The emergence of advanced therapeutics, including cell and gene-based therapies (CGTs), presents significant opportunities for treating unmet clinical needs, and specifically, has demonstrated the potential to provide personalized therapies. Amidst the exciting science and clinical opportunities however, there are unique challenges that arise from manufacturing and delivering patient-specific CGTs.
In this guest blog, Dr. Qasim Rafiq will explore some of the opportunities, hurdles, and the overall role that a decentralized manufacture model could play in advancing personalized therapeutics. The thoughts expressed in this blog are personal reflections following the completion of a feasibility study investigating the development of cell microfactories for the decentralized manufactured of CGTs conducted in collaboration with the UK Cell Therapy Catapult, GSK, Loughborough University and University of York.
Decentralized Manufacture: The Drivers and Barriers
Traditional manufacturing processes for medicines, including pharmaceutical and biopharmaceutical products, is based upon the principle of centralized manufacture where the medicinal product is manufactured at scale, usually via a scale-up approach, and cost savings are achieved through ‘economies of scale’, and at multi-product facilities, through additional ‘economies of scope’. As such, numerous allogeneic (off-the-shelf) CGTs currently in development are adopting this manufacturing approach. This will not be possible, however, for autologous (personalized) CGTs given the need for individual units of manufacture which require a scaled-out approach to ensure patient material is segregated throughout the process and material cross-contamination is prevented. There is, therefore, increasing activity exploring the manufacture of CGTs across multiple sites in a decentralized model.
There are several clinical and commercial drivers for decentralized cell manufacture. Concerns over capacity, early investment in capital equipment, avoidance of waste, delivery of cells without the need for cryopreservation (which may affect product potency) and removal of long-distance, low-temperature supply chain are key examples. Moreover, for some CGTs, where material is initially isolated from the patient, have a limited shelf-life and are sensitive to transport conditions, decentralized manufacture may be the only feasible manufacturing model.
Personalized healthcare provides a services-based business model where the complex logistics surrounding manufacture and delivery of live cells create significant opportunity. The logistics must be carefully considered as there are significant operating costs associated with implementing this supply network for a product with a short shelf life. Personalized therapies will therefore likely require a decentralized approach, where smaller, localized manufacturing facilities are employed. Proposed models for decentralized manufacture are illustrated in Figure 1. This may, depending on the business and manufacturing model, include manufacturing facilities at specialist hospitals and clinical point of care centres of excellence. For non-cryopreserved cells or constructs, the transport to the administration site (and from the isolation facility) represents a critical step which may influence critical parameters of the final product. Moreover, in the case of centralized manufacture, validation of the product transport procedure is necessary with a range of factors to consider including time, physical stress, temperature and logistic arrangements at reception site amongst others. Being able to manufacture in a decentralized facility local to the isolation/administration site reduces the significant cost burden associated with the long-distance transport of fresh-preserved CGTs (i.e. require delivery at 37°C).
Figure 1: Proposed models for decentralized manufacture
Manufacturing product at multiple sites also reduces the risk associated with single site production with the potential ability to redeploy staff across sites should one site be unavailable without having a significant impact on production. To develop decentralized manufacturing processes however, it is necessary to show how the ownership of liability for quality can be managed in a decentralized model and whether the economies of scope that may be necessary for the manufacturing equipment can be built in.
A decentralised manufacturing approach creates the need for local automation which can be capital intensive for academic/clinical centres/SMEs and, more importantly, the requirement to demonstrate comparability between these manufacturing sites. The latter is likely to be the major hurdle for the adoption of a decentralized manufacture model. With a multi-site decentralized model, managing quality and variance in manufacturing output across the ‘satellite’ sites is critical; this will incur high costs and necessitates significant process and product understanding. Moreover, this type of approach stretches the current FDA and EMA regulatory framework, with many issues still unexplored. For example, there is ambiguity as to whether a Qualified Person (QP) would be required at each satellite site to authorise product release. Additionally, in a hypothetical scenario with fifty satellite facilities, if a significant change to the manufacturing process is required, there are questions as to whether production at all fifty sites would need to cease to implement the change. Concerns also emerge as to how resource intensive this would be not just for the Market Authorization Holder, but also for the regulator. Additional uncertainties arise with respect to liability following adverse events, particularly in a situation where third-party automated manufacturing systems are used to manufacture the product, however this may be offset by contract stipulations.
Decentralized models of manufacture offer attractive advantages in terms of cost and flexibility. Ultimately however, the manufacturing strategy for any CGT product will be determined by the underlying business model, following a full economic assessment which takes into account the nature and characteristics of the product (i.e. autologous/allogeneic, fresh/cryopreserved, product shelf-life etc.), market requirements and regulatory standards. The latter is critical and drives the need for establishing the manufacturing strategy as early as possible in the development process. Leaving this too late in development risks, at best, conducting extensive comparability studies and at worst, repeating clinical trials
The successful establishment and adoption of decentralized manufacture requires concerted, collaborative effort across multiple stakeholders, including clinicians, academics, technology developers, CGT manufacturers and regulators. It also necessitates the development of innovative measurement and control technology to enable real-time release, coordination of activities between innovators and regulators, transfer of knowledge between other relevant manufacturing sectors (e.g. aeronautical and automotive) and importantly, better process and product understanding to facilitate site-to-site comparability and, ultimately, equivalency.
In spite of the current challenges of localised production, the demand for efficacious, personalized, advanced medicines will drive organizational and technical innovation and it is my view that decentralized manufacture will play a central role in the manufacture of the next generation of advanced therapeutics.
Interested in some additional reading? To learn more about the important variables to consider if you have a cell-based therapy in development and the unique logistical challenges associated with autologous cell therapies, please download Cell Therapy Logistics: Beyond the Basics.