For many medicinal products, storage and transportation temperatures are a highly significant factor in maintaining the quality of medicinal products throughout the distribution network. The distribution chain is seldom simple and distribution systems can vary enormously.
The pharmaceutical industry is evolving from the use of synthetically obtained active pharmaceutical ingredients (APIs) to the development of highly selective and in many cases personalised active ingredients obtained biotechnologically. Synthetic APIs are typically compounds of low molecular weight and with proper chemical and physical stability at room (ambient) temperatures, while APIs obtained by biotechnology are typically macromolecules, which in many cases, require storage and handling at low temperatures. Some of them even stored at lower temperatures (2 – 8 °C) but protected from freezing. Namely, even a brief period at sub-zero temperatures may irreversibly denature protein and lead to a loss of efficacy, and therefore such medicinal products must be maintained within a narrow temperature range above freezing point throughout the distribution chain.
One of the consequences of these changes in the pharmaceutical industry is the growing need for effective and safe ways of transportation of medicinal products at low temperatures and with monitoring and tracking of real-time conditions. From the quality point of view, the preservation during transport becomes extremely critical and conventional transport companies cannot provide robust solutions to avoid negative impact on quality, safety, and efficacy of medicinal products. It is the responsibility of the supplying distributor (this includes manufacturers of medicinal products as well) to ensure that storage conditions (temperature, relative humidity) are maintained within acceptable limits during transport. A risk-based approach should be utilised when planning transportation. The method and time of transportation, the local seasonal temperatures and the nature, size and temperature control requirements of the load should all be considered when arranging cold-chain distribution. Regardless of the mode of transport, it should be possible to demonstrate that the medicinal products have not been exposed to conditions that may compromise their quality and integrity.
The distribution of temperature sensitive medicinal products defines the supply chain as a cold chain, a cool chain, or simply a temperature-controlled supply chain. With this definition comes the need for temperature to be consistently maintained and that the cold chain is not broken to ensure medicinal product quality is not compromised. The typical cold transport conditions are refrigerated (2 – 8 ˚C), frozen (- 20 ˚C), ultra-cold (- 80 ˚C) and cryogenic (≤ – 150 ˚C). To achieve these conditions during transportation, it is necessary to use passive preservation and protection elements that help mitigate the risk of negative impact on quality, safety, and efficacy of medicinal products and to ensure compliance with Guidelines on Good Distribution Practice of medicinal products for human use (EU GDP).
As per EU GDP distributors of medicinal products should identify key equipment and perform initial and periodic qualification/calibration. For cold chain medicinal products and equipment used during transporting, anything used in a distribution to store or transport medicinal products must be qualified and/or calibrated. Temperature monitoring probes should be calibrated to ensure that they are operating within the manufacturer’s specifications for that probe. Qualification is an action of proving that any premises, systems, and items of equipment work correctly, leads to the expected results, and fulfils an intended purpose. Compared to qualifying equipment such as cryogenic shippers or freezers, and rooms, the qualification of an entire network is much more complex and requires significant analysis and process documentation.
Where transportation is performed by a third party, the contract in place should encompass the requirements of EudraLex Volume 4 Good manufacturing practice guidelines Chapter 7. Outsourced activities of transportation to companies providing the shippers for the safest and compliant transport should be audited and should have a suitable quality management system (QMS) and implemented good practices for the validation of the elements and their performance, considering that they are routinely refilled (dry ice, nitrogen) and reused.
Below is a list of some regulations/guidelines related to storage and transportation of medicinal products from various organization’s websites:
- European Commission and European Medicines Agency
- U.S. Food and Drug Administration
21 CFR 205.50 Minimum requirements for the storage and handling of prescription drugs and for the establishment and maintenance of prescription drug distribution records
21CFR 203.32 Drug sample storage and handling requirements
21 CFR 203.36 Fulfilment houses, shipping and mailing services, comarketing agreements, and third-party recordkeeping
21 CFR 211.150 Distribution procedures
21 CFR Part 11 Electronic records, electronic signatures
- Centers for Disease Control and Prevention and Canadian Guidelines
- WHO – World Health Organization
- Health Products Regulatory Authority (HPRA)