The domino effect

The logistics of clinical trials is a process of shipping test products to investigational sites around the globe. Shipments will include pharmaceuticals and biopharmaceuticals that require transport at specific temperatures, or precision and personalised medicines, such as cellular therapies and regenerative medicine in the form of stem cells, which are becoming increasingly prevalent. Every step in the process could be considered a cold chain task that requires ultra-low or cryogenic temperatures, anything below -70°C, during shipment and storage.

Cold chain management of temperature-sensitive products – frozen and refrigerated – as they travel along the supply chain is particularly important in the pharmaceutical industry. Temperature-controlled shipments play a crucial role in the distribution of drugs to patients, but it is an intricate process and the risk of temperature excursions, where a product diverges from its designated safe temperature limits, is potentially detrimental to the outcome of a trial.

If drug quality is compromised due to exposure to inappropriate conditions during storage and transport, trial participants in receipt of that drug may experience adverse side effects. Consignments must be monitored incredibly closely to ensure that they have not strayed from their temperature excursion maps, which set predefined restrictions for temperature deviation events – such as allowed time and temperature limits – to ensure that a product’s stability is not affected. Any deviation could result in an unsafe product reaching a trial recipient.

Transporting temperature-controlled products is big business – the industry was estimated to be worth $13.4 billion in 2017, and is projected to reach $16.6 billion by 2021. The growth of temperaturecontrolled products is increasing at a rate of 5–6%, more than twice the rate of their non-temperaturecontrolled counterparts. This surge can be attributed to greater volumes of biopharmaceuticals reaching the market, which are often more sensitive to environmental conditions and therefore require greater care as they travel along the supply chain, to an increasing need for insulin products and the adoption of vaccines in underdeveloped countries, all of which need to be kept cool.

Keep cool

Most pharmaceuticals need to be kept between 2–8°C, with the precise temperature dependant on the specific tolerances of the product. Small molecule-based pharmaceuticals once shipped at ambient temperature must now be kept within a controlled room temperature (CRT) – usually 20–25°C with admissible excursions between 15–30°C. Although drugs in this group are less sensitive to environmental conditions, their temperature must be properly maintained.

As the prevalence of such biologically active products grows, so does the need to safely transport them. Shipping temperature-controlled pharmaceuticals is much more than simply moving them from A to B – it’s a moveable form of storage that requires special consideration to guarantee the temperature of the product does not deviate from safe values.

The pharmaceutical industry is still learning how to more efficiently manage the cold chain. Currently, pharmaceuticals are placed in insulated packaging – which might be a custom-designed capsule for a specific application, or an active container capable of heating and cooling the drug when necessary – along with temperature-monitoring electronics. There are a wide variety of products available to monitor and control temperature, from simple temperature data loggers that record the temperature of the product throughout its journey, to more complex machines that measure temperature, humidity, shock vibration and other variables. Some data loggers are even equipped with GPS, meaning they can be tracked in real time, while others use RFID tags to communicate and for data collection.

2–8°C
Temperature at which most pharmaceuticals must be safely stored.
WHO

But there are still improvements to be made. Often, trials with temperature-monitored shipments are missing data on potential temperature excursions, or have no temperature data altogether. Long investigations into temperature excursions are not possible in the midst of clinical studies, particularly when decisions on acceptability of the product need to be made within a few days, or in some cases, a few hours.

A need has arisen to develop an automated process where investigational sites are prevented from handing over clinical trial kits if temperature data is either unavailable or shows that an excursion has occurred. It also has to possess the ability to alert investigators if there is a fault with the shipment and advise against its use.

One potential solution currently under consideration is an automated receipt process, a means of more efficiently tracking temperature-controlled shipments from start to finish.

“The automated receipt process refers to the receipt process for temperature-monitored shipments in clinical trials using an interactive response technology (IRT), a technology widely used to support international multicentre clinical trials in terms of trial management, site management, subject management, drug supply management and logistics,” states Henk Dieteren, senior clinical supply manager at Grünenthal, a research and development pharmaceutical company specialising in pain, gout and inflammation.

The IRT automatically quarantines temperaturemonitored consignments when a temperature excursion has occurred during shipment or when no temperature data would be available at acknowledgement of the concerned shipment in IRT, Dieteren explains.

“A complex data integration between the depot distribution vendor, the IRT and the temperature monitors has been developed in order to make this automated process for temperature-controlled trial medication fly,” adds Dieteren, who supervises the strategic direction of the clinical trial supply department, involving vendor qualification and the set-up of IRT systems.

During many trials involving temperature-monitored shipments, the company was not immediately made aware of potential excursions or missing temperature data, meaning the in-time evaluation of the excursions took place at a highly critical time, just before the concerned kits were assigned to subjects. But the introduction of an automated receipt process has changed this.

“For Grünenthal, we were able to cut the evaluation of associated temperature data of a concerned trial medication to zero days, and consequently, either the release of this medication could take place on the same day, or if applicable, a replacement shipment could be triggered on the same day,” says Dieteren. “Consequently, we have neither an effect on patient safety resulting from potentially impacted trial medication, nor do we have an interruption of patient treatment caused by a delayed release of concerned medication from quarantine.”

$16.6 billion
Projected value of the temperature-controlled transportation industry by 2021.
Pharmaceutical Commerce

The IRT generates an email alerting authorised staff of an interrupted acknowledgement of a shipment in IRT, meaning there is an immediate awareness of the issue. Since the concerned trial medication is automatically put in quarantine by the IRT, there is no chance that it could assign trial medication that could potentially have been impacted by temperature excursions to a randomised trial patient.

“At the moment, we are in the process of finalising a similar process for trial medication stored at, for instance, investigational sites,” explains Dieteren. “This is expected to be available by the middle of 2019. From then, we will have a fully automated end-to-end control of temperature excursions for trial medication being in transit, as well as for medication being stored.”

As a result, Grünenthal will no longer be dependent on human reporting of a temperature excursion, and trial medication impacted by such an excursion is immediately quarantined by the IRT, after certain temperature-associated thresholds have been met. “The benefits are that human weaknesses during the reporting process of temperature excursions are fully taken away,” Dieteren adds.

Allegiances to one side

But in order to make an automated receipt process work, Grünenthal needs to integrate various systems, which requires the sharing of processes and information from other companies and vendors, something they are not always willing to divulge. It also requires an IRT that receives input from the depot and from temperature systems about which temperature monitor is associated with which shipments. The systems needed to be integrated and data points coded so that the correct information was available at each investigational site to acknowledge receipt of a shipment.

Dieteren continues, “The challenges we had to face during the set-up of the process were related to the different data models that had to be aligned between the different systems, and the different road maps at the different vendors that had to be aligned in order to meet the due date for the first clinical trial at which we wanted to try this process. This pilot trial confirmed that the process was an excellent example of quality by design.”

The pilot study contained 65 shipments, of which 39 contained temperature monitors. Out of these, eight were quarantined automatically and authorised staff notified. Once temperature data had been verified, these kits were able to be released the same day.

Dieteren also analysed 4,000 shipments, all IRT-managed trials conducted by Grünenthal over the past few years. Of the 4,000, 93 experienced temperature excursions, but there were many issues in reviewing the data as the company was not always aware that there was an issue. It took, on average, 29 days to gather and evaluate the data to determine which kits could be safely used, because there had been no critical excursions or need for resupply kits. During this time, some of the kits could have been assigned to clinical trial subjects, which was the impetus to create the automated receipt process.

The cold chain distribution process is an extension of good clinical practice that all trials must follow, and good manufacturing process that all drugs and biological products must adhere to. Dieteren strongly advises that any company distributing temperaturecontrolled products implement a form of automated receipt process.

“According to good clinical practice, the sponsor should ‘take steps to ensure that the investigational products are stable over the period of use’.

“In other words, the sponsor has the obligation to have documentation in place that proves the trial’s medication has been processed within the temperature range following the stability data of the products,” continues Dieteren.

“A risk assessment must be made of the transportation routes. The results of this risk assessment have to be part of the transportation planning. Temperature monitoring has to be done if no risk assessment was carried out or if the risk assessment led to the result that a temperature control is necessary,” he adds. “The automated receipt process helps to accurately document that no trial medication being impacted by – potential – temperature excursions was assigned to randomised trial patients, and that a proper evaluation of the temperature data did not interrupt patient treatment. We at Grünenthal believe that, in using this process, we can help to improve the lives of patients.”

Implementing an automated receipt process streamlines the cold chain, removes the possibility of human error and ensures that only those investigational kits that are 100% safe are passed onto participants. It could make the difference between knowing that no clinical trial participant has received a test product that deviated from its safe temperature range during storage and shipment, and just thinking it.