Decisional Tools for Supply Chain Economics of Cell and Gene Therapy Products

Gene therapy products have tremendous therapeutic potential for indications such as cancer and even curative potential for some genetic diseases. Most of today’s gene therapy products are viral vector-based, typically relying on plasmid DNA supply for their production, and many are autologous ex vivo applications (e.g. chimeric antigen receptor T-cell therapy – CAR T), hence the supply chain of these products is highly complex. Given the relative infancy of the sector, there is a strong drive towards adopting technologies that minimise costs and supply chain complexity. This thesis aims to explore these avenues by developing and applying advanced decisional tools that analyse the gene therapy supply chain systematically whilst capturing multiple stakeholder perspectives. The decisional tools employed in this thesis included bioprocess economics models tailored to autologous CAR T-cell therapy and viral vector products. From the cost perspective, models were built to compute manufacturing costs, namely cost of goods (COG) and fixed capital investment (FCI), and coupled with brute force optimisation to identify optimal manufacturing strategies. In addition, a cost of drug development model and a cash flow model were built to evaluate the impact of process changes at different stages in the drug development pathway and evaluate the profitability of different manufacturing strategies. The case studies presented in this thesis explored the autologous supply chains and automation, a range of viral vector manufacturing flowsheets and viral vector process changes. In particular, the autologous supply chain case study provides a feasibility analysis of the optimal number of sites for the decentralised enterprise models and gives new insights into the feasibility of bedside models and impact of quality control (QC) automation. For example, for autologous CAR T cell therapy commercial manufacture, the tool predicted that bedside models such as "GMP-in-a-box" can be more profitable than the regional model for low demand scenarios and identified the critical demand where the regional model starts to outperform bedside manufacture. The viral vector manufacture case study offers the first thorough analysis of the COG associated with a range of flowsheets employing different cell culture technologies for multiple gene therapy product type and process performance scenarios. For lentiviral vector manufacture, it was found that suspension culture or adherent cell culture using fixed bed technology can offer cost savings in the order of 95% when compared to traditional manufacturing approaches in multi-layer vessels. Moreover, suspension cell culture was found to be more suitable for supplying large indications due to its high scalability potential. The process change case study offers a detailed evaluation of the switch from transient transfection to a stable producer cell line for viral vector manufacture by capturing the impact on key financial outputs for both drug development and commercial manufacture, in the case of four topical gene therapy product types. The analysis highlighted that the optimal time to switch was most sensitive to the pDNA requirement and unit cost, the expected delay to market and the titre differences. For example, for products associated with a low pDNA requirement (e.g. CAR T and AAV), switching to stable cell lines post-approval was found to be more attractive than switching early if delays to market were incurred. This thesis provides an account of how the advanced decisional tools employed can help decision-makers create optimal manufacturing strategies so as to maximise patient accessibility and provides a methodology for building decisional tools for emerging products

Proton Threshold States in the 22Na(p,gamma)23Mg Reaction and Astrophysical Implications

Proton threshold states in 23Mg are important for the astrophysically relevant proton capture reaction 22Na(p,gamma)23Mg. In the indirect determination of the resonance strength of the lowest states, which were not accessible by direct methods, some of the spin-parity assignments remained experimentally uncertain. We have investigated these states with Shell Model, Coulomb displacement, and Thomas-Ehrman shift calculations. From the comparison of calculated and observed properties we relate the lowest relevant resonance state at E=7643 keV to an excited 3/2+ state in accordance with a recent experimental determination by Jenkins et al.. From this we deduce significantly improved values for the 22Na(p,gamma)23Mg reaction rate at stellar temperatures below T_9=0.1K.Comment: 8 pages, 4 figures, 6 table

Economics of lentiviral vector processes

With the recent market approvals of autologous CAR T-cell therapies, lentiviral vectors (LVs) have been in the spotlight as a potential bottleneck to their already hindered scalability. Unstable at room temperature, LVs are routinely manufactured in multi-layered vessels using transient transfection methods. However these traditional processes are not sufficiently scalable or cost-effective for future anticipated demands. This poster discusses five different cell culture platforms that have been reported to deliver LVs: the 10-layer vessels, hollow fibre bioreactors, fixed bed bioreactors, rocking motion bioreactors in microcarrier mode and single-use bioreactors in suspension mode. These are compared from a process economics perspective across a range of scenarios that include different titre and dose size scenarios. The use of LVs for two therapeutic approaches are explored, namely for CAR T-cell therapies and haematopoietic stem cell/gene therapies. Costs of goods (COG) trends are described for a range of demands, target process parameters are identified and uncertainty analysis is carried out to capture the impact of variations in titre on the performance of each type of process

Gene therapy process change evaluation framework: Transient transfection and stable producer cell line comparison

As the gene therapy sector grows, decisions related to the best time to switch from the typical transient transfection expression system to more reproducible and scalable stable producer cell line (SPCL) systems have garnered much interest. This paper describes the application of a decisional tool to identify the most attractive expression system and optimal timing for the process change for four hypothetical gene therapy products based on either lentiviral (LV) or adeno-associated virus (AAV) vectors using suspension culture processes. The tool comprised models to analyse the cost of goods, cost of drug development, project lifecycle cost and profitability to evaluate the major trade-offs such as the reliance on costly plasmid DNA supply with transient transfection versus the longer cell line development times with SPCL. The tool predicted that switching to SPCL early in development, with no delay to market, was the most attractive strategy from cost of drug development and project lifecycle cost perspectives for products requiring larger quantities of viral vector. If this scenario resulted in a 10-month delay to market, then the optimal solution from a profitability perspective changed to switching to SPCL post-approval or sticking with transient transfection. Scenario analyses were performed to identify critical thresholds for the plasmid DNA costs, delays to market and SPCL harvest titre values that affect the rankings of the strategies

Lentiviral vector bioprocess economics for cell and gene therapy commercialization

Traditional viral vector processes rely on lab-scale methods that need to be industrialised so as to avoid viral vector supply shortages during commercialisation of cell and gene therapies such as CAR T-cell and HSC gene therapies. This paper describes the application of a decisional tool to identify the most cost-effective scalable cell culture technologies used in the manufacture of lentiviral vectors (LVs) across a range of products. The tool consists of a whole bioprocess economics model linked to an optimisation algorithm and analyses the cost of goods (COG) associated with adherent (e.g. 10-layer vessels (CF10)) and suspension (e.g. single-use stirred tank bioreactor (SUB)) cell culture technologies. The SUB was the most cost-effective technology across most scenarios when a suspension-adapted cell line was available, while the fixed bed bioreactor (FB) was the most costeffective when adherent cell culture was preferred instead. At large scale, the COG reduction achieved by switching from CF10 to SUB or FB was at least 90 %. The SUB capacity limits were highlighted for high dose and high demand scenarios. The cost drivers were explored and the target harvest titre required to drive down LV cost contributions to cell therapy costs was identified. Finally, the tool highlighted the impact of increasing the specific productivity in the FB on COGLV/dose for transient transfection and stable producer cell line scenarios

C. elegans feed yolk to their young in a form of primitive lactation

The nematode Caenorhabditis elegans exhibits rapid senescence that is promoted by the insulin/IGF-1 signalling (IIS) pathway via regulated processes that are poorly understood. IIS also promotes production of yolk for egg provisioning, which in post-reproductive animals continues in an apparently futile fashion, supported by destructive repurposing of intestinal biomass that contributes to senescence. Here we show that post-reproductive mothers vent yolk which can be consumed by larvae and promotes their growth. This implies that later yolk production is not futile; instead vented yolk functions similarly to milk. Moreover, yolk venting is promoted by IIS. These findings suggest that a self-destructive, lactation-like process effects resource transfer from postreproductive C. elegans mothers to offspring, in a fashion reminiscent of semelparous organisms that reproduce in a single, suicidal burst. That this process is promoted by IIS provides insights into how and why IIS shortens lifespan in C. elegans

Adaptation of the de Hoffmann–Teller frame for quasi-perpendicular collisionless shocks

The concept of the de Hoffmann–Teller frame is revisited for a high Mach-number quasi-perpendicular collisionless shock wave. Particle-in-cell simulation shows that the local magnetic field oscillations in the shock layer introduce a residual motional electric field in the de Hoffmann–Teller frame, which is misleading in that one may Interpret that electrons were not accelerated but decelerated in the shock layer. We propose the concept of the adaptive de Hoffmann–Teller (AHT) frame in which the residual convectivefield is canceled by modulating the sliding velocity of the de Hoffmann–Teller frame. The electrostatic potential evaluated by Liouville mapping supports the potential Profile obtained by electric field in this adaptive frame, offering a wide variety of applications in shock wave studies

EMPIRICAL EVIDENCE FOR RELATION BETWEEN THRESHOLD EFFECTS AND NEUTRON STRENGTH FUNCTION

In the present letter one proves, by analyzing experimental data, that the mass-dependent magnitude of threshold effects observed in deuteron stripping reactions on A ≈ 90 mass target nuclei is proportional to the 3p-wave neutron strength function. ‚ ¤ ´´µ°· ¡µÉ¥´ µ¸´µ¢¥ ´ ²¨ § Ô±¸ ¶¥·¨³¥´É ²Ó´ÒÌ ¤ ´´ÒÌ ¶·¨¢µ¤¨É¸Ö ¤µ± § É¥²Ó¸É¢µ ɵ£µ, Îɵ § ¢¨¸¨³ Ö µÉ ³ ¸¸Ò ¢¥²¨Î¨´ ¶µ·µ£µ¢ÒÌ ÔËË¥±Éµ¢,´ ¡²Õ¤ ¥³ÒÌ ¢ ·¥ ±Í¨ÖÌ ¤¥°É·µ´-µ£µ¸É·¨ ¶ ¶¨´£ ´ Ö¤· ̸³ ¸¸µ°A ≈ 90, ¶·µ ¶µ·Í¨o´ ²Ó´ 3p-¢µ²´µ¢µ°´¥°É·µ´´µ°¸¨²µ¢µ°Ë Ê´±Í¨¨