Once pharmaceutical drug products are dispatched for distribution, their efficacy depends on how well they are stored and distributed. The more temperature-sensitive a drug product is, the more challenging it becomes to maintain its integrity through the supply chain. No, we aren’t referring to standard temperative-sensitive pharmaceutical and biological products like vaccines, insulin, or monoclonal antibodies. 

We are talking about a specific class of pharmaceutical product that makes their cold chain logistics ubiquitously challenging: Cell therapies.

In this article, we will explore the logistical challenges posed by this immensely sensitive class of drugs, and how they can be maintained.

What are Cell Therapy Products? 

Cell therapy products are made from live mammalian cells, mainly human cells that are autologous or allogenic. These products require special cold chain conditions to maintain their viable state throughout storage, distribution, and till distribution.

Unlike standard small molecule temperature-sensitive pharmaceuticals and biologics, cell therapy products are highly labile, remain viable only for a short time, within specific temperature ranges, and require oxygen and other nutrients to stay metabolically active.

Therefore, these products must be delivered during administration or stored in cryogenic storage temperatures to keep the cells alive. 

While cold chain logistics are in place for standard temperature-sensitive products,  there is a lack of existing cold chain infrastructure in the commercial supply chain to handle the unique requirements of cell and gene therapy products.

Logistical Challenges Posed by Cell Therapy Products 

Cell therapy products must be distributed under controlled room temperature or refrigerated conditions. For example, Apligraf? (Organogenesis) is an Allogeneic Cell Therapy product that must be stored at 20–-23°C, whereas ChondroCelect? (TiGenix), an Autologous Cell Therapy product must be stored at 15–-25°C.

Apart from strict temperature requirements, there are various other logistical challenges for cell therapy products. Let’s briefly review each:

Temperature Control

As discussed already, maintaining strict temperature conditions is paramount for cell therapy products. Any deviation can compromise the integrity of the cells, making precise temperature management essential throughout the supply chain.

Complex Supply Chains

The supply chain of these products  involves multiple stages, including the collection of cells from patients, transportation to manufacturing sites, and delivery back to clinical sites for administration. Each step requires careful coordination to keep the cells viable and stable.

Real-time Monitoring and Tracking

Given the high value and sensitivity of cell therapy products, real-time monitoring and advanced tracking systems are necessary to ensure end-to-end visibility of shipments, so that any issues can be addressed immediately to prevent product loss.

Regulatory Compliance

Different regions have varying regulatory requirements for the transport of biological materials, including genetically modified organisms and dangerous goods. Compliance with these regulations requires thorough documentation, specialized packaging, and often, additional testing to meet local standards. 

Just-in-time Manufacturing and Delivery

Cell therapies require custom manufacturing for individual patients, leaving no room for error. Just-in-time logistics ensure that the right amount of product is delivered precisely when needed, reducing waste and optimizing the supply chain for these perishable products.

Contingency Planning

Robust contingency plans are essential to handle potential disruptions, such as delays caused by natural disasters or logistical errors. For example,  backup storage solutions and alternative transportation routes to ensure continuous supply chain integrity.

Best Practices for Maintaining Cell Therapy Cold Chain 

We have briefly discussed logistical challenges posed by cell therapy products, and how they can be dealt with. We will now limit most of our discussion to the most critical aspect - maintaining the cold chain.

Product Stability under Storage and Distribution Conditions

To remain stable during storage and distribution, it is essential to understand how cell therapy products react to various temperatures and storage times. Here, data from QC stability studies helps to establish time and temperature ranges suitable for the product during transit and storage.

For instance, a cryogenically frozen product might be shipped for up to two weeks in the vapor phase of liquid nitrogen to a clinical site, stored in a -80°C freezer for two days, transported to a surgery suite on dry ice, thawed, held at room temperature for an hour, and then administered to a patient. 

Even with well-designed storage and shipping systems, transient warming events are inevitable as products are transferred between containers. This is where it is necessary to have data confirming that short-term warming events do not impact product quality. The data is then used to design storage and shipping equipment and define shipping and transfer procedures, which brings us to another key aspect - the qualification of shippers. 

Qualification of Shippers

Shippers are ultimately responsible for maintaining products within specified temperature ranges throughout the shipping duration. This is where the performance qualification of shippers comes in, which is based on development testing, simulated distribution test, and route verification.

Development Testing

Development testing is conducted before performance qualification to determine the appropriate insulated shipping container and refrigerant configuration, specifying packing for minimum and maximum loads and testing with ambient profiles to represent expected transit conditions. This ensures that the configuration can withstand routine shipments year-round. 

Simulated Distribution Test

A simulated distribution test confirms the shipping container's ability to protect its contents from damage, involving drop, vibration, and compression tests according to industry standards like ASTM D4169, followed by an examination to assess whether the container provides adequate thermal and physical protection. 

Route Verification

Route verification refers to mock shipments between shipping and receiving sites to confirm acceptable performance and temperature monitoring. It evaluates logistics and receiving procedures while considering variations in transit temperatures based on location and time of year, such as summer in Arizona versus winter in Moscow.

Conclusion

Optimizing cold chain logistics for cell therapy products helps maintain their efficacy and viability. The highly sensitive nature of cell therapy products poses unique logistical challenges, including strict temperature management, complex supply chains, real-time monitoring, and adherence to varying regulatory requirements. Just-in-time manufacturing and robust contingency planning further ensure the integrity of these therapies. Adopting best practices, such as comprehensive product stability data, rigorous qualification of shippers, and thorough route verification, can make the cold chain logistics for cell therapy products efficient and reliable so that the patients receive the therapies in the most optimal condition.

About the Author

Saher Haider

Saher Binte Haider is a pharmacy graduate from Dow University of Health Sciences. She started her career as a Quality Management professional in the pharmaceutical industry where she developed a keen interest in good documentation practices, SOP creation, and content writing. She has 7+ years of experience in healthcare & life sciences content writing. Her key areas of expertise are healthcare, pharmaceuticals, health tech, and AI in healthcare.