Innovations in modern medicine create logistics and patient safety challenges.
Cellular therapies are changing the face of modern medicine. These new regenerative and immunotherapy treatments offer the potential of improving the practice of medicine and providing resources to patients who currently have limited or no treatment options. The promise of regenerative therapies through the use of stem cells or reengineered tissue includes the possibility of growing tissues and organs in a laboratory and implanting them in a patient to restore normal function. Immunotherapies harness the power of a patient’s own immune system to fight disease.
One of the most exciting areas of immunotherapy research today is the discovery of CAR T-Cell therapies to fight cancer. These tumor-targeting therapies are generating remarkable results in cancer research. The premise is simple: extract a patient’s T cells from blood and train them to recognize and kill cancer cells and then re-infuse them back into the patient. The engineered cells have the power to recognize and kill cancerous cells, while reactivating other immune players that have been dampened by cancer’s inhibitory signals.
As reported by the Alliance for Regenerative Medicine, at the close of 2015, there were 631 clinical trials underway, with 74 approved and/or marketed products worldwide, many only approved to be marketed in specific regions and/or countries. Of the 631 total trials, 192 were in Phase I, 376 in Phase II, and 63 were in Phase III. An estimated 15 percent of this is industry-sponsored and the remainder is being sponsored by leading academic centers around the world.1
New Therapies Present New Supply Chain Challenges
While these new trials are filled with great potential, cell therapies are substantially more complex than small molecule or biologic therapies. The manufacturing process for these therapies is complex and usually requires tissue or blood from the patient or donor to manufacture the treatment. Traditional pharmaceutical products have a linear supply chain model (such as a manufacturer ships to distributor who ships to provider to administer to patient).
Many of these cellular therapies have a circular supply chain. For example, autologous therapies are made from a patient’s own cells. The process requires obtaining cell materials from a patient, sending it to the manufacturing facility, and then shipping the final treatment back to the same patient for administration. There is no room for error in tracking or traceability. Allogeneic treatments are made with cells harvested from a single donor used to treat multiple patients. However, allogeneic therapies still require strict traceability back to the original donor.
Global Distribution and Zero Tolerance for Temperature Deviations
The multi-leg or circular supply chain may have both a cold chain and a cryo-frozen chain component. The entire process requires intensive planning and constant communication between the treatment centers and the manufacturer in planning patient visits and shipping schedules. The initial tissue or cells harvested may be shipped from the treatment center to the manufacturer via a cold chain shipper. Not only is a constant temperature required, but cell loss and degradation start almost immediately so timing must be well planned. There’s usually only 36 to 48 hours to get the harvested biomaterials to the manufacturer. In addition, traditional distribution and shipping solutions, such as dry ice, not only presents hazardous material and handling risks, but the temperature instability can lead to accelerated loss of the cells required to make the treatment.
Most of the time, there is a single manufacturing facility that serves a global patient population. The manufactured therapies are usually cryopreserved and sent back to the treatment facilities in dry vapor liquid nitrogen shippers. These treatments also require strict temperature compliance with zero tolerance for temperature excursions. Liquid nitrogen dry vapor shippers are aluminum dewars that use liquid nitrogen (LN2) to reach cryogenic temperatures, but they are non-hazardous and typically weigh less that standard LN2 shippers. These shippers can be validated to maintain a stable temperature below -150°C for an average 10-day in dynamic shipping conditions. All shippers should be validated and must also have the ability to resist transit related impacts (weather, equipment, volume-based risks) either through immunity to events via superior insulative properties or the ability to be actively managed.
Extended Holding Times Required for Global Shipments
A critical complication in the global transportation strategies for regenerative therapies is the unpredictability of flight schedules and the customs brokerage processes. Global transport requires the ability to control temperature for an extended period of time (at least 7-10 days).
Regulatory bodies are starting to take notice and establish specific criteria related to the storage and distribution of these types of therapies. In addition to GxP standards, the International Organization for Standardization (ISO) is currently reviewing guidelines for the storage and distribution of regenerative therapies. ISO /TC 212 and ISO/TC 276 will be the standards by which all regulations are likely to be established. ISO 212 specifically outlines the testing requirements that must be met and maintained when evaluating the quality and potency of these therapies. ISO 276 will define the standards for storage and distribution of these therapies including storage and packaging validation, comparability, and metrology. It is anticipated that part of these standards will dictate the limits of environmental temperature excursions acceptable during distribution of these therapies and the level of detail required for the packaging qualification and validation.
The future of temperature-managed delivery of critical, irreplaceable samples will be dominated by two primary packaging options. Any shipments that fall in the range of -20°C to -40°C will be packaged in active, reusable systems that have very exacting temperature control ability and can be plugged in when subjected to significant transportation delays. Any shipments that require frozen conditions -80°C to -196°C will be transported in cryogenic dry vapor liquid nitrogen dewars which have superior holding times and are largely immune to external temperature changes. Both of these transportation options provide superior risk mitigation competencies. The packaging alone, however, won’t be sufficient in supporting the regulatory requirements (ISO 212 & 276) necessary for supporting distribution of these types of therapies. Since both of these types of packaging are reusable, significant care must be used to ensure that the qualification and validation procedures, cleaning protocols, data management, and historical performance details are captured and adequately managed.
Moving from Limited Patient Populations to Commercial Access
As these therapies move through the clinical trial process to commercial approval, it is important that pharmaceutical manufacturers have a robust logistics strategy in place that can scale from addressing a limited patient population to the post-approval commercial patient populations. Unfortunately, even with robust risk mitigation strategies temperature excursions may occur. The ability to actively monitor shipments with real time, GPS-enabled data logging can be a critical component of the total solution in order to track and intervene when needed. The ability to consolidate transportation carrier scans, temperature, location, event, equipment qualification, and validation is an important addition to the quality management system.
The harvesting of the required biomaterials to make the treatments is often a long and painful process. Losing a shipment could subject an already weak patient to additional, invasive procedures. While the design and execution of these comprehensive strategies are difficult and resource intensive, it is the only way to truly protect patients and provide to them access to life saving therapies.
- “Promise and Potential.” Alliance for Regenerative Medicine. http://alliancerm.org/page/promise-and-potential