By Faryar Tavakoli, packaging program manager, Adept Packaging
Gene and cell therapies are showing tremendous promise for the treatment of a variety of life-threatening diseases, and, currently, there are over 900 gene and cell therapy clinical trials1 in progress worldwide. The promising results of these therapies, especially in curing cancer and its impact on social health and longevity, are immeasurable. The temperature-sensitivity of these products, their personalized nature, and their circular (“vein-to-vein”) supply chain make maintaining a seamless supply chain critical; however, it is not easily achieved. There are four areas which require careful consideration to ensure safe delivery of these products to patients:
- Packaging engineering
- Hazardous material qualification
- Cold chain
- Chain of identity — traceability
Generally, the packaging system, which includes primary, secondary, and tertiary packages, must provide closure integrity, maintain product stability, and allow for easy access to the product, while displaying chain of identity information to clinicians, manufacturers, and end users. The package should fully meet user and regulatory requirements for GMP. The packaging design and development plan for gene therapy products should consider the following:
- The packaging system must remain functional through thermal and mechanical stresses exerted during operational qualification, performance qualification, and actual shipment during commercialization.
- The primary and secondary packages must be designed to withstand cryogenic temperatures without a change in state (e.g., glass transition temperature) or durability.
- The system should meet relevant regulatory measures such as:
- adequate separation between primary containers
- leakproof primary and secondary containers, e.g., hermetic sealing of Primary bags
- use of absorbent sheet for possible leakage during transport
- internal pressurization test for primary package.
- Tertiary and secondary packaging labels
- Labels should be qualified against adhesion and abrasion test standards after mimicking actual storage and shipping conditions (i.e., accelerated and real-time ageing studies).
- Tamper-evident labels
- Hazardous-related labels
- Provide impermeability to undermining gases such CO2 and liquid/vapor nitrogen. Any contamination in these mediums could contaminate samples, especially if held in screw-capped plastic vials.2
Hazardous Material Qualification
Gene therapy drug products and intermediates are categorized into different hazardous classifications (e.g., exempt human specimen, category B, and category A). Regulations from various regulatory bodies, such as the International Air Transport Association (IATA), the United Nations (UN), the Department of Transportation (DOT), and the FDA, are applicable to any given hazardous classification. Because the requirements of each hazardous classification would affect both the design and packaging process of a gene therapy product or intermediate, a comprehensive packaging and labeling requirement document should be developed for each. For instance, if a closure is used for the primary packaging, application torque specifications must be developed and verified for each shipment using a qualified torque tester. The closure should also be designed to prevent leakage during an internal pressurization test, as required per IATA regulations. A loose stopper will most likely not meet the pressurization test.
Inadequate preparation and development of packaging design or components could result in a compromise of primary packaging during qualification testing or actual clinical and commercial launch. Additionally, noncompliance with associated regulations can result in large penalties. In the case of hazardous material leakage during transport, an FDA audit is probable. The strict requirements for shipping hazardous materials and dangerous goods must be followed, and improper shipments can result in monetary fines and penalties. The regulations require the shipper to be trained and able to correctly identify, pack, mark, and label the shipments. In addition, the appropriate paperwork must accompany these shipments. Individuals who improperly ship hazardous materials may be subject to criminal and civil penalties. Fines can range from $250 to $500,000 per violation. And, per the IATA regulations, a certified shipper must be recertified every two years.
The manufacturing process of CAR-T therapy includes an apheresis process at collection sites, delivering to the manufacturing facility from collection sites, T-cell engineering at the manufacturing facility, and, finally, transport to the administration site from the manufacturing facility. Each supply chain step requires unique packaging and temperature parameters that should fully comply with regulatory agencies and ensure patient safety. Robust and comprehensive stability data is required to establish temperature range requirements for each product (e.g., apheresis kit, viral vectors, Dynabeads) and possible allowable temperature excursions. Each temperature-controlled system for each step of the supply chain should be vigorously qualified under simulated extreme conditions (operational qualification) and actual transport conditions (performance qualification). Generally, for gene therapy drug products, the shipping container should withstand exerted physical and thermal stresses during handling and shipping while maintaining the integrity of primary packages and the product itself. Most gene therapy products need to be kept at cryogenic temperatures, below -60 or -150 degrees Celsius, to remain potent, i.e., keeping cell count and viability optimal. Commonly, two shipping systems are capable of accommodating this temperature requirement: dry ice shipper and dry nitrogen vapor (Dewar) shippers. The pros and cons of each shipping system should be thoroughly evaluated prior to design freeze-and-transfer process. The choice of primary package and stability data of the product would also affect the sourcing and development process of the shipping container.
The thermal shipping systems should ideally include sensors and built-in temperature monitors situated at worst-case locations. The shipping system should be equipped with sensors that measure the actual temperature of payload and provide information on orientation, shock, vibration, and real-time GPS. The couriers or third-party logistics providers should be able to provide end-to-end logistics support and nonstop monitoring due to the high monetary value of gene therapy products and their narrow temperature range of stability. Information about nonconformity at any critical control point during distribution should be delivered to end users, allowing for early intervention to minimize the risk of temperature excursions. The courier should provide temperature-monitoring technology that sends alerts at milestones throughout the supply chain to ensure adherence to relevant protocols and procedures such as dry ice replenishment and liquid nitrogen recharge. A robust refurbishment and closed-loop supply chain is needed from the courier or manufacturer to ensure performance consistency between individual uses. Ideally, a Web dashboard should be provided by the courier to track all the relevant sensor outputs such as temperature, orientation of the shipper, light, shock, and altitude. This dashboard needs to display overall costs and shipment history across the supply chain as well. The hazardous goods documentation for IATA compliance should be also supplied by couriers, if needed. Design, qualification, and implementation of a shipping system that meets all the pre-approved requirements are crucial.
As each autologous cell therapy product is personalized for a patient through a rapid manufacturing cycle when compared to established biologics, maintaining chain of identity and custody throughout the supply chain is vital. Chain of identity allows each therapy product to be tracked to the patient (patient identification), whereas chain of custody shows the location of the therapy product through the supply chain. The process of chain-of-identity creation and tracking should be documented and clearly visible in the batch record. The documentation should include apheresis collection data up until patient therapy delivery. The main challenge is to reduce human errors and nonconformities typically caused by manual procedures. The recent decade has brought advances in traceability solutions specific to the biopharmaceutical industry. Nonetheless, its use for gene therapy chain-of-identity use cases is still rather new and requires careful configuration, testing, and implementation.
Gene therapy companies should outline a robust front-end planning strategy to proactively tackle intricacies related to packaging qualification and temperature-controlled supply chain. Having a clearly defined sequence of activities and business processes related to packaging and temperature-controlled transport will ensure a smooth transition from clinical trials to commercialization.
- Annual Data Report, Alliance for Regenerative Medicine, 2017, https://alliancerm.org/wp-content/uploads/2018/05/ARM_Annual_Report_2017_FINAL.pdf.
- E. Woods and S. Thirumala, Packaging considerations for Biopreservation, Transfusion Medicine and Hemotherapy, 2011; 38: 149-156.
About the Author:
Faryar Tavakoli is a senior packaging engineer at Adept Packaging, an international packaging and serialization consulting company. While at Adept, he has served as packaging consultant at Genentech and Juno Therapeutics. Prior to joining Adept, he worked as product development engineer and research assistant focused on heat transfer (e.g., cold chain) and fluid dynamics. He holds a Ph.D. in mechanical engineering from the University of California, Los Angeles (UCLA). You can reach him at Faryar.firstname.lastname@example.org.