Towards real-time temperature monitoring
In June 2017 global news reports contained the alarming news that a ‘vaccination error’ involving 300 people in South Sudan had resulted in the deaths of at least 15 children and the severe illness of 32 others.(1) The vaccine concerned was an immunisation against highly contagious measles virus and it turned out that the batch of vaccines concerned had been exposed to unacceptably high temperatures.
Although it is not often that stories like this hit the mainstream press, such incidents are not isolated events. In March 2017, thirty-seven people were arrested in eastern China over the selling of illegal vaccines that had not been properly refrigerated or transported.(2)
The fact is that pharmaceutical drugs are complex chemical or biological preparations that can be rendered ineffectual, or even toxic, if they are subject to extremes of temperature. Temperatures that are too high promote pathogenic growth while freezing reduces the efficacy of medicaments containing proteins. This temperature sensitivity has resulted in a requirement for temperature traceability by means of a measured temperature history to become a mandatory element of GDP compliance.
Few, if any, pharmaceutical products are unaffected by extremes of temperature. Even the simplest medicines are comprised of chemical constituents which exhibit varying degrees of lability when exposed to heat or cold. Some medicines however are particularly quickly and dangerously affected by temperature variations. They might become totally inactive or lose their therapeutic potency which can be a life-threatening result or, in the case of vaccines, leave the recipient unwittingly exposed to dangerous pathogens.
The effects of temperature on biological drugs and vaccines is well documented and these 'living' medicines are easily damaged. One study, for example, showed that insulin stored for 28 days at an ambient temperature of above 30°C showed a decrease in potency and biological activity of up to 18% compared to the same product correctly stored at 5°C.(3) Furthermore, in many cases, the effects of temperature degradation is cumulative.(4) And each exposure to a temperature elevation results in a progressive and irreversible degradation of potency.
It is not only hot temperatures that are a threat. Most vaccines and some drugs like insulin will lose their effectiveness if they freeze. The problem is that with most medicines it is impossible to tell visually if they have been exposed to damaging extremes of temperature. Most will look no different after a deleterious exposure.
Conventional temperature logging
Although there is a widespread understanding of the need for controlling the temperature of drugs during storage and transportation, much of the monitoring that takes place still follows outdated practices that involve intermittent physical readings, manual data entry and old-fashioned reporting and sharing methods. This introduces delays and inconsistencies that can greatly undermine the entire temperature surveillance process.
Evolution of temperature management
In the earliest days of pharma temperature monitoring, the product temperatures were simply measured using standard mercury or alcohol thermometers. This system was limited to the periodic manual inspection and recording of single-point temperature measurements. Although fragile ‘max-min’ thermometers could indicate the lowest and highest temperatures reached they were not time able to pinpoint the time of occurrence. Over time, at least for some applications, this manual thermometer analysis gave way to visual chemical temperature indicators. These are heat-sensitive labels register a visible change in colour when subjected to a pre-determined temperature limit. Like thermometers, these ‘accept/reject’ alerts are point-in-time indicators which require subjective visual appraisal. Nonetheless, although they have limited accuracy, limited shelf life and need training in use, these indicators are very cheap to produce and are not easily damaged. It is these benefits that have ensured that chemical indicators remain in widespread use, especially in the distribution of vaccines in developing regions. However, their limitations in use are seeing them being gradually replaced by more reliable, more accurate and more functional electronic temperature tags. A big breakthrough in temperature management came when time- and temperature-sensitive data loggers started to be widely used in the 1970s and 1980s. These are battery-powered temperature recorders capable of virtually continuous temperature measurement which can store the data collected on-board until it is possible to extract it to an external device or system for subsequent interpretation, analysis and distribution. However although this new functionality made reliable temperature monitoring much easier, a reliable temperature management regime was still heavily dependent on manpower resources, time, training and special equipment. The cost and effort involved can result in both the frequency and extent of temperature checking being compromised and is one of the reasons why organisations such as WHO strongly recommend that, wherever possible, the process of recording temperature data should be made automatic.(6)
New age devices
There is no doubt that these semi-automatic time-and-temperature devices represented a step-change in temperature control, with these devices a shipper still has to wait until it receives a shipment and downloads the data from the temperature logger before it finds out if a drug’s temperature has been compromised. However, the latest generation of data-loggers which come with integral data transmitters are taking temperature monitoring to another level. According to an article in World Pharmaceutical Frontiers: (7) "up to just a few years ago, the radio transmitters in these devices were only powerful enough to be short range, today, mobile-phone radios can be incorporated into them, allowing each recorder to communicate directly with the cellular network. Not only does this give operators flexibility when it comes to choosing vendors but it also means the infrastructure around temperature monitoring is a lot less costly to develop."
On demand, shared-access monitoring
The combination of new-generation devices and the latest data transmission, capture, sharing and analysis technologies that can be implemented on the digital cloud is the latest development in pharma temperature monitoring.
The cloud is revolutionising data collection and dissemination while advanced data analytics is helping to interpret the huge volumes of data that is collected. Continuous and virtually continuous temperature measurement with both local and remote storage is opening the door to predictive temperature analysis with the emphasis on the dynamic control of storage spaces rather than post-event reactive responses. The problem with most digital temperature loggers is that they must be connected to a host device in order to download recorded data which means that, in practice, they have no real-time data interactivity. The result is after-the-fact analysis for claims, loss in quality and related issues.
As one cold-chain practitioner put it: “some in-built systems are reactive or historical in nature rather than preventative or predictive. In other words they effectively tell you that a product's safety envelope has been violated, rather than tell you that it is in danger of being violated. The way things are at present, there can be lengthy gaps, not in the recording of information, but in its timely receipt. Knowing that something has been corrupted or contaminated after it has happened is of great benefit in preventing the affected product entering the chain of consumption, but it has no preventative value other than the learnings that might emerge from a post-event inquest”.(8)
In contrast, with a real-time monitoring system, the data-logger will alert the shipper in advance to temperature conditions that might result in product impairment or regulatory non-compliance. The focus in the first place therefore becomes one of predicting and eliminating cold-chain breaks and temperature excursion incidents rather than on detecting and removing violated products from the supply chain. It is a change in emphasis that means that the big challenge ahead will be less about capturing the data and more about the ability of supply chain stakeholders to successfully analyse and act timely on the complex data that is generated.
Benefits of real-time monitoring
There are several benefits from investing in the latest temperaturemonitoring equipment including the possibility of reacting quickly to a temperature event and the ability to make better decisions based on continuous live data. When an alarm event occurs, the difference between instant notification and a post-event notification several days, or even weeks, later might be the difference between a safe shipment delivery or millions of dollars of product write-off, a regulatory investigation, mountains of bureaucratic hassle and, most important of all, potentially failed patients.
- Automatic alerts
Real-time temperature monitors with GPS capabilities can trigger automatic alerts when fixed temperature limits have been exceeded or when predetermined temperature patterns have been recorded. The immediacy of the notifications means that it can be possible to prevent, mitigate or rectify the consequences of a temperature excursion and prevent costly product damage. For example, if it was known that a pharma product had been exposed to potentially damaging temperatures during a sea-freight leg, a back-up shipment could be dispatched by air even before the affected reefer arrives.
- 24-7 data access
A cloud-based monitoring platform fed by wireless dataloggers permits immediate access to temperature data from practically anywhere in the word for immediate action.
- Multiple, simultaneous data sharing
Different supply chain stakeholders can be afforded controlled access to temperature information as it happens which means that potential problems that may arise during shipment can be addressed in advance.
As well as minimising the need for local scrutiny, exception reporting allows numerous devices to be accessed and monitored from a single location for a very cost-efficient service.
- Proof of Regulatory Compliance
The concern of regulatory bodies is to provide consumers and patients with products that are safe and have full therapeutic properties. “Regardless of the mode of transport, it should be possible to demonstrate that the medicines have not been exposed to conditions that may compromise their quality and integrity.”(9) In order to demonstrate regulatory compliance therefore requires documentary proof of temperature management and this recorded verification is a mandatory element of all GDP regulations and guidelines. And in cases where a GDP auditor might require sight of temperature records, the ease of sharing and ready availability of digital temperature data is a huge benefit. If these records are scattered throughout the supply chain and stored in different formats it might be very difficult to demonstrate compliance.