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International Clinical Trials

Holistic Approach

To spur growth in the wake of expiring patents, dwindling pipelines and increased global competition, pharmaceutical companies are conducting more clinical trials than ever before. However, the rising costs, complexity and increasingly global nature of these clinical trials present significant challenges for companies seeking to effectively manage their clinical trial supply chain.

As with any supply chain, the fundamental challenge in distributing clinical trial materials is ensuring that supplies arrive at the site on time and in good condition. To efficiently manoeuvre the global R&D landscape meticulous forecasting, tactical planning, strategic partnerships and scalable storage infrastructure are a necessity. Clinical supply chain managers must also have a keen awareness of regulatory requirements and the associated documentation (that is, import/export forms, USDA and FDA labels) needed to import/export clinical trial materials. These requirements change from country to country and can be quite intricate. China, for example, requires companies to make entry arrangements with a Chinese corporation that has a relationship with the Chinese government. Otherwise, the supply may be delayed or the company may need to use a freight forwarder with a Class A license. In India, the commercial invoice is stamped and becomes the import permit (1).

Adding to these complexities is the growing need to transport temperature-sensitive materials, such as tissue samples, cell banks and active pharmaceutical ingredients. These materials are playing an increasingly important role as drug developers focus on personalised medicine, genomics and biomarker development. Furthermore, the shift from small-to largemolecule drugs, which require strict temperature stability, has made maintaining temperature conditions across the supply chain a major concern. Consequently, supply chain managers are now faced with complex challenges that have not previously applied to the traditional supply chain.

As such, this article will highlight the growing role of cold chain management in supply chain processes and emphasise the various factors that ensure on-time, compliant transportation of temperature-sensitive clinical trial materials and supplies.


Cold chain management defines how temperature-sensitive materials are packaged, transported and stored throughout the R&D process. Weakness or failure at any point in the chain can compromise product integrity, breach security, delay shipments and ultimately result in financial loss or liability. It is therefore vital for clinical trial materials to be packaged and shipped in compliance with industry and government standards, and closely monitored by properly trained individuals. A lack of compliance can subject study sponsors to fines ranging from a few hundred to thousands of dollars. Moreover, even minor temperature excursions during the storage, handling or distribution of clinical trial materials pose significant safety and financial risks, including:
  • The patient could be administered an unsafe product
  • A lack of compliance with global regulatory and standards-based requirements can increase liability
  • Thermal variability can lead to inconsistency of results between and within batches of samples
  • The shipment can be rejected by the quality department, therefore leading to costly delays – increasing the complexity of trial management (2)

To ensure compliance and reduce both financial and legal risk, study sponsors should take a holistic approach to cold chain management with considerations for regulations and customs, specialised packaging, temperature tracking and establishing strategic logistic partnerships.


The US Department of Transportation (DOT) Hazardous Materials Regulations (HMR) and International Air Transport Association (IATA) Dangerous Goods Regulations (DGR), along with other country specific regulations, specify requirements for the safe transportation of hazardous materials by railway carriage, aircraft, shipping vessel and motor vehicles (3,4). These regulations dictate specifications for classification, packaging, hazard communication, shipping papers, incident reporting, handling, loading, unloading, segregation and movement of hazardous materials. Fines and shipping delays often result from lack of compliance with these regulations.

Customs regulations in emerging regions are also complex and strictly followed by customs staff. Any issues with the shipment itself, or the accompanying paperwork, can result in material being held in customs for prolonged periods. With the current growth in temperature-sensitive products and timesensitive shipments, developing a strategy to avoid these issues is essential. For example, when materials face possible delays at customs, consigning shipments with a courier who is capable of replenishing refrigerant while awaiting clearance may be difficult.

Rigorous demands from authorities and industry associations worldwide necessitate that standard operating procedures (SOPs) be set in place not only for shipping, but also for labelling and documentation. Any controlled transport storage conditions, as well as warning statements or content identification, should be clearly stated on the label applied to shipping containers. Labelling must comply with IATA guidelines, be securely attached and clearly state that materials are to be transferred to a specified storage temperature upon receipt.


Once optimum temperatures for clinical materials have been defined, the logistics process must be designed to maintain the sample temperature and reduce fluctuations during shipment. Temperature-sensitive materials are transported in one of three states – frozen, refrigerated or controlled room temperature. Structural integrity, insulation and refrigerant (typically dry ice) are obvious elements of suitable packaging, but the size of the package and the placement of contents are also important. If the package is too large, excess air will enter and cause dry ice to dissipate too quickly. Qualified packaging solutions, along with IATA- and DOT-approved packing techniques, exist to help safeguard materials in transit.

For liquid nitrogen shipments, the shipper must utilise properly validated dry shipper canisters. Prior to packaging samples into dry shippers, they must first be properly charged in accordance with the manufacturer’s instructions. Also, to avoid compromising the integrity of refrigerated biological materials that must be maintained at 2 to 8°C, packaging must be properly pre-conditioned before shipping. To do this, the temperature-controlled refrigerants inside the shipping carton need to be brought to the required temperature approximately 24 to 48 hours before packing, depending strictly on manufacturer guidelines. Once the refrigerants are preconditioned and placed inside the shipping carton, the carton should rest for one to two hours to ensure the payload compartment reaches the desired shipping temperature. The payload compartment can then be filled (5).


When stringent and detailed tracking is required, reusable data loggers can be placed inside the packaging to monitor temperature and time continuously. This data can be downloaded for graphing, reporting and inclusion in audit trails. If temperature excursions occur outside the predetermined temperature range, it should be evaluated and documented by logistics personnel. As a SOP, corrective action should be implemented, when necessary, and documented. Clear directions should be provided to the recipient for the evaluation or disposition of the indicators and products.


To maximise margins in today’s volatile economic climate, sponsor companies are increasingly outsourcing many of their clinical supply chain activities to specialised providers. As clinical trials become more complex and involve more players, it becomes crucial for trial sponsors to properly plan, manage and control activities occurring between contractors and clinical sites. Selecting a clinical trial supply chain partner is a complex, strategic proposition. The risks associated with choosing the wrong partner can be devastating, so it is not a process that can be taken lightly. Only by carefully screening and evaluating all of the available options can you identify those businesses that operate with a partnership focus. Set standards high and search for reputable suppliers with global experience and resources, the flexibility to adapt to trial changes, proven capabilities in your area, and an integrated network at an affordable price.


The globalisation of clinical research has brought with it the potential of faster clinical trials, but also presents greater distribution and logistical challenges. Supply chain managers are now faced with more obstacles and potential hazards than ever before, which has made global distribution a science in itself. The increasing amount of temperature-sensitive materials generated during clinical trials requires precise project management and logistics expertise throughout every link of the global cold chain. Burgeoning environmental responsibilities, revolving regulatory guidelines and stringent protocols for advancing technology only add complexity. Therefore, choosing the right logistical service partner to oversee the global transportation of clinical trial materials is becoming a necessary component to an efficient clinical study. Such alliances also enable sponsors to have immediate access to technological innovations and cold chain expertise, thereby possibly resulting in speedier trials. However, only by having the necessary processes and resources in place to plan and manage the flow of materials between outsourced partners and investigators, can sponsor companies realise a possible strategic advantage over their competitors.


  1. Frank L, Gourley D et al, Global Supply Chain Management, Applied Clinical Trials, June 2009
  2. Bishara R, Good Cold Chain Management Practices for Clinical Trial Materials/Investigational Medicinal Products, Pharmaceutical Outsourcing 9(2): pp14-21, March 2008
  3. Department of Transportation, Research and Special Programs Administration, 49 CFR Chapter I, Hazardous Materials Transportation; Advisory Guidance; Offering, Accepting, and Transporting Hazardous Materials
  4. International Air Transport Association, Dangerous Goods Regulations 51, 2010
  5. Ball L, Safe Transportation of Clinical Trial Samples, Journal of Clinical Research Best Practices 6(3), March 2010

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As the Global Director of Supply Chain at BioStorage Technologies, Russ Hager manages all supply chain activities for relocation services, logistics and all the company’s facilities. Recognised as a subject matter expert on warehousing and transportation, Russ possesses extensive experience with domestic and international supply chain management. He is also considered a leading expert in cold chain logistics support within GMP environments. With a strong background in the FDA-regulated medical device and pharma industries, Russ has developed business continuity plans for manufacturing and logistics operation. Email:
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