Storage and transport for cell and gene therapies

The storage and transportation of cell and gene therapies can typically be broken down into six key sections:

1. Product stability
2. Packaging and labeling
3. Storage conditions of cell and gene therapies
4. Handling
5. Distribution
6. Continuous monitoring

1. Product stability

Considering product stability is particularly useful when attempting to understand and define the lifespan of your cell and gene therapy, especially downstream of its creation. Any risk of denaturing to the product must be identified and mitigated or minimized to ensure it is in a state that is ready for safe patient administration.

Container materials and temperature control are two key factors that impact product stability. As cell and gene therapies are likely to interact with container surfaces, an appropriate material container solution is needed to reduce product loss, enable the product to withstand ultra-low cryogenic temperatures and to achieve regulatory compliance.

Storage and handling requirements for cell and gene therapies

Most cell and gene therapies require storage and transport at ultra-low cryogenic temperatures of approximately ~-196°C. However, manual handling is still required between shipping solutions and storage, which can increase the risk of temperature fluctuations. This handling time can be minimized through improved processes and equipment such as cryocarts and dry shippers, but changes in temperature will still likely occur. To mitigate the risk of changes to product stability, the impact of temperature excursions must be documented and detailed, including allowable Time out of Environment (ToE), critical high temperature limits and critical low limits, if applicable.

2. Packaging and labeling

There are several key risks that must be addressed in the packaging and labeling of cell and gene therapies. Cell and gene therapy materials are stored primarily in a liquid nitrogen (LN2) vapor phase, which is a reliable method to ensure the integrity and functionality of cell and gene therapies. However, there is still the risk of LN2 ingress into packaging which, with an expansion rate of 696 times in size from liquid to gas, can cause packaging to rapidly expand when handled, leading to breakage of the packaging and compromising the product.

As mentioned in the product stability section above, packaging material type is integral to reducing product loss. There are several additional requirements for packaging and labeling used in cell and gene therapy transportation and storage, including:

• Material sterility
• Container closure integrity
• Ultra-low cryogenic temperature resistance (material becomes brittle)
• Break resistance
• Insulation
• Legibility
• Traceability.

4. Handling

As shown in the process flow earlier in this article, manual handling is a prominent recurring process in the lifecycle of cell and gene therapies. Care must be taken to protect the packaging and cell and gene therapy material during handling and excess handling must be avoided to minimize temperature excursions. Temperature deviations can lead to safety concerns and impact therapeutic efficacy. Even a temporary rise in temperature could cause cells to partially thaw, which may lead to altered functionality or even cell death. Errors in handling can pose a serious risk to patient safety and have severe financial implications due to product loss.

All staff involved in handling cell and gene therapies must be thoroughly trained in cold chain protocols and emergency procedures to avoid critical errors, with this training documented under the site Quality Management System (QMS). Maintaining a clear chain of custody through documentation in adherence to Good Documentation Practice (GDP) standards is essential to confirm that the cell and gene therapy material has been handled correctly at every stage of the process. Ensuring an accurate and complete audit trail will also be vital during a regulatory review in the event of an investigation or recall.

Specialist equipment can be used to minimize excursion times during handling from temperature-controlled shipping containers to storage containers and vice versa. For example, cryocarts and dry ice containers allow operators to take material straight from a shipper or storage container and place it into an identical temperature environment to verify the labeled information. It is of course necessary to ensure that all equipment used during storage, handling and distribution is validated or qualified for use. Details of equipment validated or qualified by a storage/distribution facility will be covered in a site Validation Master Plan (VMP), the responsibility of whom should be listed in your site standard operating procedures (SOPs).

An audit of a potential storage/distribution site is required prior to completing a service agreement, quality agreement and contracts. It is recommended that any audits be completed in person rather than online. A tour of the facility will be invaluable to gain an understanding of how the site’s standard operating procedures function, as well as the overall cleanliness of the site and potential out–of–specification risks regarding material handling.

6. Continuous monitoring

Continuous temperature monitoring is indispensable for cell and gene therapies, covering the storage, handling and distribution lifecycle. Temperature sensors and data loggers can track temperature in real-time and store the data for all audit and compliance purposes. It is essential to monitor temperatures at all stages of the cell and gene therapy lifecycle using validated temperature monitoring systems/solutions.

Continuous monitoring procedures must be in place, with additional emergency response procedures in the event of a disaster or temperature excursion. If the handling site is not open 24 hours a day, it is important to confirm there is an on-call team responsible and trained to respond and handle the material in the event of an excursion outside of business hours. The amount of time your temperature monitoring system takes to notify the on-call team should also be confirmed, along with their required response time. This should be checked against your ToE requirements, as mentioned in the product stability section above.

Continuous monitoring is crucial for maintaining the following:

• Patient safety
• Regulatory compliance
• Product integrity
• Cost efficiency
• Quality assurance
• Early issue detection

As product integrity, safety and regulatory compliance are paramount, continuous monitoring ensures that conditions are maintained within the required specifications and potential issues are prevented. Overall, this helps deliver safe and effective therapies to patients.

Opportunities for innovation

Across each of the areas mentioned above, there is still significant room for innovation in the packaging and transport of cell and gene therapies. Some of the key areas where advancements could be made include:

• Smart packaging via integration of sensors
• Biodegradable materials to develop more environmentally friendly packaging options
• Modular packaging systems that can adapt to different sizes and types of therapies to reduce costs
• Improvements in insulation to enhance the performance of cryogenic shippers
• Incorporating telematics solutions to provide detailed logistics data for shipments to ensure safe and efficient shipping
• Alternative transport methods via drone delivery or autonomous vehicles, which could expedite deliveries to clinical sites
• User-friendly designs to simplify the packaging, leading to easier handling and preparation, ensuring therapies are administered promptly and correctly
• Streamlining compliance with regulatory requirements, which can help speed up the approval process for new, life-changing therapies

Ultimately, improving the efficiency of storage and transport for cell and gene therapies would be a valuable contribution to the healthcare industry and help to increase patient access to these life-saving therapies.