The global pharmaceutical cold chain logistics industry will be worth more than $13 billion in 2017 and, as more pharmaceuticals and biopharmaceuticals require shipping at specific temperatures, it is easy to see why the industry is expected to grow by 11% this year.

The ideal temperature for perishable products

‘Cold chain’ refers to the management of temperature-sensitive products – frozen and refrigerated – as they move through the supply process, and is especially important in the pharmaceutical industry. If drug quality is compromised by exposure to inappropriate conditions during storage and transport, the consumers of that drug may suffer adverse effects.

“Cold chain management is a special case of temperature-controlled distribution, which has the ability to manage the temperature control of the relevant products along the complete supply chain,” explains Philippe François, Novartis’ global head of supply chain management. “The cold chain ensures that perishable products are distributed under refrigerated temperature conditions. Generally speaking, it is important to keep all pharmaceutical products within their defined temperature limits without variations to avoid any impact on their quality and stability that might affect their efficacy for patients.”

The growth of temperature-controlled products is continuing at more than double the rate of non-temperature-controlled products. This is due, in part, to the increasing volumes of biopharmaceutical products that are reaching the market, which tend to be more sensitive to environmental conditions and need more care as they travel along the supply chain. Most pharmaceuticals require shipping at 2–8°C, although the exact temperature depends on the specific tolerances of the actual product that is being shipped. Biologics also tend to fall within the same bracket.

Similarly, there is a new focus on drugs that must be kept within a controlled-room temperature (CRT) – usually defined as 20–25°C, with allowable excursions of 15–30°C, so long as their mean kinetic temperature remains in the defined range. Drugs in this group – such as small molecule-based pharmaceuticals that were once shipped at ambient temperatures – are less sensitive to environmental conditions, but it is reasonable to expect that their temperature is maintained properly; however, this increases shipping costs at a time when many pharmaceutical companies are reducing budgets for logistics and supply chain operations.

The evolution of precision medicine, such as cellular therapies, biomarker testing or regenerative medicines in the form of stem cells, may involve extracting blood and/or tissue, and transporting it to a facility that is used for genetic or other forms of manipulation. These could all be considered a cold chain task with tight constraints on monitoring the condition of equipment. Indeed, many products, such as cell therapies and tissue cultures, are preferably shipped cryogenically.

Another driver of this increase is the growth in internationalisation of the pharmaceutical trade, and a tightening of requirements for life science shipments, which now need to be refrigerated. There has also been growth in the number of insulin products and vaccines that are being adopted in underdeveloped countries. With more products requiring shipping at certain temperatures, it is important that a company’s budgets accommodate providing enough visibility on temperature maintenance, particularly in times of austerity. “We need to be proactive in terms of continuous quality improvements, and use our scale to contain costs, run regular tenders, look for partnerships, reduce the number of providers (sharing bigger volume), follow regulations closely and run stability tests on products,” states François.

Preventing temperature variation in shipments

Transporting temperature-sensitive products has become much more than simply moving them from A to B; it is now a mobile form of storage and needs special consideration to ensure that the temperature of the product remains within safe values. As a means of ensuring that a shipment reaches its destination on time and in the manner expected, its position should be mapped out throughout the entire process. That means considering where the supply chain is going geographically, and determining how to monitor products and validating this process. Other factors, including operational efficiency, quality systems structure and budgets, will also come into play and define how a cold chain management system is constructed.

Perhaps the first thing to consider is how the product will be packaged. This is becoming more important in helping to maintain the temperature of a shipment and can vary from completely passive and custom-designed for a specific application, to an active container that is capable of heating and cooling the drug when necessary.

Transporting temperature-sensitive products has become much more than simply moving them from A to B.

Products might be shipped on dry ice, liquid nitrogen or phase-changing material and it is important to consider what is best for an individual product. For instance, the accepted practice for shipping biomarker samples is on dry ice, but this method has been linked to a 15–30% product compromise or failure rate; many companies now prefer to ship biomarkers at cryogenic temperatures to eliminate any potential risks.

It is difficult to gauge what temperature to ship a product at, particularly early on in a clinical trial as a pharmaceutical’s stability may be unknown. It is important to exercise extra caution and take steps to protect against changes in environmental conditions.

A risk assessment considering packaging, payload configuration, temperature monitor placement, transport routes and potential risks will help this decision-making process.

François states that there are several other packaging options for preventing temperature variation, including thermo blankets; air freight containers with variable-active temperature control; passive insulated boxes/containers that are equipped with cooling elements called temperature-controlled vans/trailers; and temperature-controlled sea containers known as reefers.

Overcoming regulatory challenges with data logging and quality control

Cold chain distribution is an extension of the good manufacturing process to which all drugs and biological products must adhere. However, regulations are complicated and are becoming more challenging; there are more than 30 good distribution practice documents from various organisations and multiple countries, and they are all different. Compliance has become especially challenging for clinical trial shipments as suppliers must scrutinise their global network, enhance tracking and improve quality standard. Regulatory authorities expect pharmaceutical manufacturers to take a risk-based approach, and enforce audits and quality agreements. The good news is that the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use is attempting to align key documents to help smooth the way, but this may take some time.

The idea of temperature management through the supply chain is quite broad, as are the products that are available to monitor and control temperature.

There are simple temperature data loggers that provide a record of the product’s temperature from the beginning to the end of the shipment, and there are more complex data loggers that not only measure the temperature but also the humidity, shock vibration and other parameters. It does not stop there – some data loggers are equipped with GPS that enables real-time tracking and reporting, while others communicate by radio-frequency identification tags to simplify data collection.

“It provides evidence that products have been kept within the defined and approved temperature ranges. It enables informed decision-making that ultimately ensures patient safety,” says François. “Temperature monitoring is essential for identifying potential weak points and determining appropriate corrective measures for improving the temperature control during transport, and therefore reduces the risk of temperature fluctuations. Temperature monitoring is either used for routine monitoring of commercial shipments and/or for the monitoring of test shipments for route qualification purposes.”

Systems for ensuring cold chain success

The cold chain can be managed by a quality management system, which is analysed, measured, controlled, documented and validated. Validation requires several levels of qualification on things such packaging, operations and performance to ensure that there is no negative impact on the safety, efficacy or quality of a product.

Several matters need to be considered to ensure the success of a cold chain: will the shipment be sent using refrigerated cars/trucks or a reefer ship overseas, and should it be packaged in an insulated container or specialised packaging? Carriers and logistics providers should assist with the real-time monitoring of status using data loggers, and provide tracking information for the location of the shipment.

Documenting the data is critical; established protocols need to be followed and proper records maintained.

“Real-time monitoring and alarming can help to act/react to a potential variation proactively so that any variation in temperature and potential write-off can be avoided,” explains François. “The real-time data will support the QA department for a fast release of the product to the market.”

Documenting the data is critical; established protocols need to be followed and proper records maintained. An internal documentation system is necessary, along with multi-party communication standards and protocols to track information across the supply chain. Equipment should be monitored, product temperature history recorded and the custody chain logged to ensure that the product reaching the endpoint is safe and effective; however, the process is constantly evolving and regularly corrects anomalies.

Transporting pharmaceuticals and biopharmaceuticals at controlled temperatures is no easy task, but it is necessary for ensuring the safety and efficacy of products. There is much to consider when undertaking such a duty in regards to packaging, shipping and monitoring, in order to ensure that products don’t drift out of the safe temperature gradient, while being tracked and documented at all times. The changing cold chain seems to be growing at an enormous rate.