Innovative Strategies to Maintain Product Integrity in Biologic and Biosimilar Clinical Studies

Understanding Cold-Chain Shipping Challenges and Comparing Solutions for Temperature-Sensitive Product Handling

The number of biologic new molecular entities approved by the U.S. Food and Drug Administration (FDA) has increased over the last five years, which indicates a growing focus on biosimilars and targeted therapies. In this highly competitive area of research, clinical studies have become more complex due to the use of strategies designed to accelerate development and ultimately gain market approval faster. These highly targeted studies generally compete for a smaller pool of potential patients, often on a global level, and are increasingly employing complex protocols, such as adaptive designs, which have a direct impact on the clinical supply needs.

Efficiently managing complex biologic/biosimilar studies requires a keen understanding of the clinical supply challenges associated with handling these highly sensitive products and developing a solid plan to mitigate the risk of potential delays and to safeguard product integrity. While some setbacks in a clinical trial are unexpected and can occur with even the best of planning, there are proactive steps sponsors can take to better manage supply chain performance. This paper discusses the potential impact of clinical supply disruptions and presents several strategies and options for cold-shipper technologies to maintain product integrity during transit.

Understanding Cold-Chain Shipping Challenges

Any interruption or delay in clinical supplies can have a detrimental effect on the study timeline and potentially prevent patients from receiving timely treatment. In addition to being highly sensitive, cold-chain investigational medicinal products (IMPs) and reference products may also be high value or limited in supply. To avoid replacement costs or long lead times, sponsors need to first understand common cold-chain shipping challenges, especially if shipping supplies on a global basis.


Getting to the Root Cause of Common Reference Product Sourcing Obstacles

Beyond maintaining a global cold chain, several challenges commonly encountered when sourcing reference products can also threaten biosimilar and biologic development projects. In these extremely competitive studies in a high-stakes market, sourcing is generally more complex and potentially carries greater risks.

PA_Q121_CAT_65_Sidebar_1For example, some innovators may request upfront information about the study and the intended use of the drug before even considering a sale. Sponsors may also face marketplace shortages, high costs, and long lead times. Even if the product is readily accessible, it may not be available in the desired packaging, quantity, or format, such as single or multi-lots.

Finally, a lack of stability data for the reference product is a common challenge that requires stringent end-to-end cold-chain management to avoid temperature excursions. These products require precise handling from acquisition to administration to maintain an unbroken chain of custody. Purchasing teams must plan accordingly for especially difficult-to-source or special order products that may require longer lead times to ensure that product will be available when needed and to avoid study delays.

Accommodating a New Era of Biosimilars with New Materials Technology

Along with a robust strategy for ensuring a sufficient supply of the reference and innovator product, cold biologic and biosimilar studies need temperature-controlled packaging: a system that combines packing materials with specific thermal characteristics to ensure that the thermal integrity of the payload is maintained for a defined duration. 

Standard or older technology consists of expanded polystyrene (EPS) and water-based coolants. These single-use products can be purchased in a range of sizes. EPS systems are commonly used for 72- or 120-hour durations, and the cost of these units is low compared with newer products. However, they are vulnerable when external temperatures are extremely hot (above 25 °C) or extremely cold (below 2 °C). 

The newest technologies for cold-chain shipping are vacuum-insulated panels (VIPs) and phase-change materials (PCMs). PCMs replace the water-based components and gel packs that have traditionally been used in EPS systems. VIPs provide ten times better insulation and are thinner than traditional materials; for instance, 25 mm of VIP is equal to 250 mm of EPS. VIP materials are also remarkably space efficient. Whereas many standard EPS systems leave little room for the actual product, VIP products use a thinner insulation, so there is more room in the shipper for the product itself. 

PCMs work by absorbing and then releasing thermal energy to maintain a regulated temperature. It absorbs cold and heat while in solid form as the external temperature changes. The PCM temperature mirrors the external temperature until the PCM melting point is reached, allowing product to stay at a designated temperature for much longer periods of time than possible with an EPS system. 

The new VIP/PCM systems provide many operational benefits. First, physical storage requirements are lessened, because the assembled shippers and components themselves take up less space than EPS products. In addition, the amount of required coolants and components is also reduced, and year-round pack-outs are available, eliminating the need to seasonally change the ratio of coolant materials (e.g., more ice and less water in summer). The likelihood of human error decreases, and the newer materials are quicker to pack, so distribution personnel can both reduce their cycle time and increase the number of shipments that can be packed in any given day or shift. 

PCMs also have the edge over EPS systems when it comes to performance. Due to the way PCMs work, these units can hibernate, which extends the performance duration. A packed cold-chain shipper can be held under refrigeration while awaiting courier collection, and the product will remain at +2 to 8 °C for as long as the refrigerator is operating at or close to the phase change temperature of +4 °C. Once removed from the refrigerated environment and handed to the courier, the performance duration commences. This ability to hibernate can lead to substantial time savings by not having to repack and replace components during storage and transit, especially in the case of shipping or customs delays. 


Recognizing the Commercial Benefits of VIP/PCM systems 

Compared side to side at the point of purchase, VIP/PCM systems are more expensive than EPS/water systems, but clinical study sponsors should look beyond just the unit cost and consider other factors in their choice of shipping system, including:

  • Reduced shipping costs. Based on volumetric weight, it can be less expensive to ship products using VIP/PCM components.
  • Reduced storage costs. VIP/PCM offers reduced storage costs, as these systems require less physical storage space.
  • Reusable systems. Some VIP/PCM systems are reusable, and some of the components are more recyclable than the significant amounts of expanded polystyrene found in traditional EPS systems. Additionally, with reusable systems, the recipient (most often the clinical site) can, upon receiving the shipment, immediately remove the product, put it under the correct storage conditions and then give the reusable shipper box back to the waiting courier. This saves the recipient the future hassle and cost of disposal. 

It should be noted that, while reusable VIP/PCM systems work in most circumstances, in some countries it is difficult to get the components back once they have been delivered. Single-use systems are being developed to work in these situations that use less-expensive components than those found in reusable systems. 

Clinical sponsors can also take advantage of the additional levels of monitoring typically included with most VIP/PCM systems, which may include real-time GPS tracking and environmental sensors that monitor exposure to light and vibration. Technology monitors can indicate when a shipment was delivered and can alert the sender if the enclosed temperature monitor has not been started, for instance. Technologies such as these are shaping the future of cold-chain distribution by helping to preserve product integrity. 

Implementing a Network Strategy to Support your Clinical Trial 

Distribution logistics represent another way to safeguard products in a study. At Catalent, we use full-service primary and secondary packaging, which is augmented by storage and distribution services in core regions, such as the Americas, Europe, and Asia-Pacific. We also provide backup sites for contingency planning and risk mitigation, taking into account geopolitical upheavals and other world events. Regional hubs support core sites and provide secondary packaging and labeling capabilities in key locations. 

By providing clinical supplies closer to the patient, sponsors can expect more support for critical patient-centric protocols and studies. Our team goes through rigorous audit, operational, and governance processes to ensure that all sites operate within established standards. Depending on their study’s challenges, clinical sponsors may benefit from using a dynamic demand-led supply approach instead of relying on traditional supply models that offer little to no flexibility. Given that time to expiration for a biologic is generally short compared with chemical drugs, speed to clinic is especially critical. While traditional supply models have long upfront lead times, produce large, finished lots, and generally struggle with aging inventory and a high percentage of clinical waste, demand-led models are more agile and efficient. 

PA_Q121_CAT_65_Sidebar_2Unlike a traditional supply model, Catalent’s demand-led approach decouples secondary packaging from primary packaging to enable a much more efficient and responsive approach based on actual patient demand. This approach draws upon strategically located regional supply inventories instead of a large, central inventory. The result is an approach that can significantly shorten clinical supply lead times and support faster site activation. Harmonized processes minimize supply chain risk to create an efficient approach that can reduce clinical waste and improve supply chain performance. One key benefit of the demand-led approach is that temperature-sensitive products spend less time in transit, since they are physically located closer to where they are needed. 

Rely on our specialized expertise in cold-chain shipping and logistics to avoid unnecessary and costly delays and maintain the integrity of your valuable products. Using new technologies, such as VIP/PCM systems, we can help you to mitigate distribution risk and safeguard product integrity.


Mark Woolf

Mark Woolf is the Global Director of Depot Networks for Catalent Clinical Supply Services, where he manages a team covering all aspects of supplier management and global operations. He has an extensive background in global storage and distribution for clinical trials for over 15 years, and has over 35 years of experience in transport, storage and logistics, as well as quality management. Prior to Catalent, he lived and worked in the Philippines, serving in a Regional QA role with Zuellig Pharma Asia Pacific. He also spent time with Almac Clinical Services in both the UK and USA, and worked as a freight forwarder and distributor within Free Trade Zones in Turkey and Africa.