Storage and transport for cell and gene therapies

23 Oct 2024 24min read

In recent years there has been an increasing focus on the need to accelerate patient access to potentially life-saving cell and gene therapies. Achieving this will require a range of approaches, from effective clinical bioprocess development, to novel methods for speeding up the manufacture of personalised medicines.  

It is important to consider the storage and transportation of cell and gene therapies. Defining a structure that runs smoothly from creation to patient administration is important to ensure the integrity of your cell and gene therapy, as well as patient safety. This will also reduce negative impacts on your commercial viability through the reduction of waste. This remains an integral part of ensuring therapies can be administered safely, while retaining compliance to Good Manufacturing Practice (GMP) requirements 

The storage and transportation of cell and gene therapies can typically be broken down into 6 key sections: 

    1. Product stability
    2. Packaging and labelling
    3. Storage conditions of cell and gene therapies
    4. Handling
    5. Distribution
    6. Continuous monitoring
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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 minimalised, 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 ~ -196°C. However, manual handing is still required between shipping solutions and storage, which can increase the risk of temperature fluctuations. This handling time can be minimised 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 labelling

There are several key risks which must be addressed in the packaging and labelling 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 breakages of the packaging, compromising the product. 

As mentioned, in the product stability section above, packaging material type is integral to the reduction of product loss. There are several additional requirements for packaging and labelling 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. 
Image depicting cell and  gene therapy

3. Storage conditions of cell and gene therapies

Appropriate storage conditions are essential to maintaining the integrity of the cell and gene therapy material and minimising denaturing. In addition to the storage requirements identified through product stability testing, storage facility location is another key component to ensuring the safe storage of cell and gene therapies. Things to remember when deciding on a storage facility include, but are not limited to, the following: 

  • Patient dosing locations 
  • Import/export restrictions 
  • Ease of access for land and air transport 
  • Qualified GMP site 
  • Regulatory compliance 
  • Clear, defined internal processes 
  • Compliance with internal Quality Management System (QMS) 
  • Accommodating of onsite audits. 

For example, referring to the above storage facility location considerations, if your patients are predominantly based in the EU, it would be beneficial to select a storage facility that is also in the EU. Less documentation is required when shipping between EU countries, with no need for additional international shipping requirements such as commercial invoices. This can greatly reduce the risk of a shipment getting stuck in customs and save valuable time, which could make all the difference when getting a shipment to the storage or dosing facility whilst still being within the required temperature limits. 

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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 minimise temperature excursions. Temperature deviations can lead to safety concerns and impact therapeutic efficacy. Even a temporary rise in temperature would be able to cause cells to partially thaw, which could lead to altered functionality or even cell death. Errors involved with handling can pose a serious risk to patient safety and have severe financial implications due to product loss. 

All staff involved in the handling of cell and gene therapies must be thoroughly trained in cold chain protocols and emergency procedures to avoid critical errors, with this training to be 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 minimise excursion times during handling from temperature-controlled shipping containers to storage containers and vice versa. For example, the use of 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 labelled 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 are completed in person and not online. A tour of the facility will be invaluable to get an understanding of how the site’s standard operating procedures function, as well as the overall cleanliness of the site and potential outofspecification risks regarding material handling.

5. Distribution

Understanding the distribution requirements for your cell and gene therapy will allow you to select an appropriate storage and distribution site. Key factors to bear in mind when selecting a site are whether it will require international shipping, or transport from remote locations. International distribution of temperature sensitive materials introduces additional complexities, such as: 

  • Varying regulations 
  • Different climates 
  • Customs delays 

There are several distribution solutions which can help alleviate some of these complexities. For example, emerging smart packaging solutions which allow for real-time temperature and other environmental monitoring such as the ELPRO LIBERO Gx. A few of these solutions have the ability to send alerts/alarms in real-time or even adjust internal conditions to ensure the required internal temperature is maintained. 

Remote locations add a unique challenge to transportation and storage, as the therapies may need to be stored in smaller sites without the required facilities. Portable refrigeration units for example, may need to be used at the receiving site to store the cell and gene therapies at the correct temperature prior to patient dosing. 

Different climates can also impact the lifespan of temperature-controlled shippers, such as LN2 Dry Shippers. During audits it is important to view the executed shipper qualification protocols and to ask about international distribution studies. If the receiving site is not in a country that has been covered in a distribution study, it would be beneficial to trial the shipping lane prior to the start of the cell and gene therapy clinical study. This will ensure that the shippers are able to maintain the required temperature requirements during transit to the required locations and minimise any potential customs delays.

Image depicting transport of cell and gene therapies

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 important to make sure temperatures are monitored 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 out of 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.

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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 advancement could be made include: 

  • Smart packaging via integration of sensors 
  • Biodegradable materials to develop more environmentally friendly packaging options 
  • Modular packaging systems that can adopt 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 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. 

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