Cell and gene therapies (CGTs), particularly autologous therapies like CAR-T/TCR-T cells, represent a breakthrough in personalized medicine. These treatments offer life-changing outcomes for patients with conditions such as blood cancers and genetic disorders. However, their highly individualized nature presents significant manufacturing, logistics, and distribution challenges. Unlike traditional pharmaceuticals, which can be mass-produced and stocked in hospitals or pharmacies, CGTs require a complex, patient-specific supply chain that demands precise temperature control, rapid transportation, and seamless coordination between clinical sites, manufacturing facilities, and logistics providers.

A major hurdle in the widespread adoption of CGTs is global accessibility. While these therapies are already approved and available in some countries, many regions—especially low- and middle-income countries—lack the infrastructure to support cryogenic storage and rapid distribution. This limits patient access to cutting-edge treatments, despite clinical advancements. Additionally, ensuring a consistent cold chain across multiple countries is a logistical challenge for CGT developers conducting international clinical trials. Variations in regulatory requirements, customs procedures, and supply chain infrastructure can introduce risks that impact trial timelines, patient safety, and ultimately, the success of therapy development.

As the industry moves toward commercialization and global expansion, addressing the cold supply chain challenges will be critical to ensuring treatment accessibility, affordability, and scalability. This article explores the key cold chain challenges in the CGT space and discusses potential solutions, such as temperature-stable cell transport media and protein-free and DMSO-free cryopreservation media, that can help overcome these barriers. By leveraging innovative tools and strategies, the industry can make life-saving therapies available to a broader patient population worldwide.

“Vein-to-Vein” Process

Autologous CAR-T cell therapies follow a highly individualized supply chain known as the “vein-to-vein” process, emphasizing a bidirectional flow where the patient serves as both the donor and recipient of the therapy. This patient-centric model requires precise coordination between clinical and manufacturing sites to ensure timely and effective treatment. The key stages in this process include:

1. Apheresis (Cell Collection) – The process begins at a specialized apheresis centre, where a patient undergoes leukapheresis to isolate peripheral blood mononuclear cells (PBMCs), primarily T cells. These collected cells are then cryopreserved or shipped fresh, depending on the specific therapy requirements, and transported under controlled conditions to the manufacturing site.
2. Manufacturing (Genetic Modification & Expansion) – Upon arrival at the manufacturing facility, the key therapeutic processes will be carried out:
   • T cells undergo expansion & activation using cell culture media containing GMP-grade human serum.
   • Genetic modification (e.g., lentiviral or transposon-based transduction to express CAR constructs).
   • Ex vivo expansion to generate a sufficient cell dose for treatment.
   • Formulation and cryopreservation to ensure product stability.
   • Quality Control (QC) and Quality Assurance (QA) to verify potency, sterility, and identity before release.
3. Cryogenic Storage & Transportation – The final product, referred to as Cryogenic Frozen Drug Product (CDP), is maintained at ultra-low temperatures (typically ≤-150°C) using liquid nitrogen vapor-phase storage to preserve cellular viability. CDP is then transported via specialized cryogenic logistics providers to either a regional distribution hub (if applicable) or directly to the infusion centre.
4. Infusion at the Hospital – Upon arrival at the infusion centre, the cryopreserved CAR-T product undergoes thawing and final preparation before being reinfused into the same patient from whom the cells were originally collected. The patient is then closely monitored for potential adverse events, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).

This highly complex and time-sensitive supply chain necessitates precise coordination across multiple stakeholders, including clinical teams, manufacturing sites, logistics providers, and regulatory agencies.

Key Elements of an End-to-End CGT Supply Chain Network

A robust end-to-end supply chain for CGT requires seamless coordination across multiple interconnected networks. Each stage—from patient cell collection to final delivery—must ensure product integrity, traceability, and compliance. Here’s a breakdown of the essential components:

1. Clinical Network – Clinics and Apheresis Centers
   • Clinics and Apheresis Centers: These facilities handle patient enrollment, cell collection (e.g., apheresis for CAR-T), and administration of the final therapy. Proper training and standard operating procedures (SOPs) at these sites are critical to maintaining product quality and patient safety.
     • To maintain cell viability during apheresis and transport, clinics can leverage temperature-stable cell transport media, which ensures cells remain viable at 2–8°C for up to 4 days, even for sensitive cell types like modified stem cells.
   • Site Selection and Qualification: Sites must be qualified based on their ability to meet regulatory and operational standards, including handling cryopreservation, cold chain management, and timely patient scheduling.
   • Patient Scheduling Coordination: Precise scheduling between collection and treatment is crucial due to the time-sensitive nature of patient-specific therapies.
2. Supply Network – Supplier Selection
   • Supplier Selection: Reliable suppliers are chosen to provide high-quality raw materials (e.g., viral vectors, reagents, cryopreservation media, cell culture media containing GMP-grade human serum) and specialized equipment. Ensuring compliance with GMP is essential.
     • Atlantis Bioscience has a DMSO-free and protein-free cryopreservation media that offers a safe, non-toxic alternative for preserving sensitive cells, ensuring compliance with GMP standards and reducing risks associated with traditional cryoprotectants. This is important to achieve temperature-controlled transport so that your
   • Supply Chain Redundancy: Dual sourcing strategies mitigate risks associated with supply disruptions, which could delay patient treatments. As demand for CGTs grows, supplier capacity and reliability must be evaluated to prevent bottlenecks.
   • Inventory Management: Maintaining appropriate stock levels for critical materials ensures continuous production while adhering to just-in-time (JIT) practices to reduce waste.
   • Raw Materials and Reagents: Sourcing of high-quality vectors, media, and reagents is essential, with a focus on regulatory compliance and reliability.
3. Production Network – Manufacturing Site Location and CMO Selection
   • Manufacturing Site Location: Sites are selected based on proximity to patient populations, regulatory jurisdiction, and access to skilled labour. Regional manufacturing hubs can reduce logistics complexity and turnaround times. During manufacturing, temperature-stable cell transport media can be used to safely transfer cells between large facilities, ensuring viability and reducing the risk of temperature excursions.
   • In-House vs. Contract Manufacturing Organization (CMO): Companies must decide between building proprietary manufacturing capabilities or outsourcing to CMOs specializing in CGT production.
   • Manufacturing Scalability and Automation: The ability to transition from small-scale, manual processes to automated, large-scale production is a key factor in long-term sustainability.
4. Distribution Network – Distribution Structure and Logistics Service Provider Selection
   • Distribution Structure: This defines whether logistics are handled internally or outsourced to specialized couriers. Centralized or decentralized distribution models impact efficiency and turnaround time.
   • Logistics Service Provider (LSP) Selection: Specialized LSPs with expertise in cryogenic and temperature-controlled transport are essential. Providers must offer real-time tracking, contingency planning, and secure handling to maintain the Chain of Identity (COI) and Chain of Custody (COC).
   • Customs and Regulatory Compliance: International distribution must account for import/export regulations, including customs clearance, biosafety requirements, and compliance with global regulatory frameworks (e.g., FDA, EMA).

Key Cold Chain Challenges

1. Temperature Sensitivity and Stability

Autologous CGTs require strict temperature control at various stages:

• Apheresis collection (2–8°C for fresh cells).
• Cryopreservation (-150°C or lower for frozen cells).
• Final product storage and transport (typically cryogenic conditions).

Even slight temperature excursions can lead to loss of viability, potentially delaying patient treatment. Pharmaceutical manufacturers face $35 billion in annual losses due to temperature deviations in the supply chain.

Challenges:

• Limited Cryogenic Infrastructure – Not all regions have the facilities to store and transport ultra-low temperature therapies.
• Packaging Limitations – Existing cryogenic shipping containers have limited hold times, requiring frequent replenishment of liquid nitrogen.
• Real-Time Monitoring Gaps – Many current tracking systems lack real-time alerts for temperature excursions.

2. Time Constraints and Logistics Complexity

CAR-T therapies have a short turnaround time, often requiring treatment within weeks of cell collection. Each step in the process, from apheresis to infusion, has strict deadlines to ensure the final product is viable. Any delay in transport, processing, or customs clearance can jeopardize the treatment.

CGT shipments are heavily reliant on third-party logistics providers for transportation and tracking. Given the global nature of CGT supply chains, sponsors have limited direct control over shipments, leading to critical visibility gaps. While real-time tracking systems are in place, they rely on fragmented data sources from external partners, often lacking the granularity needed for effective planning and risk mitigation. Factors such as traffic congestion, airline delays due to storms or strikes, and customs clearance issues can cause severe disruptions. Without an integrated alert management system, sponsors may only learn of delays when end users—such as clinical sites—report missing shipments. This reactive approach increases the risk of product loss, treatment delays, and ultimately, patient harm.

Challenges:

• Tight Manufacturing Timelines – Processing patient cells takes days to weeks, leaving little room for error.
• Cross-Border Logistics – International shipments face potential delays due to customs regulations and compliance checks.
• Weather and Transit Disruptions – Unexpected delays from storms, strikes, or airline issues can impact delivery times.
• Sponsors have restricted oversight of shipments, resulting in significant gaps in supply chain visibility.

3. Customs Clearance and Cross-Border Logistics 

Autologous therapies often require cross-border shipping, which can be delayed by:

• Customs hold-ups due to incomplete paperwork.
• Variability in national regulatory requirements.
• Limited infrastructure for cryogenic storage at international transit points.

The CGT supply chain must comply with strict regulatory guidelines, including Good Distribution Practices (GDP), Good Manufacturing Practices (GMP), and International Air Transport Association (IATA) regulations.

Each shipment requires extensive documentation, such as customs clearance forms, temperature records, and chain-of-custody logs. However, regulatory inconsistencies across regions create hurdles in international CGT distribution.

Challenges:

• Inconsistent Global Standards – Regulations differ across regions, complicating multinational trials and commercial distribution.
• Paper-Based Systems – Some regions still rely on manual documentation, increasing the risk of errors.

4. Security and Chain of Custody

CGTs are high-value, patient-specific treatments, making security and traceability critical. Unlike mass-produced biologics, they require precise patient-specific tracking to ensure the correct therapy is delivered to the intended patient without mix-ups.

Chain of Identity (COI)

COI ensures that each patient receives the correct therapy by maintaining a permanent and transparent link between the product and the patient throughout the entire lifecycle—from tissue or cell collection to post-treatment monitoring.

To protect sensitive patient information (e.g., name or date of birth), anonymized COI identifiers are used. These unique alphanumeric codes provide a bidirectional link between the donor and the intended recipient. As the therapy moves through the supply chain, the COI identifier is systematically exchanged, verified, and documented at each stage. This process forms the Chain of Custody (COC), ensuring a clear, traceable path as the therapy changes hands.

Chain of Custody (COC)

COC documents the handling, transportation, and transfer of the therapy. It provides a continuous, auditable record of custody from the point of collection to final delivery. This log tracks all patient-specific materials and identifies who is responsible at each stage, safeguarding against mismanagement.

Failures in COI/COC tracking can have severe consequences, including patient harm due to incorrect or compromised treatments. Lost or damaged shipments not only result in financial losses but may also deprive patients of potentially life-saving therapy.

Key Challenges

• Risk of Misidentification: Errors in labelling or documentation may result in patients receiving the wrong therapy.
• Potential Tampering or Theft: The high value of CGTs necessitates robust security measures to prevent unauthorized access or interference.
• Supply Chain Visibility Gaps: Transitions between multiple stakeholders, especially during international shipments, increase the risk of errors if information is not accurately transferred and verified.
  • Different systems used by collection sites, manufacturing facilities, and couriers may not integrate seamlessly, causing delays or loss of critical tracking information.
  • Limited Real-Time Monitoring: Without continuous tracking of location and environmental conditions (e.g., temperature), deviations may go undetected, compromising product quality and patient safety.
  • Incomplete Chain of Custody Records: Gaps in documentation during transport or processing may obscure who had custody at a given time, making it difficult to trace or resolve discrepancies.

Solutions to Cold Chain Challenges

The time-sensitive and highly individualized nature of CAR-T therapies necessitates a robust logistics strategy to mitigate risks associated with transportation delays, fragmented tracking systems, and reliance on third-party logistics providers. Addressing these challenges requires a combination of process optimization, technological advancements, and enhanced regulatory coordination to improve supply chain resilience and ensure the timely delivery of patient-specific therapies.

1. Enhancing Visibility with Real-Time Tracking and Digital Orchestration

Digital solutions can enhance supply chain visibility, reducing the risk of delays or temperature excursions. Maintaining temperature stability is crucial for CGT companies, particularly given the ultra-low temperature requirements of CAR-T therapies (≤-150°C). Temperature excursions during transit can compromise product integrity, making robust cryogenic storage and shipping solutions essential. Sponsors can enhance logistics resilience through the following strategies:

• Deploying Smart Cryogenic Containers: Utilize self-monitoring containers equipped with IoT-enabled sensors for real-time temperature tracking and immediate alerts in case of deviations.
• Partnering with Specialized Logistics Providers: Collaborate with providers experienced in CGT transport, ensuring priority handling and adherence to strict temperature controls for time-sensitive shipments.
• Implementing On-Site Cryopreservation: Establish cryopreservation capabilities at clinical sites to minimize reliance on long-distance transport of fresh apheresis material, reducing the risk of temperature fluctuations.
• Utilizing Liquid Nitrogen Dry Vapor Shippers: Maintain ultra-low temperatures over extended periods with reliable dry vapour technology, ensuring product stability throughout the supply chain.
• Adopting Smart Packaging: Use insulated containers with integrated temperature sensors to continuously monitor conditions and prevent excursions during storage and transit.
• Automating Cryogenic Storage: Implement automated freezers and storage systems to reduce human error, improve handling accuracy, and ensure consistent temperature maintenance.

A real-time, centralized tracking and alert management system is crucial to address visibility gaps in CAR-T therapy shipments. Current tracking methods rely on fragmented data from third-party logistics providers, often lacking the detail required for proactive risk mitigation. An integrated system consolidating real-time data from multiple external partners enables end-to-end visibility from apheresis to infusion.

A digital orchestration system can:

• Automate Alerts: Detect and notify stakeholders of shipment deviations, such as customs delays, temperature excursions, or airline disruptions, enabling rapid intervention.
• Unify Chain of Custody (COC) and Chain of Identity (COI) Data: Link all events and documents within the COC and COI into a fully searchable, reportable format. Authorized users can access, review, and download a complete audit trail in real-time or retrospectively for regulatory reporting and audits.

An AI-driven logistics management system can also:

Improve Courier Coordination: Integrate data-sharing protocols with logistics providers, granting sponsors greater oversight and control throughout the shipment process.

Utilize Predictive Analytics: Identify potential transit risks in advance and trigger preemptive actions to prevent delays or temperature excursions.

2. Strategic Geographic Expansion of Manufacturing and Cryopreservation Hubs

Most cell therapies depend on centralized manufacturing facilities, which can lead to prolonged turnaround times due to long-distance shipments. To reduce shipping delays and improve patient access, CGT manufacturers are increasingly adopting regional manufacturing hubs closer to patient populations.

To mitigate cross-border transit risks, sponsors can:

• Establish Regional Cryopreservation Hubs: Set up facilities near manufacturing sites to store and process apheresis material, reducing transit time and preserving cell viability.
• Adopt Decentralized Manufacturing Models: Implement automated cell processing units at regional centres to bring production closer to patients, enhancing speed and scalability.
• Partner with Local Logistics Providers: Collaborate with specialized couriers familiar with regional regulations to streamline customs clearance and ensure timely, compliant delivery of CGT shipments.

These strategies help reduce logistical complexities, minimize product handling risks, and accelerate patient access to life-saving therapies.

3. Enhancing Cold Chain Logistics with Advanced Cryogenic Packaging

Maintaining temperature stability is critical for CGT companies, especially given the ultra-low temperature requirements of CAR-T therapies (≤-150°C). Temperature excursions during transit can compromise product integrity, making robust cryogenic storage and shipping solutions essential. Sponsors can strengthen logistics resilience through the following strategies:

Strategies to Enhance Cold Chain Logistics

1. Deploying Smart Cryogenic Containers
   • Use self-monitoring containers equipped with IoT-enabled sensors that provide real-time temperature tracking and alert stakeholders to deviations.
   • Smart containers ensure continuous monitoring, reducing the risk of temperature excursions and maintaining product integrity during transit.
2. Partnering with Specialized Logistics Providers
   • Collaborate with providers offering dedicated CGT transport solutions, including priority handling for time-sensitive shipments.
   • Specialized logistics providers ensure adherence to strict temperature controls, minimizing delays and ensuring timely delivery of therapies.
3. Implementing On-Site Cryopreservation
   • Establish cryopreservation capabilities at clinical sites to reduce reliance on long-distance transportation of fresh apheresis material.
   • For on-site cryopreservation, DMSO-free, protein-free cryopreservation media provides a safe, non-toxic solution for preserving sensitive cells. Its ability to maintain cell viability of MSCs ≥85% for up to 10 days at 4°C makes it ideal for short-term storage and transport.
4. Utilizing Liquid Nitrogen Dry Vapor Shippers
   • Ensure ultra-low temperatures are maintained over extended periods with reliable dry vapour technology.
   • Liquid nitrogen dry vapour shippers provide consistent temperature stability, even during long-haul shipments.
5. Adopting Smart Packaging
   • Employ insulated containers with integrated temperature sensors to monitor conditions and prevent temperature excursions.
   • Smart packaging solutions offer real-time monitoring and alerts, ensuring product integrity throughout the supply chain.
6. Automating Cryogenic Storage
   • Use automated freezers and storage facilities to minimize human error and improve handling precision.
   • Automated systems enhance temperature control and reduce the risk of deviations during storage.

These advanced solutions enhance supply chain reliability, safeguarding the quality and viability of CGT products throughout the distribution process.

4. Proactive Risk Management and Contingency Planning

Atlantis Bioscience’s DMSO-free and protein-free cryopreservation media, CryoEase provides a safe, non-toxic solution for preserving sensitive cells. This versatile media also functions as a hypothermic reagent, maintaining cell viability of MSCs ≥85% for up to 10 days at 4°C, making it ideal for short-term storage and transport.

• Pre-established Contingency Routes and Backup Couriers: Identify alternative shipping routes and engage backup logistics providers to address unexpected disruptions, such as airline strikes or weather-related delays.
• Automated Logistics SOPs: Develop Standard Operating Procedures (SOPs) that trigger predefined mitigation measures when shipment risks are detected, ensuring quick corrective action.
• Regulatory Engagement for Global Harmonization: Collaborate with regulatory agencies to streamline customs handling for CGT shipments, reducing cross-border delays and facilitating faster clearance.
• Shipping Mock Runs and Qualifications: Conduct simulated shipments under real-world conditions to validate shipping protocols, identify potential risks, and ensure the supply chain can withstand operational challenges.

Potential Solutions:

• Pre-Approved Shipping Routes: Partner with regulators to establish expedited customs pathways and clearance processes for CGTs.
• Secure Transport Protocols: Implement tamper-proof packaging and GPS tracking to protect shipments and maintain supply chain visibility.
• Standardized Training for Logistics Personnel: Ensure all personnel handling CGT shipments receive specialized training in cold chain management and emergency response procedures.

By adopting these measures, sponsors can minimize disruptions, improve supply chain resilience, and ensure the timely and secure delivery of patient-specific therapies.

Compliance Considerations

A robust cold chain management system requires comprehensive documentation across all supply chain stages. This includes stability data, geographic and climatic information, shipping durations, and contingency plans for temperature deviations or delays. With multiple stakeholders—from manufacturers to healthcare providers—maintaining accurate records is critical for regulatory compliance and ensuring product integrity throughout the supply chain.

The Future of Cold Chain Logistics in CGT

The future of cold chain logistics in CGT depends on continuous innovation and collaboration across the industry. As CGT therapies become more prevalent, overcoming challenges like temperature control, transit delays, and regulatory complexity is essential to ensure patient safety and product integrity. By investing in advanced technologies—such as AI-driven logistics planning, real-time tracking, and automated cryogenic storage—companies can enhance supply chain efficiency and resilience.

Additionally, adopting decentralized manufacturing models and fostering global regulatory harmonization will further reduce logistical bottlenecks and expand patient access. With a strategic focus on digital tracking, automation, and secure transport protocols, the CGT industry is poised to deliver these transformative therapies reliably and at scale, making them accessible to a broader patient population and an integral part of modern medicine.

References

• ICH Harmonised Tripartite Guideline: Stability Testing of New Drug Substances and Products Q1A(R2)
• ICH Harmonised Tripartite Guideline: Quality of Biotechnical Products: Stability Testing of Biotechnical/Biological Products Q5C
• ICH Harmonised Tripartite Guideline: Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances Q6A
• ICH Harmonised Tripartite Guideline: Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Biotechnological/Biological Products Q6B
• 21 CFR 203.32 Drug sample storage and handling requirements. (https://www.ecfr.gov/current/title-21/chapter-I/subchapter-C/part-203/subpart-D/section-203.32)
• 21 CFR 203.36 Fulfillment houses, shipping and mailing services, comarketing agreements, and third-party recordkeeping. (https://www.ecfr.gov/current/title-21/chapter-I/subchapter-C/part-203/subpart-D/section-203.36)