by Dominic Hyde

Pharmaceuticals are designed to save, heal and enhance lives so it’s no surprise that they need to be transported and delivered in a fully-functional condition. One of the most important criteria when it comes to maintaining the clinical efficacy of many types of drug is that of temperature.

A huge proportion of pharmaceuticals need to be transported and stored within established temperature ranges if they are not to have their therapeutic properties diminished or even eliminated. It’s a situation that presents enormous problems for the pharma industry, which must ensure as far as possible that each one of the trillions of drug doses it produces annually arrive in perfect condition with millions of customers and patients right across the globe.

This has resulted in the development of what is commonly referred to as the pharma “cold chain” or sometimes, the pharma “cool chain.” To effectively ensure that the integrity of pharma products is maintained throughout their journey to market, a number of factors and events must be considered.

The Need for Pharma Temperature Monitoring

All temperature-sensitive pharma medications have different chemical and biological compositions and this means they are all potentially affected in different ways by the application or removal of heat. In practice this variability has largely been overcome from a transportation and storage perspective through the use of defined temperature ranges — sometimes referred to as “temperature bands” — to which products with different prescribed temperatures limits can be assigned. These temperature ranges, and any allowable temperature excursions from them, are generally derived from stability data from product tests.

Cold Chain Route Qualification

Regulatory obligations make it necessary for producers to validate cold chains and qualify their associated shipping lanes to demonstrate that the necessary controls are in place to ensure product and, ultimately, patient safety.

In order to provide the necessary evidence that such stipulations are being met, pharmaceutical equipment is subject as a requirement of Good Distribution Practice (GDP) to validation and qualification protocols in order to demonstrate its fitness for intended purpose. These validation exercises are designed to provide shippers and regulators with a high degree of assurance that the transportation arrangements in place can meet consistently all the requirements placed on it. In the case of shipping containers, a product needs to be ‘operationally and performance qualified’ as part of an overall validation process.

This means that all cold chain packaging systems, vehicles and storage facilities, together with all attendant methodologies and operating procedures, need to be approved and performance-validated through a rigorous programme of pre-testing, field trials and ongoing data capture. Transportation validation is part of the overall pharmaceutical quality control process. It is essentially a systematic approach to collecting and analyzing the necessary data to give reasonable assurance and documented evidence that a specified coldchain system and protocol will consistently operate as expected within specified parameters.

Temperature Profiling

Guidance from regulatory authorities, including Parenteral Drug Association (PDA) advises the need to “anticipate the ambient temperature variations and duration to which a product may be exposed during transportation.” Such “temperature profiling” is another tool for ensuring that disparate products can be risk-controlled and managed in the multitudinous environments they might encounter along the distribution chain. Temperature profiles are designed to accurately reflect the expected temperature conditions on a given route and form the basis for the design, configuration and qualification of temperature-controlled shipping systems. Different profiles may be compiled to reflect different exposure conditions, for example summer and winter, or an ‘all-season’ profile may be preferred.

However, such profiles can be produced from a wide range of sources, both static and dynamic, may contain assumptions which require robust substantiation and are not, in themselves, the subject of regulatory oversight, so it is essential that they are rigorously formulated. In particular they must capture the likelihood of temperature extremes, which due to their unpredictability, infrequency and lack of measurability may not feature in relatively unsophisticated or so-called ‘standard profiles’. Such standard profiles sometimes form the basis for a container design. However, they should never be relied on for the validation of a shipping lane because they will often rely heavily on such assumptions and be of limited value with respect to guarding against the type of extremes that are likely to cause dangerous thermal excursions.

Shipping Container Selection

When it comes to shipping containers, two different classes of thermal protection exist, namely active and passive. And, although there are areas where one or other is the only solution, there are a lot of situations where there can be a case for either.

A passive container is much like it sounds – one that has no active mechanisms or moving parts, and requires no human interaction in order to function when in use. ‘Passive’ packaging solutions rely on clever design and the presence of suitable insulants and energy sources in order to perform. In accordance with the Second Law of Thermodynamics the temperature inside a passive container will always be progressively warming as its cold source slowly equalizes with the external ambient on the outside so long as the external air is warmer than the set-point for the package. It is important to note that temperature-control containers are not designed to act as pre-coolers. Both active and passive containers and their contents must be temperature-stabilised in suitable cooling facilities prior to packing and transit in order to maintain the product temperature and ensure the performance of the container is not seriously compromised. Passive units are typically designed to function reliably within pre-defined temperature ranges normally ranging from about -20°C to +30°C.

On the other hand, large active containers generally rely on well-proven compression or dry-ice cooling technologies to perform. Active containers, like their passive equivalents, are also just like they sound. These units are dynamic in nature being fitted with thermostats that are continuously monitoring the internal temperature and which trigger an active response to any deviations caused by external conditions. This makes them environmentally reactive unlike passive containers which must be designed with the built-in functionality to store and release energy in order to deal with unexpected extremes such as a sudden cold snap, solar exposures, significant time spent in shade or extended delays such as a random customs internment. Active containers are typically able to perform effectively at ambient temperatures of between at least -20°C to +40°C. This enables them to perform at all the recognized temperature bands. Some of these active units are pre-fitted with integral tracking and monitoring solutions, others support third-party equipment for location, payload condition and the ambient monitoring to ensure maximum flexibility and compatibility.