With any new high-tech industry that’s growing very rapidly, standards often lag, and this has been the case for the manufacture and distribution of cell and gene therapies. The industry determined that the establishment of new standards for the transportation of these advanced therapies has become a necessity since these products are considerably more sensitive to their environment during transit than more conventional therapies. For traditional biologics and small molecule products, there is a significant allowance for time out of environment (TOE), but in the cell and gene therapy space, the TOE tolerance is essentially zero. As such, the existing paradigms used for pharmaceutical distribution are not appropriate, and it was necessary to redevelop methodologies from a distribution standpoint that would eliminate those allowances for TOE and similar criteria and be significantly more rigorous.
Developing New ISO Standards
The new guidance ISO 21973:2020 has been in process for about three years, beginning with a working group by the Japanese arm of ISO examining a number of different standards in the manufacturing of cell therapies, including related issues like biobanking and bioprocessing.1 As is typical for ISO, they consulted with a range of experts, including the Alliance for Regenerative Medicine, the U.S. FDA, and the National Institute of Standards and Technology (NIST). They formed a spinoff working group to specifically examine the transportation of therapeutic cells, and it was at that point that we joined other industry and academic specialists to help draft a set of standards for the transportation of therapeutic cells.
The resulting guidance covers a fairly broad set of criteria establishing a basic traceability standard for all equipment, systems, and processes, encompassing the actual transportation, shipping containers, validation, qualification, packaging and labeling, and even things like temporary storage during transit, and the responsibilities of the transportation provider, the consignor, and the consignee.
These products are not only significantly more expensive than traditional therapies but may represent an irreplaceable, final opportunity to treat certain patients. If anything happens to the therapy in transit, that could mean loss of the last opportunity for that particular patient. While it is impossible to truly eliminate all risks during transportation, these new standards aim to establish consistency and mitigate as much risk as possible.
ISO standards are voluntary recommendations published as sets of best practice guidelines rather than absolute requirements. However, once best practices become fully standardized, GMP auditors learn of the standard and would question a scenario in which these best practices are not being followed. Over time, the FDA and other regulatory bodies will likely incorporate elements of the standards into their mandates, and the standards will evolve from “nice to have” to must-haves to manufacture, scale-up, and distribute the products.
Compliance Considerations Require Paradigm Shifts
Due to the zero tolerance for excursions associated with these products, additional scrutiny is critical. Traditional distribution required careful tracking of three primary components: chain of condition, or the temperature of a particular drug product at a given moment in time; chain of identity, meaning that the product that emerges from the package at the end-user matches what was placed in it at the beginning of the supply chain; and chain of custody, meaning who had possession of the package through its transportation.
At Cryoport, we introduced a fourth consideration, the essence of which was incorporated into ISO 21973:2020: Chain of Compliance® — the establishment of a compliance standard to collect and manage all data concerning the performance characteristics of the packaging and the transportation partners to establish a lower risk paradigm for the distribution of these therapies. Chain of Compliance® employs many of the same traceability standards as GMP — the usage, performance, maintenance, and calibration histories of a given piece of equipment; performance characteristics of the standard operating procedures; and the underlying transportation and distribution parameters — and can be viewed as an extension of the GMP environment from its typical endpoint to the point of use. The shipping container is upgraded from a shipper to a validated storage container that complies with GMP, which is a very different paradigm from that used for conventional small molecules and biologics. Providing a comprehensive historical record for the distribution of these therapies unequivocally reduces the risk paradigm for distributing them over time.
Considerable Additional Standardization Required
Cell and gene therapies also call for a reappraisal of where the supply chain must be considered to begin and to end. The starting point is a little bit easier to define, with the inspection process well proceduralized and standardized. Most cell therapy products undergo fill-finish into an IV bag or a closed aseptic vial and are cryogenically frozen in suspended animation at –150 °C. Once the frozen therapy departs the manufacturing site, it is considered in transit and bound by the ISO 21973:2020 standard until it is received at the point of use — the hospital or clinical environment in which it will be administered. Once it has reached the clinic, the guidance no longer applies, but the cryogenic products must still be kept in their shipping containers until the point of use, and the zero TOE tolerance still applies. Another standard is currently being drafted to ensure maintenance of integrity and efficacy within the hospital environment, and we anticipate many more being released to cover quality control during manufacturing and administration. The supply chain is only as strong as its weakest link, and there is considerable work to be done to standardize the entire supply chain for these therapies.
Another benefit of establishing further standards is that they will allow expansion of automation throughout the supply chain. The industry badly needs to find ways to reduce the cost of goods across the board, especially with these very expensive therapies, and one of the clearest ways to do that is by increasing efficiency and automation. However, that is impossible when different organizations use different vial types, labeling conventions, shipping containers and accessories, and other elements.
Within the next few years, We anticipate a lot more standardization of the primary and secondary packaging and labeling conventions, which has already started (to a certain degree) in terms of things like ISB2128 labeling for cell therapies.
Preparing for Forthcoming Approvals
The FDA has projected that the cell and gene therapy space may be seeing as many as 20 new drugs approved per year by 2025. While many of these products remain second- or third-line therapies for relatively rare conditions, these numbers may remain manageable, but we may soon see approvals of therapies for solid tumors, cardiovascular conditions, and other potentially large-volume products, which will likely reveal additional bottlenecks in the supply chain and the industry broadly.
ISO 21973:2020: Biotechnology — General requirements for transportation of cells for therapeutic use. International Organization for Standardization. Jun. 2020. Web.