Decisional Tools for Enabling Successful Manufacture and Commercialisation of Cell Therapy Products

Cell therapy products offer the potential for treatment and possibly cure of a number of indications, such as cancer, diabetes and heart disease. However, a number of economic, regulatory, logistical and technical challenges need to be addressed so as to achieve successful commercialisation of cell therapy products. With more cell therapy products reaching commercial stage, there is an increased interest in developing and evaluating novel manufacturing strategies to enhance cost-effectiveness while accommodating the unique features of cell therapy products. This thesis aims to develop and apply advanced decisional tools so as to provide an integrated approach that offers valuable insights to some of the dominant challenges faced by cell therapy developers. The decisional tools developed in this thesis comprise the following models tailored to cell therapy products: a technology-specific detailed factorial method for fixed capital investment (FCI) estimation, a process economics model for computing cost of goods (COG), brute force optimization, a multi-attribute decision making model, a robustness analysis model and a risk-adjusted net present value model. A key novel contribution is the detailed factorial methodology for estimating FCI and footprint for bespoke cell therapy facilities that accounts for technology-specific factors for key manufacturing platforms as well as the implications of single-use technologies and open versus closed operations. This is used to derive benchmark values for short-cut Lang factors for typical cell therapy facilities according to the technologies and commercialisation scenario selected. A set of industrially-relevant case studies is presented for topical cell therapies, namely mesenchymal stem cell (MSC) therapies and chimeric antigen receptor (CAR) T-cell therapies. The case studies explored different aspects of the manufacturing strategy of 5 cell therapy products such as optimal technology selection, process robustness, performance targets for successful commercialisation, fixed capital investment requirement, the cost benefits of allogeneic cell therapy products with respect to autologous cell therapy products and the effect of decentralised multi-site manufacture of autologous products. In particular, the MSC case study provides a more holistic approach to evaluating different technologies that considers both financial and operational features. The CAR T-cell case study provides the first in-depth economic analysis and set of insights at both the technology level and an enterprise’s facility configuration level. The work in the thesis illustrates how the decisional tools developed can facilitate the design of cost-effective manufacturing strategies for cell therapy products

Decisional tools for successful commercialisation of novel vaccine technologies

With the emergence of personalised cancer vaccines and more recently with the COVID-19 pandemic, the increasing need for novel and disruptive manufacturing and supply chain strategies to deliver affordable vaccines has been highlighted. Decision-support tools are essential to accelerate and enhance decision-making during the development, commercialisation and distribution of prophylactic or therapeutic vaccines across the globe. This presentation will share our most recent insights from UCL’s Bioprocess Decisional Tools research on modelling the economics of integrated and intensified manufacturing technologies for viral vectors and mRNA vaccines. On the mRNA front, UCL collaborated with Univercells Technologies and Quantoom Biosciences to explore novel identified, integrated and automated platforms for the production of personalised cancer vaccines, and we evaluated the benefits and limitations of the technology across a range of demands and dose sizes. Furthermore, we simulated the same manufacturing technology for the production of a prophylactic mRNA vaccine against an infectious disease at a pandemic pace, focusing on the adequate and rapid supply of vaccines in developing countries. The case study used the COVID-19 pandemic as a real-world example to determine the necessary infrastructure and manufacturing capacity in Africa to support a rapid response across the continent. In the analysis, we considered two vaccine technologies; an adenoviral vector and an mRNA vaccine, aiming to determine the required facility footprint, the capital investment and the cost of goods. Moreover, for each vaccine technology we compared an integrated with a conventional manufacturing platform for a centralised and a regional manufacturing and supply chain network. These case studies have highlighted the importance of utilising decision-support tools in bioprocessing to gain an in-depth understanding of the necessary infrastructure and the associated cost to manufacture and supply affordable vaccines

Experimental and economic evaluation of different culture systems for mesenchymal stromal/stem cell expansion for clinical applications

The translation of cell therapies into clinical practice requires a scalable, efficient and cost-effective manufacturing process. This study presents an integrated experimental and cost analysis of different cell culture technologies for commercial manufacture of a novel umbilical cord-derived cell therapy, currently in early phase clinical trials for the treatment of acute graft-versus-host disease (aGvHD). The experimental analysis assessed the expansion and harvest potential of mesenchymal stromal cells (MSCs), derived from umbilical cord matrix (UCM-MSCs), in different scalable cell culture technologies: a multi-layer vessel (ML), a stirred tank bioreactor with microcarrriers (STR), a hollow fiber bioreactor (HF) and a packed-bed bioreactor (PB). The presentation will highlight differences in cell proliferation rate, expansion fold and harvesting efficiency across the technologies. The cells retained their functional properties post culture in all the technologies evaluated. The experimental results were incorporated into a bioprocess economics tool comprising a stochastic cost of goods (COG) and sizing model to evaluate the commercial economic feasibility and robustness of the technologies. The financial and risk rank orders predicted by the tool will be presented, as well as their sensitivity to the reimbursement scenario selected. The model determined industrially relevant scenarios for which no technology will yield a satisfactory gross margin, indicating that many studies are still needed to establish an optimized manufacturing process