Evolving advanced therapy medicinal product regulations require new logistics complexity
New operations and capabilities a must
For the sake of patient safety, regulators are prompting ATMP developers to adopt new facilities, technologies, and workflows as well as supply chain strategies and tactics to assure availability for patients and timely supply to the point of care. Producing and delivering these advanced therapeutics to patients is complex:
- Frozen storage requirements — Cryogenic storage and distribution capabilities must be established for many ATMPs. Distribution in deep-frozen or cryogenic conditions needs specialist shippers, which keep the temperature stable and track the location and conditions during the shipment’s progress.
- Short shelf lives — When an ATMP or starting material contains fresh cells or tissues, extremely short shelf lives of between 12 to 96 hours are applicable. Very short shelf lives of cell products can demand point-of-care manufacturing or set up of a regional network of manufacturing facilities close to patients.
- Seamless chain of cold-chain custody — For autologous therapies, a seamless chain of custody is vital to assure safety of patients.
Documentation is stipulated by governments worldwide for specifications of storage conditions, maximum period of storage, transport conditions, and precautions for raw materials and starting materials. Specifications for the finished product must also include storage and transport conditions and precautions with particular attention to the cryopreservation stage, where temperature changes could impact the quality of the product.
Any deviation from storage, distribution, or traceability requirements has the potential to impact the quality of the ATMP and therefore the safety of patients. Storage and distribution under current good manufacturing practice (GMP) and good distribution practice (GDP) guidelines are applicable for CGTs — as with any other medicinal product. However, specific standards for CGTs and investigational CGTs are published in EU, US, and international guidelines.
The regulatory framework is developed in parallel with pharmaceutical development, but as it evolves it may not quite meet the specific requirements of ATMPs. For example, allogeneic cell therapies (a type of ATMP that modifies living cells from a single donor to create a therapy for a group of patients) usually rely on a central facility to modify cells which lead to international distribution of donated cells to this facility, and the finished products need a global storage and distribution network. Autologous therapies often still have a very limited number of manufacturing sites, with some therapies often having just one located in US. The EU import process requires certification of this single patient-specific batch manufactured in a third country by a qualified person (QP), even for autologous therapies, for example, the US. This can typically delay the process by as much as two days before patients can access their therapy which presents a risk for the patient waiting urgently for this often life-saving therapy.
There is no exemption or variation from labeling and re-test labeling either. Updates of shelf life must be conducted as with any other investigational medicinal product (IMP) and require an additional label stating the new expiry date while repeating the batch number. This can impact the integrity of cryopreserved ATMPs and requires storage at a GMP-licensed manufacturing facility offering secondary packaging and labeling of IMPs.
More harmony and awareness of regulations for gene therapies containing genetically modified cells or viruses is needed as well. Although human therapies are exempt from GMO regulations, application of dangerous goods classification for distribution and restrictions of storage times at distribution hubs and treatment centers can be applied by manufacturers and local authorities. Short stock times of a few days are not enough to ensure timely access by patients wherever they access their treatments.
Although the field is still in its infancy with just 22 treatments approved by the US Food and Drug Administration (FDA) and 11 approved by the EU’s European Medicines Agency (EMA), the development pipeline is growing fast. Currently, there are approximately 1,000 CGTs in development and clinical trial, including several in Phase 3.1
The time for regulatory reform is now
These regulatory requirements have the potential to impact launch timelines, patient access (and patient safety in turn), and the price of these therapies. Medicinal risk-based approaches and further adaptations of current regulations must be considered by regulators to protect the integrity of these products before they freeze investment and development of these breakthrough therapeutics.
Fortunately, the ATMP industry is finding logistics solutions with third-party cryogenic logistics partners. According to a recent World Courier study of 100 companies in the sector, most ATMP innovators are currently leveraging third-party providers to remove complexity and rise above technical challenges associated with ATMP logistics.
Respondents indicated that without the expertise, global network, and technical capabilities of third-party logistics providers, it is going to be extremely tough to meet regulators’ expectations. The ATMP regulatory framework is evolving, and regulators are beginning to recognize the special logistics demands of ATMP storage and distribution. Although there is general agreement between the FDA and EU regulators, there are tough issues sponsors must face regarding importation, labeling, and GMO framework. If advanced ATMP drug products are to enter the market efficiently, adjustments and harmonization are needed now to avoid impacting product integrity, costs, and patient safety.
By utilizing its global network, World Courier helps advanced therapy companies build robust logistics platforms that support the clinical development and commercialization of therapies to meet patient treatment needs. For more information, contact us.