From production to patient: challenges and approaches for delivering cell therapies.

The cell therapy industry is rapidly growing with several new products approved for clinical use over the past few years and many more currently in clinical trials. Nonetheless, a number of challenges remain in getting cell therapies to the market and into routine use. For instance, cell therapy bioprocesses still need to be optimised, but if these therapies are to be widely adopted there must also be clear routes for their delivery from the site of manufacture to the clinic and the patients. This review explores the currently available routes, the factors that need to be taken into consideration when choosing a route and the challenges that remain with respect to cell therapy logistics

Automating decentralized manufacturing of cell and gene therapy products.

Decentralized, or redistributed manufacture, is likely to be the manufacturing approach of choice for some cell- and gene-based therapies, in particular, personalized therapies. Such an approach will ultimately depend on the business model and will take into account the regulatory and supply chain factors. Advances in technology and integration of automated production platforms have demonstrated the potential for decentralized manufacturing, however there is a need to extend the scope of automation across the entire process including the cell isolation, distribution, tracking, administration, quality management systems and development of automated analytical techniques to facilitate real-time release. For decentralized manufacture to be successfully integrated for cell and gene therapy production, lessons from other accepted healthcare-associated models of manufacture can provide useful insights and perspectives to make informed decisions. Such models share similar characteristics to decentralized manufacture in that they are patient-specific and have a limited time-frame for administration. These existing approaches, which have successfully incorporated aspects of automation, can provide a blueprint for success and may expedite the decentralization of patient-specific cell and gene therapy manufacture

Overcoming the translational challenges of the effective administration and delivery of cells

Of the few cell-based therapies widely available today the most mature are the treatment of blood-borne cancers and wound healing. The routes of administration for these applications are well understood and a great deal of research has resolved the many biological, pharmacological and engineering challenges associated with the delivery of cells by these methods. These delivery methods are only suitable for a small proportion of the possible cell therapies. Many other treatments under development for illnesses that affect organs – such as diabetes, dermatological conditions and degenerative diseases – require more complex tools and methods to ensure cells are efficiently and effectively delivered to structures such as the pancreas, skin and brain. Injuries to musculoskeletal tissues such as cartilage, intra-vertebral disc and bone may be more easily accessed; however, they present different challenges, as the delivery methods must not reduce the long-term mechanical function of the tissue the treatment is attempting to repair. Oversights can occur due to the reliance on existing and often unsuitable pre-clinical models for delivery and experimental methods and data that cannot be readily translated into the clinic. Different cell types and their behaviours will also lead to complications, so too will engineering challenges such as dosing accuracy, delivery to the appropriate site, engraftment and cell viability after shear and thermal stresses. The delivery method and device used should be considered a crucial part of the cell therapy as a whole. Many companies in regenerative medicine have designed their own delivery device often in series, not in parallel, with the development of their product. As more treatments get closer to clinic many more different devices will be required, thus presenting opportunities for those who understand the generic delivery challenges in the field

Centralised versus decentralised manufacturing and the delivery of healthcare products: A United Kingdom exemplar

Background. The cell and gene therapy (CGT) field is at a critical juncture. Clinical successes have underpinned the requirement for developing manufacturing capacity suited to patient-specific therapies that can satisfy the eventual demand post-launch. Decentralised or ‘redistributed’ manufacturing divides manufacturing capacity across geographic regions, promising local, responsive manufacturing, customised to the end user, and is an attractive solution to overcome challenges facing the CGT manufacturing chain. Methods. A study was undertaken building on previous, so far unpublished, semistructured interviews with key opinion leaders in advanced therapy research, manufacturing and clinical practice.The qualitative findings were applied to construct a cost of goods model that permitted the cost impact of regional siting to be combined with variable and fixed costs of manufacture of a mesenchymal stromal cell product. Results. Using the United Kingdom as an exemplar, cost disparities between regions were examined. Per patient dose costs of ~£1,800 per 75,000,000 cells were observed. Financial savings from situating the facility outside of London allow 25–41 additional staff or 24–35 extra manufacturing vessels to be employed. Decentralised quality control to mitigate site-to-site variation was examined. Partial decentralisation of quality control was observed to be financially possible and an attractive option for facilitating release ‘at risk’. Discussion. There are important challenges that obstruct the easy adoption of decentralised manufacturing that have the potential to undermine the market success of otherwise promising products. By using the United Kingdom as an exemplar, the modelled data provide a framework to inform similar regional policy considerations across other global territories

A 3D-bioprinting exemplar of the consequences of the regulatory requirements on customised processes

Computer-aided three-dimensional (3D) printing approaches to the industrial production of customised 3D functional living constructs for restoration of tissue and organ function face significant regulatory challenges. Using the manufacture of a customised, 3D-bioprinted nasal implant as a well-informed but hypothetical exemplar, we examine how these products might be regulated. Existing EU and US regulatory frameworks do not account for the differences between 3D-printing and conventional manufacturing methods or the ability to create individual customised products using mechanised rather than craft approaches. Already subject to extensive regulatory control, issues related to control of the computer-aided design to manufacture process and the associated software system chain present additional scientific and regulatory challenges for manufacturers of these complex 3D-bioprinted advanced combination products

Decentralized manufacturing of cell and gene therapies: Overcoming challenges and identifying opportunities

Decentralized or “redistributed” manufacturing has the potential to revolutionize the manufacturing approach for cell and gene therapies (CGTs), moving away from the “Fordist” paradigm, delivering health care locally, customized to the end user and, by its very nature, overcoming many of the challenges associated with manufacturing and distribution of high volume goods. In departing from the traditional centralized model of manufacturing, decentralized manufacturing divides production across sites or geographic regions. This paradigm shift imposes significant structural and organisational changes on a business presenting both hidden challenges that must be addressed and opportunities to be embraced. By profoundly adapting business practices, significant advantages can be realized through a democratized value chain, creation of professional-level jobs without geographic restriction to the central hub and a flexibility in response to external pressures and demands. To realize these potential opportunities, however, advances in manufacturing technology and support systems are required, as well as significant changes in the way CGTs are regulated to facilitate multi-site manufacturing. Decentralized manufacturing is likely to be the manufacturing platform of choice for advanced health care therapies—in particular, those with a high degree of personalization. The future success of these promising products will be enhanced by adopting sound business strategies early in development. To realize the benefits that decentralized manufacturing of CGTs has to offer, it is important to examine both the risks and the substantial opportunities present. In this research, we examine both the challenges and the opportunities this shift in business strategy represents in an effort to maximize the success of adoption

Facilitating the operational readiness of the NHS for the in-house manufacture and delivery of autologous cell therapy [210]

Facilitating the operational readiness of the NHS for the in-house manufacture and delivery of autologous cell therapy [210

The management of risk and investment in cell therapy process development: a case study for neurodegenerative disease

Cell-based therapies must achieve clinical efficacy and safety with reproducible and cost-effective manufacturing. This study addresses process development issues using the exemplar of a human pluripotent stem cell-based dopaminergic neuron cell therapy product. Early identification and correction of risks to product safety and the manufacturing process reduces the expensive and time-consuming bridging studies later in development. A New Product Introduction map was used to determine the developmental requirements specific to the product. Systematic Risk Analysis is exemplified here. Expected current valuebased prioritization guides decisions about the sequence of process studies and whether and if an early abandonment of further research is appropriate. The application of the three tools enabled prioritization of the development studie

Putting a price tag on novel autologous cellular therapies

Cell therapies, especially autologous therapies, pose significant challenges to researchers who wish to move from small, probably academic, methods of manufacture to full commercial scale. There is a dearth of reliable information about the costs of operation, and this makes it difficult to predict with confidence the investment needed to translate the innovations to the clinic, other than as small-scale, clinician-led prescriptions. Here, we provide an example of the results of a cost model that takes into account the fixed and variable costs of manufacture of one such therapy. We also highlight the different factors that influence the product final pricing strategy. Our findings illustrate the need for cooperative and collective action by the research community in pre-competitive research to generate the operational models that are much needed to increase confidence in process development for these advanced products

Centralized or decentralized manufacturing? Key business model considerations for cell therapies

The choice of manufacturing strategy for cell-based therapeutics is one that is best made early in product development. Expense and delay may result from any additional bridging studies following changes to manufacturing process design late in development. The chosen strategy will be strongly influenced in turn by the preferred business model. Business models may favor either centralized or distributed manufacture. There are advantages and disadvantages to each and variants may be suitable in certain circumstances. An appropriate choice depends upon a combination of regulatory, economic and supply-chain factors. In this article the factors are examined and described in the context of hypothetical examples. In general the degree of decentralization will depend on a balance of manufacturing features. The investment risk of building a centralized facility at the projected capacity, the cost of managing quality and the cost or quality implications of long-distance cold supply chains must be considered. No single business model will suit all cases. For any innovation the decision must be based on an operational analysis at the projected capacity required