.

Emerging markets such as China and India, considered key growth opportunities for many pharmaceutical companies, are notorious for their challenging transport and supply chain infrastructure. And even established supply chains to Europe and the US can be unpredictable and difficult to control. Pharmaceutical companies therefore need to take a proactive approach to risk management, according to supply and cold chain management expert Marc Sotty, head of R&D for clinical supplies distribution at Sanofi.

"If you just look at Europe, in markets such as Spain or Sweden, the temperature can be very variable," Sotty says. "You can use specific qualified boxes for summer and winter but that still leaves mid-season, when temperatures can vary a lot."
The danger inherent in temperature excursions is simple enough. They can stop drugs from working as they should, potentially rendering whole batches unusable and needing to be destroyed.

"If you do not check that the temperature of the drug has been stable, or as it should be, then you may end up having an issue with that drug; simply that it will not work as it should," says Sotty. "If it is not stored or transported in the right conditions, this can lead to an allergic reaction to the drug or other safety issues for the patient.

"Pharmaceutical companies are developing more complex drugs, especially vaccines and monoclonal antibodies. These, of course, are often able to combat rare or difficult diseases. But, if they have been damaged during storage or transit, you cannot use them."

Do not exceed dose
At the end of 2013, the European Union updated its guidance on the good distribution practice of medicinal products for human use. This, it makes clear, requires that storage conditions for medicinal products should be maintained during transportation, "within the defined limits as described by the manufacturer or on the outer packaging".

Furthermore, according to the EU, if a deviation such as temperature excursion or damage to the product does occur during transportation, "this should be reported to the distributor and recipient of the affected medicinal products". A clear and robust procedure should be in place for investigating and handling temperature excursions.
"It is the responsibility of the wholesale distributor to ensure that vehicles and equipment used to distribute, store or handle medicinal products are suitable for their use and appropriately equipped to prevent exposure of the products to conditions that could affect their quality and packaging integrity," the guidance adds.

As Sotty points out, what this means in practice is that it is vital to have an audited, inspected and well-trained supply chain network in the field.
"We work with 55 countries and have a number of affiliate partners around the world. That means we can transport drugs into countries knowing we have dedicated people for project management. Our depot contractors are all audited and regularly monitored; we also have 70 investigational product managers around the world who follow our processes."

"One of the key challenges is to ensure you have people who are specialists in managing this throughout the chain, right the way from the warehouse through to the pharmacist, so as to ensure the shipping process is simply not an issue," he adds.
For Sanofi's clinical supplies scientific core platform, this means ensuring each shipment uses the appropriate qualified box, transport and temperature-monitoring device (TMD). Qualified shipping containers or boxes are always used for shipments within the EU, or from the EU, emphasises Sotty.

Indeed, the use of qualified boxes and temperature recorders is mandatory for all investigational medicinal products shipments (IMPs), whether cold or ambient products, to and from European countries, he points out.

Qualified boxes are designed to take into account any extreme conditions likely to be experienced during transportation. It is also vital that the best and most appropriate transport is identified for each stage of the process as well as any additional equipment, such as pallet covers.

Another important prerequisite is being able to track transportation conditions, for which the use of TMDs is vital. They will allow you to identify and assess, using stability data, any temperature deviations during the transportation.

Market research
One problem is that big pharma is a global business and, outside Europe, the legislative and regulatory environment is varied. Indeed, research on ambient transportation carried out among local contacts in October 2013 by Sanofi, identified a worryingly varied environment and a laissez-faire attitude.
When respondents were asked, "does legislation regarding transportation of ambient IMPs exist in your country?", just 10% answered "yes".
The survey drilled down into the current practices in each country regarding ambient investigational medicinal product transportation, finding that slightly more than half of respondents used standard boxes only.

Around a fifth (21%) used several solutions for their transportation needs, while only 14% used qualified boxes and TMDs, 7% standard boxes and TMDs and 3% qualified boxes alone.

There also didn't appear to be much appetite among regulators to bring things more into line with the EU. When asked, "are you expecting a change in regulation concerning ambient IMP transportation in your country?", 86% said "no".
Sotty points out: "People need to be trained, but you also need to have the same policies and follow the same processes. With the right training, monitoring and inspection, you can make your ambient chain no more challenging than your cold chain. Everything should be monitored."

Another important issue when a clinical trial gets to the patient testing stage is the need for education and awareness around temperature control at the patient's end.
"You need to ensure that, when the patients take their drug home, they know how to store it correctly and at the right temperature," Sotty says. "So you need to ensure the cold chain goes right through to the patient at home."

Sotty highlights the benefit of IMP cool bags with gel packs delivered on the investigational site specifically for patients. These can help to ensure the integrity of the IMP is maintained during transportation from site to the patient's home.

Technology is another key area when it comes to overcoming temperature monitoring issues. There has been a big drive in the past few years, for example, to develop low-cost, wireless temperature recorders and automate temperature recording.
These include the development of smart label recorders, which are applied during packaging, and are readable with radio frequency identification (RFID) readers. These are often 3G or 4G readers that offer remote, live temperature monitoring -in the warehouse and during transportation. Indeed, the use of RFID chips and readers, along with temperature sensors, is becoming more commonplace within temperature recording, Sotty says. "For the future there is a lot of work going on around temperature recording, especially around RFID for temperature recording."

Partial recovery
With conventional, manual time-out-of-refrigeration tracking sheets and data loggers, once a pallet has been identified as having suffered a temperature excursion, the only solution normally is to dispose of the whole pallet. But the sophistication of RFID solutions applied at packaging level means that you have a much greater chance of saving at least part of the pallet if it has not all been degraded.

"With RFID, you have a reader that can read a chip on the box. It can be more accurate in that it can help you save, say, half the box if it is only some of it that has been lost. It makes your ability to track and monitor much more specific for each drug," points out Sotty.

Another innovation coming through is the use of quick response (QR) codes.
As Sotty says: "A patient can now scan the package with their smartphone and the QR code can explain to them how to store the drug - whether it needs to be kept in the fridge and so on."

But he also adds a cautionary note. "There are a lot of advances being made around technology but, if the technology is not used correctly, they will not work."

Ultimately, however, while new technologies can play their part, effective cold chain management comes down to old-fashioned process, procedure, awareness and education - putting in place robust, consistent temperature monitoring and stability protocols.

"If we want to maintain the cold chain from the warehouse to the patient, what we need first of all is good training on all the different drugs, but also good communication to the clinician, pharmacist and patient," Sotty says.
"So it is all about good communication, on top of the all the material, technological and regulatory control that go with effective cold chain management."