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

Please click Additional Files below to see the full abstract

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

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