A roadmap to successful commercialization of autologous CAR T-cell products with centralized and bedside manufacture

The availability of two CAR T-cell therapies on the market has cemented the therapeutic potential of these products to treat oncology patients. However, in order for CAR T-cell therapies to be available to a wide number of patients, cell therapy developers must carefully design their manufacturing and commercialisation strategy. This analysis must take into account multiple factors related to the target market characteristics (EU v USA), the product features (e.g. dose size), manufacturing process (e.g. automated v manual platforms) as well as facility network (e.g. centralised v bedside manufacture) and supply chain requirements (e.g. fresh v frozen products). This presentation aims at assessing the implications of the choices made for each of these critical factors to provide a clear framework for decision-making during early stages of the development process of autologous CAR T-cell products. The resulting roadmap enables the successful commercialisation of these powerful therapeutics. This analysis was carried out using an advanced decisional tool developed at University College London. The case study assesses the economic and operational effects of the decisions made at the different levels of manufacturing and commercialisation strategy by computing metrics such as cost of goods, fixed capital investment, net present value, personnel requirement and facility footprint, while considering potential constraints relating to technology capacity, viral vector stock availability, product shelf life, market access and reimbursement strategies. Cost of goods (COG), net present value, process economics, supply chain, reimbursement, centralised, decentralised, bedside, GMP-in-a-box, market acces

Facility design concepts for adoptive T-cell immunotherapy

Autologous chimeric antigen receptor T-cells (CAR T-cells) have been proposed as a possible treatment for multiple oncology indications. In order to overcome some of the challenges associated with autologous processes such as high COG, batch-to-batch variability and complex logistics there is increasing interest in developing allogeneic CAR T-cell products. The manufacturing process of allogeneic CAR T-cell products includes a 2-step genetic modification and magnetic purification in order to integrate the target CAR into the T-cells and to minimize the chances for graft versus host disease (GvHD). This presentation describes a detailed economic analysis of different facility design concepts for the commercial scale manufacture of allogeneic CAR T-cell products: fed-batch versus perfusion cell culture and centralized versus decentralized manufacture. This analysis was carried out using an advanced decisional tool developed at University College London. The case study assesses the impact of fed-batch versus perfusion cell culture on current limitations of DSP technologies for magnetic purification of CAR T-cells. The key cost drivers across these scenarios were identified through a detailed sensitivity analysis. A detailed NPV analysis was carried out with the aim of capturing the potential economic and technical benefits of using a single centralized facility compared to multiple facilities for the manufacture of allogeneic CAR T-cell products over several years

Cost-Effective Manufacturing Strategies For Feasible Commercialisation Of Autologous Car T-Cell Products

Chimeric antigen receptor T-cells (CAR T-cells) have been proposed as a possible treatment for multiple oncology indications, showing significantly high response rates in patients which have failed to respond to previous treatments. The manufacturing process of these promising products poses challenges inherent to autologous therapies. These challenges include: high COG, high labour and high facility footprint requirement. This presentation describes a detailed economic analysis of the commercial scale manufacture of multiple CAR T-cell products. This analysis was carried out using an advanced decisional tool developed at University College London. The case study assesses the cost effectiveness of multiple combinations of technologies for whole process manufacture of CAR T-cell products, using different viral vectors under multiple dose size and demand scenarios. The key cost drivers across these scenarios were identified through a detailed sensitivity analysis. This allowed process performance targets for feasible commercialisation of CAR T-cell products to be set, under different reimbursement plans. The case study was also extended to explore the potential cost benefits of shortening the cell culture process through process optimisation. Multiple process schedules were explored in order to reduce resource requirement and facility footprint, and a detailed NPV analysis was carried out with the aim of capturing the potential economic and technical benefits of using different manufacturing strategies over several years including: manufacturing technologies, process schedules, viral vectors and facility configurations (centralised manufacture vs decentralised manufacture vs hospital site manufacture)

A method for estimating capital investment and facility footprint of cell therapy facilities

Capital investment is an important factor to be considered when selecting a manufacturing strategy. For stainless steel facilities (chemical and biopharmaceutical), this is estimated often through the use of the “Lang” factor method. Cell therapy facilities present significantly distinct characteristics to traditional biopharma and chemical engineering facilities, including the use of expensive cleanrooms for open processing, the requirement for additional material storage space, and the reduced utility space and piping requirement. These factors call for the need of a dedicated method for estimating the capital investment and facility footprint of cell therapy facilities. This presentation proposes a method for the estimation of both these parameters. The method described here was developed at University College London, and recognizes that different technologies require different cleanroom classifications and have different equipment footprints. The footprint and area classification of each technology were used to estimate the facility building costs. Additional cost parameters considered in the capital investment calculation include: equipment, validation, commissioning and engineering costs. This method was used to calculate the facility costs and footprint in autologous and allogeneic scenarios, which were compared with the costs of existing cell therapy facilities

Brazilian Botanic Gardens

We argue that botanic gardens, as plant conservation focused institutions, have been tested in temperate regions that possess a relatively robust conservation infrastructure and a relatively low number of threatened species. The ability of the Brazilian botanic gardens to support plant conservation is especially challenging, given their small number relative to Brazil’s plant diversity and the increasing rate of habitat loss and plant endangerment. This study, the first for Brazil, assesses the conservation capacity of Brazilian botanic gardens. An assessment is made of the status of conservation facilities in Brazilian botanic gardens and the conservation status of their plant collections.This was based on a survey sent to thirty-six Brazilian botanic gardens in 2011– 2013 using information from the 2008 Brazilian Red List, and seven state conservation lists. The results identified a small percentage of threatened species (n =102/21 per cent) in ex situ collections of 22 botanic gardens and less than 10 per cent representation for each state red list. An assessment based on the updated Brazilian Red List (2014) showed that 425 threatened species were maintained in living collections of 18 botanic gardens. Despite the extensive size of some collections, the proportion of threatened species in the collections was found to be very low. Improvement in infrastructure, technical capacity, including horticultural skills, and development of policies and protocols will benecessary to increase the effectiveness of the collections for conservation aims

Manufacturing strategies for sustainable supply of ultra-low cost vaccines for global health

economics, optimisation, decisional tools, process intensification, process integration, perfusion, facility design The ability for governments across the globe to protect infants from diseases caused by viruses such as polio, human papillomavirus and rotavirus through immunization is highly contingent on the development and manufacture of efficacious and cost-effective vaccines. Historically, vaccine manufacturers operate at large, and at times, overstretched capacities to benefit from economies of scale. However, this has led to expensive batch failures that have added to cost and interrupted supply. This presentation describes a detailed economic analysis of multiple approaches for the manufacture of a Pichia pastoris-based vaccine with the aim of proposing strategies to produce a ultra-low cost vaccine against rotavirus with a target COG per dose of ¢15 for the finished drug product. This analysis was carried out using an advanced integrated decisional tool developed in-house. The case study assesses the cost-effectiveness of multiple manufacturing flowsheets combining different upstream and downstream techniques (e.g. fed-batch v perfusion, chromatography v crystallisation) as well as different facility designs (e.g. in-house v outsourced reagent production, fully integrated process v segregated process steps), across different geographic locations (Europe v India) and number of manufacturing sites. The key cost drivers across these scenarios were identified through a detailed sensitivity analysis. This allowed for process performance targets for sustainable supply of ultra-low cost rotavirus vaccines to be identified using an optimization algorithm. The key output of this work is to break the economies of scale model and explore how advances in manufacturing can be integrated into decisional tools models to facilitate the guaranteed, uninterrupted supply for low cost vaccines for Global Health

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

Double layer SiO2–TiO2 sol–gel thin films on glass for antireflection, antifogging, and UV recoverable self-cleaning

Double layer thin films, mechanically stable and adhering to glass, were produced through the sol–gel process, using tetraethyl orthosilicate and titanium butoxide as precursors. The refractive index of the titania and silica– titania composite layers were typically 2.1 and 1.7, and their physical thicknesses were approximately 65 nm and 81 nm, respectively, as determined by ellipsometry. These optical constants allowed attainment of quarterwave optical thicknesses at the center of the visible spectrum (550 nm) as designed, with an increase of 3.4% in transmittance. The nanometric surface roughness, measured by optical profilometry, was effective to decrease light scattering and water contact angles to below 10◦ . As novelty in dip-coated sol–gel films, superhydrophilicity for self-cleaning, antifogging, and antireflection in the mid-visible spectrum were simultaneously attained with durability of 9 weeks in the dark. Further application of UV light allowed regeneration of contact angles for self-cleaning