By: Nina Vas - Vice President, Clinical Distribution - Cell & Gene Supply Chain - Marken
Cell and gene therapies promise life-changing outcomes for patients facing debilitating and rare diseases. Immunotherapies and stem cell treatments have given new hope to cancer patients, while gene therapies have the potential to cure by targeting the root cause of disease.
To date, the FDA has approved a total of 21 cell and gene therapies and has issued 52 Regenerative Medicine Advanced Therapy (RMAT) designations for cell and gene therapy products.1 In 2019, the agency said it expected to approve 10 to 20 cell and gene therapy products per year.2 While we haven’t seen that level of activity yet, it does signal a turning point in biologic development.
Because cell and gene therapies use living cells or genetic material, they are difficult to research, develop and scale. To develop these therapies, clinicians need to collect cells from a patient, deliver those cells to the manufacturer within days (following strict temperature requirements) and return the therapy to the patient - again, under strict conditions.
Due to their fragile nature and complex development pathways, cell and gene therapies place extreme demands on the clinical and commercial supply chain. Not only do they involve living substances maintained under precise environmental conditions, but because of the personalized nature of these therapies, each product has a personalized shipping process.
To bring cell and gene therapies to market successfully, pharmaceutical companies must develop a supply chain strategy that can manage all the complexities of transporting products between apheresis clinics, research sites, manufacturing facilities and patients. A successful supply chain strategy for cell and gene therapies demands heightened attention to chain of custody, environmental conditions, packaging, regulatory, technology and customs requirements.
End-to-End Process Control
A flawless cell and gene therapy supply chain requires strict process control from start to finish. Supply chain partners must employ multiple tactics to protect the patient as well as the integrity of the trial. Considering each protocol requires a distinct supply chain, these tactics will vary. Generally, however, the cell and gene therapy supply chain process involves the following best practices:
- Risk mitigation, lane mapping and upfront planning including the execution of mock shipments
- Comprehensive, 24/7 oversight of identity, custody and management using barcoding, serialization and scheduling systems to meet timelines per protocol
- Continuous, close monitoring of all environmental conditions
- Proactive site notification in advance of any samples needed for the study
- Use of technology to align sites’ scheduling systems with the storage warehouse and transit
- Employment of a wide network of cryogenic fleet, filling stations as well as temporary and permanent storage
- Use of advanced tools that not only monitor the sample journey, but anticipate needs and help fulfill documentation Requirements
24/7 Chain of Custody and Identity Management
Patient safety is paramount in any study, but it’s especially important when it comes to cell and gene therapies, which can be one-time treatments and target small cohorts of patients. Clinical trial design reflects that targeted approach. Luxturna, a novel gene therapy that treats an inherited retinal disorder, recruited 31 patients for its Phase III study.3 Sample sizes for advanced therapy medicinal products (medicines based on cells, genes or tissues) approved in Europe reported sample sizes ranging from 99 to 512 participants.4
With such small sample sizes, every patient and every sample are integral to a trial’s success. And because these experimental therapies are often the last-line treatment, strict monitoring of identity, custody and management is required.
Autologous therapies - therapies manufactured from patients’ cells - require a supply chain with highly detailed storage, labeling, traceability, custody, packaging and shipping requirements. Once cells are collected from a patient, couriers may only have 48 hours to transport the sample to the manufacturing facility. The entire process of cell collection, manufacturing, evaluation, packaging and shipping ranges from four to 20 days.
This small vein-to-vein window requires smart tracking systems and easily accessible data to ensure chain of identity (what patient it is) and custody (who has it). Just-in-time manufacturing works well for cell and gene therapies, which, by nature, use small batches and packaging runs. These products are too valuable to waste. Just-in-time manufacturing and delivery ensures sites receive the exact amount of drug needed, when needed.
For therapies custom-created for each patient, there’s simply no margin for error. Custom-built tracking systems provide real-time and end-to-end visibility of shipments from booking to delivery. Real-time data allows sponsors to confirm therapies arrive to their destinations on time and under the right specifications.
Strict Control of Conditions
When analyzing and transporting living cells and genetic material, every second counts. And every second needs to be monitored an controlled precisely to protect sample integrity.
Highly perishable autologous and allogenic therapies (therapies manufactured in large batches) utilize liquid nitrogen or temperature-controlled conditions. Strict temperature requirements, often cryogenic, must be maintained throughout the product’s short journey. Turnaround time to obtain a blood sample to the manufacturer may be 36 to 48 hours. Any longer and the sample degrades.
To deliver under these conditions, the supply chain partner must have an intact cold chain, agile logistics, integrated technology with an orchestration platform and smart packaging options. As we learned from the pandemic, a robust cold chain is crucial for storage and distribution of biologics and vaccines. That cold chain must involve a global network with multiple, strategically located cGMP depots to keep products as close to patients as possible. Not only does this type of robust network minimize risk of degradation caused by transit delays, it also protects sponsors from disruption due to unforeseen circumstances (e.g., natural disasters, border closures).
Due to tight timelines and short treatment windows, autologous therapies may require a more agile delivery approach such as just-in-time. With these therapies, there’s no inventory to manage. Instead, the supply chain partner focuses on receiving, packaging, labeling and QP release (in the EU) of the products as quickly as possible.
Smart packaging and integrated technology give sponsors 24/7 real-time oversight of their products as they make their swift journey to the patient. Monitoring and tracking systems embedded in the shipping solution allow instant access to location, temperature, shock, orientation (tilt) and other shipment data. When activated, predefined alarm points trigger automated messages, allowing a supply chain expert to intercept the shipment and proactively take action to resolve any change or challenge. GPS technology allows sponsors to geofence (set a virtual geographic area around) data locations such as airports or clinics. When shipments enter or leave geofenced areas, users receive automated notifications.
Navigating Evolving Regulatory Guidelines and Import/Export Requirements
Regulatory guidance and requirements vary by region and country. In the United States, cell and/or gene therapy clinical trials must receive approval of the product and the protocol before enrollment. Studies must comply with current Good Clinical Practice (cGCP) guidelines, genetically modified organism (GMO) directives (in the EU), dangerous goods classifications and other requirements.
Country-by-country requirements may affect design, packaging and shipping. For example, many countries have strict requirements for blood product shipment and import/export of vectors and vector copy number enhancers. Manufacturers must adjust process design and perform additional materials testing to comply with these requirements. Countries and regions also differ on documentation requirements for safety data and risk mitigation, labeling and chain of identity and chain of custody management.
Bottom line: the supply chain partner must have knowledge and expertise in GMO designations, dangerous goods classifications, QP requirements, packaging, documentation, declarations, regulatory, import/export license assistance and customs compliance for all materials involved in cell and gene therapy clinical trials. Validated transportation documentation, labeling and packaging design will prevent unnecessary delays in qualification testing and, ultimately, commercial launch.
Advanced Therapies Require Advanced Technology
Cell and gene therapy supply chains demand advanced, integrated technology with the agility required to manage tight timelines and specialized requirements. Because they’re storing and transporting personalized medicines and specimens, supply chain partners must become intimately involved in protocol development. The supply chain partner point of contact will need to know details such as when the patient will arrive at the clinic, the duration of the appointment, when to pick up specimens, the manufacturing site’s hours of operation, the duration of the production process, when the drug product can be picked up and numerous other factors.
All this information helps the supply chain partner identify the best mode of transport as well as achieve lane mapping and lane verification. An advanced technology platform that can integrate information between the sites, the manufacturer, the distribution centers and the carriers - with a dashboard for visibility - is necessary for this complex level of communication.
A secure, cloud-based supply chain management system provides end-to-end control and visibility of all products as they move between sites, labs, manufacturers and storage. The system must integrate with technology which monitors transport and tracks products. It should also connect with any mobile or web apps designed for patient use. The more advanced the integration, the better the visibility.
Other important technology tools include:
- Cloud-based label printing to streamline chain of custody and chain of identity requirements
- Online scheduling to find manufacturing slots and manage shipping logistics
- Processes to automate aspects of the regulatory Documentation
Conclusion
The demand for and potential of personalized medicine continues to grow. To accommodate studies to evaluate safety and efficacy of cell and gene therapies, supply chain solutions providers must adopt advanced technology that allows for real-time monitoring and provides end-to-end visibility. Combined with a global network of cryogenic facilities and transportation, as well as close communication and planning structured to best allow agility, the clinical and commercial supply chain will have the resources to continually improve and to support groundbreaking cell and gene therapies.
References
- Approved Cellular and Gene Therapy Products. U.S. Food & Drug Administration, Current as of 6/15/2021.
- Statement from FDA Commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Center for Biologics Evaluation and Research on new policies to advance development of safe and effective cell and gene therapies. Press Release, U.S. Food & Drug Administration, Published 2019 Jan. 15.
- Zang C, Zhang W, Chow SC. Statistical Considerations for Gene Therapy Rare Disease Clinical Trials. Ann Clin Case Rep. 2021; 6: 1925. ISSN: 2474-1655.
- Abou-El-Enein M, Hey SP. Cell and Gene Therapy Trials: Are We Facing an 'Evidence Crisis'? EClinicalMedicine. 2019;7:13-14. Published 2019 Feb 2. doi:10.1016/j.eclinm.2019.01.015.
Nina Vas is Marken’s Vice President, Clinical Distribution, Cell & Gene Supply Chain and focuses on leading Marken’s global GMP depot network as well as its fast-growing cell and gene division. She oversees their global network of liquid nitrogen storage facilities and Marken’s designated Centers of Excellence for cell and gene therapy logistics across the U.S., Europe and Asia. She brings financial, operational, quality and process improvement experience to managing the performance of the full supply chain and supporting the execution of distribution for clinical trials to global destinations. Her background includes importing and exporting of drug product (from API to finished goods and ancillaries) with clinical research organizations, pharmaceutical importers, owned facilities and third‐party depots. Nina previously served as Managing Director for one of the largest CMOs in the industry.
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