Temperature Excursions in Pharmaceutical Supply Chain -

*Photo: ESA & NASA/Solar Orbiter/EUI Team, E. Kraaikamp (ROB), 24 April 2025. CC BY-SA 3.0 IGO*

Escalating demand for temperature-sensitive biologics, vaccines, and advanced therapies intensifies the challenge of maintaining stringent temperature control throughout the entire distribution network, argues Richard Maly.

The Imperative of Temperature Control

Temperature excursions are defined as any deviation from a pharmaceutical product’s specified temperature range during its storage, transport, or handling, as determined by the manufacturer’s stability data and regulatory requirements. Such deviations critically compromise product quality, potentially leading to degradation, reduced efficacy, and significant safety risks for patients.

The ramifications extend beyond patient harm, encompassing substantial financial losses, regulatory non-compliance, and damage to a pharmaceutical company’s reputation.

The pharmaceutical supply chain, particularly across the United Kingdom and Europe, is characterised by increasing complexity and global interconnectedness, involving a massive volume of products imported and exported worldwide. A substantial proportion of new pharmaceuticals, nearly half, are temperature-sensitive, contributing to a cold chain market valued at billions and experiencing continuous growth.

The global scale of pharmaceutical trade, with Europe being a major revenue generator, means that any temperature excursion, even if seemingly minor or isolated, can have far-reaching consequences across multiple countries or regions due to the interdependent nature of supply chains. The reliance on international trade for medicines and their ingredients implies that disruptions in one part of the world, such as extreme weather events, can directly impact medicine availability and quality in the UK and Europe.

This global interconnectedness necessitates a comprehensive approach to cold chain management, extending beyond local regulations to ensure the robustness of international logistics partners and the development of contingency plans for worldwide disruptions.

Understanding Temperature Excursions and their consequences

Temperature deviations, whether excessively high or low, can trigger various forms of drug degradation. Elevated temperatures accelerate chemical reactions like oxidation, hydrolysis, decomposition, and polymerisation, resulting in assay loss and increased impurities.

For solid dosage forms, this can alter dissolution patterns, whilst liquid products may experience layer separation or discolouration. Conversely, exposure to low temperatures, particularly freezing (below 0°C), can cause irreversible damage, precipitation, or hairline fractures in glass containers, rendering the product unusable. Biological products are especially susceptible to changes in their properties due to extreme cold.

The direct outcome of temperature excursions is frequently product spoilage, leading to significant product loss and wastage. The World Health Organisation (WHO) in 2005 estimated that up to 50% of vaccines are wasted globally each year, with inadequate temperature control being a major contributing factor. Such spoilage results in substantial financial losses for the industry, estimated at $20-30 billion annually due to cold chain failures.

More critically, compromised products can pose severe risks to patient health, ranging from reduced therapeutic effectiveness and suboptimal treatment to adverse reactions, serious infections, or even life-threatening conditions. For instance, in 2021 a nationwide recall for Sandoz’s Enoxaparin Sodium Injection was issued by the FDA due to a temperature excursion during shipping, where exposure to high temperatures may have impacted effectiveness and posed a risk of blood clots.

Beyond direct health and financial impacts, temperature excursions can lead to regulatory non-compliance, resulting in warnings, operational disruptions, and costly product recalls. Such incidents also severely damage a company’s reputation and erode public trust. Whilst individual excursions might be deemed “acceptable” based on pre-defined stability data, the cumulative effect of multiple minor deviations throughout a complex supply chain can silently deplete a product’s “stability budget”. This means a product could be rendered unfit for use, even if no single excursion was “out of range” or triggered an immediate alert, if its residual stability budget is exhausted.

This highlights the critical need for continuous, end-to-end temperature monitoring that tracks the entire temperature history of a product, moving beyond simple pass/fail checks to a more nuanced risk assessment.

Regulatory Framework in the UK and Europe

Good Distribution Practice (GDP) guidelines form the cornerstone for maintaining the quality and integrity of pharmaceutical products during storage, transportation, and distribution within the UK and European markets. Adherence to these guidelines is legally required for manufacturers and distributors in the European Union and is enforced by national regulatory bodies such as the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK.

GDP mandates proper handling, stringent storage conditions, and comprehensive documentation throughout the supply chain to minimise temperature excursions and mishandling risks. The European Medicines Agency (EMA) Guidelines of 5 November 2013 on Good Distribution Practice of Medicinal Products for Human Use (EudraLex Volume 4) are a key reference.

EMA and MHRA establish clear requirements for continuous environmental monitoring systems, calibrated probes, and automated alarms. Equipment must have a resolution of 0.1°C and calibrated accuracy of ±0.5°C for cold stores and refrigerators, and ±1.0°C for temperate areas. Warehouses and storage facilities must be designed and qualified with temperature-controlled zones (e.g. 2°C–8°C cold rooms, -20°C freezers, -80°C ultra-low freezers, and controlled ambient conditions of 15°C–25°C with humidity control).

All storage equipment must undergo Installation/Operational/Performance Qualification (IQ/OQ/PQ) to ensure consistent temperature maintenance. Regular temperature mapping exercises are crucial, including empty mappings before use and seasonal (summer and winter) mappings once the facility is operational, to identify any issues with temperature management during extreme weather conditions. Re-mapping is required whenever significant modifications are made to the facility or temperature-controlling equipment.

Regulators require defined procedures for managing temperature excursions and performing impact assessments. In the event of an excursion, immediate quarantine of affected products is mandatory. A structured Corrective Action & Preventive Action (CAPA) process is required to investigate root causes, define corrective actions, and prevent recurrences. Significant deviations or incidents must be reported to the MHRA.

The MHRA and UK GDP Association explicitly warn against utilising domestic refrigerators for medicinal products due to their inability to maintain the precise 2-8°C range, often leading to freezing which renders active ingredients inert. Professional pharmacy refrigerators are recommended, designed to operate around 5°C with even air distribution and alarms.

Whilst EU GDP provides a foundational framework, national authorities like the MHRA retain the ability to provide concrete interpretations and additional specific requirements. This creates a dual layer of compliance for companies operating across Europe: they must not only adhere to the overarching EU GDP principles but also be acutely aware of and comply with specific national regulatory nuances and interpretations.

This adds a layer of complexity to pan-European distribution strategies, requiring localised compliance efforts and a thorough understanding of each market’s specific demands.

Table 1: Key Temperature Ranges and Regulatory Definitions (UK/EU Context)

Note: The EMA guidelines prefer explicit temperature ranges over vague terms like “ambient” or “room temperature” for labelling.

Causes of Excursions in European Pharmaceutical Logistics

Temperature excursions can originate at any point in the pharmaceutical supply chain, from manufacturing and storage to packaging, transportation, and final delivery. Common contributing factors include inadequate packaging, where insufficient thermal protection makes shipments vulnerable to external temperature fluctuations, especially during unexpected delays or drastic weather changes. Prolonged transit times and multiple handoff points between logistics partners significantly increase the risk of temperature deviations, a particular concern in complex international supply chains.

Human error is another prevalent cause, stemming from mistakes in handling, such as early sensor starts, late stops, incorrect sensor settings, or improper loading/unloading, which can lead to false alarms or actual excursions. The lack of proper training for personnel is a recurring issue, as evidenced by MHRA findings of deficiencies in UK pharmacies. Equipment malfunctions, including failures in refrigeration units, heating ventilation and air conditioning (HVAC) systems, or monitoring devices, can also compromise temperature control. Environmental conditions, such as extreme heatwaves as seen in Spain or very cold climates, pose significant challenges to even robust cold chain solutions.

Climate change exacerbates this challenge, increasing the risk of medicines being stored outside recommended ranges due to higher ambient temperatures. Finally, a lack of system integration, characterised by gaps in shipment visibility across third-party logistics providers and a disconnect between warehouse, enterprise resources planning (ERP) and monitoring systems, hinders timely detection and intervention, contributing to spoilage.

It is important to recognise that a significant proportion of reported temperature excursion cases, often up to half, are attributed to “false alarms” caused by procedural or technical errors rather than genuine product quality issues. While these false alarms do not directly compromise product quality, they consume substantial operational resources in investigation (requiring CAPA processes), lead to unnecessary quarantining and potential destruction of usable products, and contribute to overall supply chain inefficiencies and costs. This highlights a critical operational challenge: the need for sophisticated monitoring systems that can intelligently differentiate between genuine excursions and procedural errors, and for robust, continuous training to minimise human-induced “false” deviations.

Proactive Strategies for Temperature Management and Compliance

The pharmaceutical industry is transitioning from reactive to proactive temperature management, necessitating continuous, real-time monitoring utilising validated IoT sensors and data loggers. These systems automatically record and transmit temperature data to cloud platforms, providing live updates on shipment status.

Modern systems send instant notifications if a temperature threshold is breached, allowing for quick intervention. Predictive analytics can identify at-risk shipments before spoilage occurs, enabling proactive corrective actions and reducing product loss. This represents a significant advancement over traditional manual logging, which is no longer considered sufficient. All temperature monitoring equipment must be regularly calibrated by accredited laboratories to ensure accuracy, with specific requirements for resolution and accuracy.

Utilising qualified insulated shippers or active temperature-controlled containers is paramount. These solutions must be validated to maintain required temperatures for longer than the maximum transit time, accounting for potential delays. This includes passive coolers with gel packs or dry ice for shorter shipments, and active containers (electric refrigerating units or liquid nitrogen dry vapour shippers) for high-value or longer, ultra-cold shipments. An emerging trend is the consideration of sustainable, eco-friendly packaging solutions, with reusable components potentially decreasing the carbon footprint significantly.

Optimised logistics and contingency planning are equally vital. Strategic route planning to minimise transit time and the number of handoffs between logistics partners reduces risk. Direct flights for international shipping are preferred. Working with logistics providers specialising in healthcare, who understand the urgency and have facilities like refrigerated storage at layovers, is crucial.

The use of logistics “cold hubs” at airports can enhance safety. Robust contingency plans are essential for unexpected incidents such as extreme weather, natural disasters, or supply chain disruptions. These plans should include pre-arranged procedures for intercepting at-risk packages and intervening.

cGMP-compliant storage and facility management require warehouses to be designed and qualified for proper storage conditions, including temperature-controlled zones.

HVAC systems should maintain controlled ambient conditions with humidity control where relevant. Strict controlled access to storage areas prevents mix-ups or tampering, with only authorised, trained personnel handling inventory. Products should be segregated by status and clearly labelled. Mandatory backup generators for cold rooms and freezers, along with contingency space in alternate locations, are vital to mitigate risks from power failures or equipment breakdowns.

Finally, comprehensive documentation and continuous training are indispensable. Every aspect of temperature management—from temperature logs and alarm incident reports to cleaning records and personnel training—must be meticulously documented. This extensive documentation is critical for compliance during audits, thorough investigation of deviations, and demonstrating accountability.

Robust Corrective Action and Preventive Action (CAPA) procedures are essential for investigating root causes of excursions and implementing measures to prevent recurrence.

All personnel involved in handling pharmaceuticals must undergo appropriate and continuous training on GDP principles, temperature control, documentation practices, and emergency response protocols. This addresses the human error factor and ensures staff competence, particularly in UK pharmacies where deficiencies in temperature monitoring knowledge have been noted.

Discussion:

In Part 2, to be published soon, I plan cover other aspects of temperature excursions. But for now, having considered this topic so far, I invite an open a discussion with you. As we’ve seen before, sharing thoughts and opinions on these vital challenges helps to find improvements and solutions.

Please use the Comments section at the end of this post. Or if you prefer, please email at the usual address.

Thank you.

References and further reading

URL https://www.who.int/publications/i/item/WHO-VB-03-18-Rev-1

URL https://www.ema.europa.eu/en/human-regulatory-overview/post-authorisation/compliance-post-authorisation/good-distribution-practice

URL https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/sandoz-inc-issues-nationwide-recall-one-lot-enoxaparin-sodium-injection-usp-40mg04-ml-due

URL https://www.gov.uk/guidance/good-manufacturing-practice-and-good-distribution-practice

URL https://ukgdpassociation.org.uk/

URL https://www.sensitech.com/en/blog/blog-articles/blog-eu-gdp.html

URL https://mhrainspectorate.blog.gov.uk/2016/01/26/refrigerated-medicinal-products-part-1-receipt-and-storage-some-things-to-consider/

URL https://www.tssab.com/blog/proactive-temperature-management-the-key-to-a-more-resilient-pharma-supply-chain

URL https://www.gmp-compliance.org/gmp-news/implementation-of-good-distribution-practices-explanatory-notes-from-mhra