Clinical Trials Insight
have been exciting innovations in developing phase change materials for cold storage and using them to create shipping containers for cell therapies”. Cryopreservation also increases logistical complexity, as not all sites may have the necessary infrastructure. Beyond temperature excursions, CGT product quality is contingent on batch-to-batch variability, immunogenicity and cell surface markers, among other factors. Thus, for both in-trial and approved therapies, the quality should be assessed at multiple checkpoints along the supply chain. “We need to ensure many key criteria for safety and potency so that the product we’re shipping to the patient meets the minimum treatment criteria,” says McNeill. Additionally, traceability is essential for maintaining CGT integrity. A mix-up of samples at any step in the supply chain can mean the patient either misses the treatment window or receives the wrong dose. A chain of identity, a transparent record that assigns a sample to a particular patient, prevents that. It is complemented by a chain of custody, an audit trail of location, temperature and custody of the shipment. Lastly, CGTs that require multiple doses pose additional monitoring challenges. While the manufacturer provides all doses up front, they are administered at different points through treatment. Between doses, the therapy is stored at the clinical site, where the storage standards might not be as rigorous. “You have to make sure that every time a dose is prepared, it meets the specifications and stability demonstrated for that product,” Rochlin explains.
Manufacturing at scale The patient-specific supply chains of CGTs mean that a one-size-fits-all approach to manufacturing doesn’t always work. Instead, fit-for-purpose manufacturing models tailored for individual therapies could offer promising results in manufacturing CGTs at scale.
For instance, the low number of starting cells from patients, coupled with donor-to-donor or batch-to-batch variability, makes manufacturing consistent yields an arduous task. Flexible manufacturing processes that account for variations in quality and quantity of cells and in-process viability tracking help manufacturers deal with variable inputs. The manufacturing set-up also needs to dynamically adapt to different supplies of starting materials, such as when more patients are available or for later stages in clinical development. As a clinical trial progresses, material requirements change with each phase. “Over the lifespan of the clinical trial, the way you think about your supply chain evolves, and it should be phase appropriate,” says Rochlin. Manufacturers need to account for changes required to scale them up in later stages during initial process development. This includes figuring out technical
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aspects like process chemistry and economic aspects like future end-to-end cost of manufacture and supply. With many cell therapies, particularly CAR-T therapies, manufacturing at the point of care has emerged as a democratizing trend. This approach speeds up therapeutic delivery by eliminating the journey from a central manufacturing facility to the treatment site. Moreover, it’s been observed to generate consistent therapies despite variations in starting materials.
CGT manufacturers should decide whether to manufacture a therapy at point-of-care sites, a centralised facility, or many decentralised facilities on a case-by-case basis. These decisions can be aided by mapping out what the entire supply chain looks like. “When you understand what causes your product to go bad, how it interacts with the patients, and what you need from the patient and the treatment centre, it helps you understand where you need to manufacture it,” McNeill explains.
Supply chain visibility
Supply chain challenges in CGT clinical trials arise from their unique temperature and manufacturing considerations, and supply and demand dynamics. Therefore, supply chain expectations need to be factored into clinical trial design. It could keep stakeholders aligned throughout clinical trial development. To get more CGTs approved, manufacturers need to “work with regulatory agencies to help them understand how we’re shipping and how we’re maintaining the quality and efficacy of the products”, says McNeill. It shows the regulators that patients get the high-quality therapies that match what has been validated. In recent years, the development of user-friendly software tools that integrate and streamline different aspects of CGT supply chains has made it easier to do so. They provide complete visibility over shipping couriers, quality control and temperature loggers, and push instant alerts of any errors in the process. This allows pharma companies to not just stay regulatorily compliant but also demonstrate it. Rochlin says that “manufacturers can see what’s being done in terms of the dosing at the clinical site and the paperwork that comes back.” Conversely, it helps the clinical sites as they can see the product as it’s being made, shipped or administered. “Anyone who’s done cell and gene therapy knows that the paperwork, all of the management, all of the quality aspects that you have to control can become complex,” says Rochlin. End-to- end visibility could make their supply chain management more straightforward. “And that’s needed as a lot of these complex therapies move towards commercialisation.” ●
www.worldpharmaceuticals.net
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