Evaluating facility design and capacity planning decisions for clinical and commercial supply with hybrid continuous processes

Assessing the value potential of alternative process and facility design strategies will be critical to the successful management of continuous processes. UCL’s Decisional Tools team have developed advanced decision-support tools that effectively integrate concepts from bioprocess economics, dynamic simulation, risk analysis, combinatorial optimization and operations research to address such challenges (e.g. 1-5). This presentation will show our latest practical applications of such models to industrially-relevant problems related to facility design and capacity sourcing for long-term commercial supply when dealing with processes with either continuous upstream or downstream processes. The results can be translated across a range of products such as mammalian cell-derived monoclonal antibodies, E.coli-derived antibody fragments and labile blood factors. The first case study explores the economic feasibility of different configurations of continuous chromatography for clinical and commercial manufacture. It will address questions such as: How do the feed characteristics and resin properties impact the optimal number of columns to have in a continuous chromatography system? Does the adoption of pre-packed disposable columns change the feasibility of continuous chromatography? How does the feasibility of continuous chromatography combined with pre-packed disposable columns change across different feed characteristics, resin properties, development phases and commercial production scales? What is the optimal design of integrated continuous downstream process configurations? The second case study addresses the challenge of long-term production planning for a portfolio of commercial candidates with different product stabilities and hence requiring capacity for both fed-batch and perfusion cell culture modes. Questions that will be addressed include: How best can installed multi-site capacity be used to meet commercial demands of a portfolio containing perfusion and fed-batch based therapeutics? What is the trade-off between retrofitting existing facilities to cope with fed-batch and perfusion candidates versus sourcing capacity through CMOs or a new build? What is the impact of changeovers between perfusion and fed-batch campaigns on capacity plans across a network of multiproduct facilities

Cell therapy manufacturing strategies: Impact on cost of goods, cost of development and commercialisation

Successful commercialisation of cell therapies will be underpinned by cost-effective, robust and scalable manufacturing processes, practical supply chain solutions for delivery to patients and early planning of reimbursement. UCL’s Decisional Tools team have developed advanced decision-support tools that effectively integrate concepts from bioprocess economics, risk analysis, and combinatorial optimization to address such challenges. This presentation will provide some of our most recent process economic insights from such models applied to current and future cell therapy manufacturing processes. Bottlenecks in upstream and downstream processes will be identified and the technical innovation required to bridge the gaps constraining commercialisation will be discussed. Parallels and key differences with the historical development of biopharmaceuticals will be highlighted. A discussion of the cost of goods in relation to reimbursement will be provided for different cell therapies and compared to biopharmaceuticals. A series of industrial case studies will be presented to highlight economic challenges for different allogeneic and autologous cell therapy products. The case studies will address questions such as: What are the most cost-effective process technologies to use for cell culture, differentiation and recovery for different allogeneic and autologous scenarios? What are the cost and risk implications of process changes to more scalable and cost-effective technologies at different stages of a cell therapy’s lifecycle? How do the lower costs of commercial manufacture with microcarrier systems relative to planar technologies weigh up against the cost of development? What is the impact of centralised versus decentralised facility designs on the costs of manufacturing and logistics to reach the patients. The insights from such questions are critical to helping the cell therapy sector achieve the manufacturing and commercial success of biopharmaceuticals

Bioprocess economics and optimization of continuous and pre-packed disposable chromatography

The biotech sector is facing increasing pressures to design more cost-efficient, robust and flexible manufacturing processes. Standard batch chromatography (BATCH) is an established but expensive approach to separate impurities related with both E.coli and mammalian cells expression systems. This study uses a computational framework to investigate if the application of continuous chromatography (CONTI) and disposable technologies can provide a competitive alternative to BATCH and reusable equipment. A set of general assumptions is presented on how some of the key downstream processing characteristics, such as chromatography operating conditions, resin properties and equipment requirements, vary as a function of the chromatography mode adopted, BATCH vs CONTI, and the column type used, self-packed glass (SP GLASS) vs pre-packed disposable (PP DISPO). These assumptions are then used within the framework, which comprises a detailed process economics model, to explore switching points between the two chromatography modes and column types for different upstream configurations and resin properties focusing on a single chromatography step. Following this, an evolutionary optimization algorithm is linked to the framework to optimize the setup of an entire antibody purification train consisting of multiple chromatography steps: Alongside the chromatography mode and column type, the framework optimized also critical decisions relating to the chromatography sequence, equipment sizing strategy and the operating conditions adopted for each chromatography step, subject to multiple demand and process-related (resin requirement) constraints. The framework is validated for different production scales including early phase, phase III, and commercial scale. To facilitate decision making, methods for visualizing the switching points and trade-offs exhibited by the optimal purification processes found by the framework are provided

Time-series datamining for continuous bioprocess analysis

Continuous bioprocessing technologies are attractive to biopharmaceutical manufacturers given their potential to offer cost and quality advantages. Compared to batch processes, continuous bioprocesses requires more automation and sensors and thus generate more data. A key challenge for real-time process monitoring and control is how best to combine and transform all data sources so as to create a process fingerprint for a continuous bioprocess. This work introduces a time-series datamining technique to analyze historical continuous chromatography records generated by the BioSMBTM chromatography system for pattern recognition and anomaly detection. A dynamic time warping (DTW) algorithm combined with a K-means clustering method was applied to identify the motif patterns of various sensors so as to link the patterns with different process settings and establish process fingerprints. Case studies will be presented demonstrating how these advanced dynamic multivariate data analysis techniques can be used to rapidly detect anomaly patterns in continuous chromatography runs as well as their root causes. This work demonstrates the feasibility of real-time monitoring of continuous bioprocesses using time-series data mining methods

Business case for continuous mAb production with novel design strategies and enhanced control

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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

Industry 4.0 : a vision for personalized medicine supply chains?

Industry 4.0 foresees a digital transformation of manufacturing resulting in smart factories and supply chains. At the heart of the concept lies the vision of interconnected materials, goods and machines, where goods find their way through the factory and the supply chain to the customer in a self-organized manner. Industry 4.0 is gaining traction in high value manufacturing sectors. This expert insight article explores what this technology-driven vision has to offer the biopharmaceutical industry, and in particular cell and gene therapies

Integrated continuous bioprocessing: Costs of goods versus cost of development

A significant benefit of continuous manufacture is the potential to provide higher productivities compared to traditional batch processes. Smaller facilities with single-use technology could become preferable offering reductions in the capital expenditure. Hence, continuous bioprocessing could offer savings in the cost of goods (COG). However there are other cost factors that need to be considered when evaluating bioprocess facilities in addition to the COG. The cost of development (COD) is a key cost driver that could affect the decision to adopt new manufacturing methods. This study aims to carry out a holistic financial assessment of introducing continuous bioprocessing strategies by considering both the COG and the COD. To be able to perform this level of analysis a decisional tool was developed at University College London to evaluate the cost of implementing traditional batch or continuous bioprocessing (end-to-end and hybrid) at various stages of the drug development pathway. A range of scenarios investigated the economics of different manufacturing strategies at various demands, company sizes and stages of manufacture (pre-clinical, clinical and commercial). Therefore, through the analysis it was possible to determine whether the apparent benefits of continuous bioprocessing translate into cost savings, focusing on the development and commercialisation of monoclonal antibodies

Is regulatory innovation fit for purpose? A case study of adaptive regulation for advanced biotherapeutics

The need to better balance the promotion of scientific and technological innovation with risk management for consumer protection has inspired several recent reforms attempting to make regulations more flexible and adaptive. The pharmaceutical sector has a long, established regulatory tradition, as well as a long history of controversies around how to balance incentives for needed therapeutic innovations and protecting patient safety. The emergence of disruptive biotechnologies has provided the occasion for regulatory innovation in this sector. This article investigates the regulation of advanced biotherapeutics in the European Union and shows that it presents several defining features of an adaptive regulation regime, notably institutionalized processes of planned adaptation that allow regulators to gather, generate, and mobilize new scientific and risk evidence about innovative products. However, our in-depth case analysis highlights that more attention needs to be paid to the consequences of the introduction of adaptive regulations, especially for critical stakeholders involved in this new regulatory ecosystem, the capacity and resource requirements placed on them to adapt, and the new tradeoffs they face. In addition, our analysis highlights a deficit in how we currently evaluate the performance and public value proposition of adaptive regulations vis-à-vis their stated goals and objectives

Impact of ethanol on continuous inline diafiltration of liposomal drug products

Liposomal drug products are playing an increasing role in the field of drug delivery. With this increased demand comes the need to increase the capabilities and capacity of manufacturing options. Continuous manufacturing techniques present a significant opportunity to address these needs for liposomal manufacturing processes. Liposomal formulations have unique considerations that impact translation from batch to continuous process designs. This article examines aspects of converting to a continuous design that were previously viewed as inconsequential in a batch process. The batch process involves the removal of ethanol (EtOH) through tangential flow filtration (TFF). EtOH was found to reduce the permeability of the hollow fibers used for TFF. This effect was determined to have minimal impact on the overall batch process design but considerable influence on the design of continuous TFF such as inline diafiltration (ILDF). Using a pilot scale setup, EtOH was found to decrease permeability in an inverse manner to EtOH concentration. Further assessment found that dilution of the EtOH levels prior to diafiltration can significantly reduce the amount of ILDF stages needed and that a continuous design requires less buffer to the commensurate batch design