Multi-objective biopharma capacity planning under uncertainty using a flexible genetic algorithm approach

This paper presents a flexible genetic algorithm optimisation approach for multi-objective biopharmaceutical planning problems under uncertainty. The optimisation approach combines a continuous-time heuristic model of a biopharmaceutical manufacturing process, a variable-length multi-objective genetic algorithm, and Graphics Processing Unit (GPU)-accelerated Monte Carlo simulation. The proposed approach accounts for constraints and features such as rolling product sequence-dependent changeovers, multiple intermediate demand due dates, product QC/QA release times, and pressure to meet uncertain product demand on time. An industrially-relevant case study is used to illustrate the functionality of the approach. The case study focused on optimisation of conflicting objectives, production throughput, and product inventory levels, for a multi-product biopharmaceutical facility over a 3-year period with uncertain product demand. The advantages of the multi-objective GA with the embedded Monte Carlo simulation were demonstrated by comparison with a deterministic GA tested with Monte Carlo simulation post-optimisation

Continuous bioprocessing: the real thing this time? 10(th) Annual bioProcessUK Conference, December 3-4, 2013, London, UK.

The Annual bioProcessUK Conference has acted as the key networking event for bioprocess scientists and engineers in the UK for the past 10 years. The following article is a report from the sessions that focused on continuous bioprocessing during the 10(th) Annual bioProcessUK Conference (London, December 2013). These sessions were organized by the 'EPSRC Centre for Innovative Manufacturing in Emergent Macromolecular Therapies' hosted at University College London. A plenary lecture and workshop provided a forum for participants to debate topical issues in roundtable discussions with industry and academic experts from institutions such as Genzyme, Janssen, Novo Nordisk, Pfizer, Merck, GE Healthcare and University College London. The aim of these particular sessions was to understand better the challenges and opportunities for continuous bioprocessing in the bioprocessing sector

End‐to‐end continuous bioprocessing: impact on facility design, cost of goods and cost of development for monoclonal antibodies

This article presents a systematic approach to evaluate the business case for continuous processing that captures trade-offs between manufacturing and development costs for monoclonal antibodies (mAbs). A decisional tool was built that integrated cost of goods (COG) with cost of development models and new equipment sizing equations tailored to batch, hybrid and end-to-end continuous processes. The COG analysis predicted that single-use continuous facilities (sized using a dedicated DSP train per bioreactor) offer more significant commercial COG savings over stainless steel batch facilities at annual demands of 100-500 kg (~35%), compared to tonnage demands of 1-3 tons (~±10%) that required multiple parallel continuous trains. Single-use batch facilities were found to compete with continuous options on COG only at 100 kg/year. For the scenarios where batch and continuous facilities offered similar COG, the analysis identified the windows of operation required to reach different COG savings with thresholds for the perfusion rate, volumetric productivity and media cost. When considering the project lifecycle cost, the analysis indicated that while end-to-end continuous facilities may struggle to compete on development costs, they become more cost-effective than stainless steel batch facilities when considering the total out-of-pocket cost across both drug development and commercial activities. This article is protected by copyright. All rights reserved

Estimating capital investment and facility footprint in cell therapy facilities

Estimations of the facility footprint and fixed capital investment (FCI) of cell therapy (CT) facilities need to consider the unique features of the single-use technologies (SUTs) selected for CT manufacture (e.g. cleanroom containment requirement, capacity, automation) and the product nature that impacts scale-out versus scale-up approaches. A novel detailed factorial methodology is proposed for estimating FCI and footprint for bespoke stick-built cell therapy facilities that accounts for technology-specific factors for key cell culture technologies as well as the implications of SUTs, open versus closed operations and the commercialisation scenario selected. This was used to derive benchmark values for short-cut cost and area factors for typical cell therapy facilities according to the technologies selected. The results provide project-specific ratios for equipment purchase costs to facility footprint (area factor) and for FCI to total equipment purchase costs (cost factor or “Lang” factor). Area factors ($/m2) were 675-6,815 and the cost factors were 2.3–8.5 for a greenfield project in a medium-developed country. The case study shows that for the same output, facility footprints and FCI values are on average 6 times higher for autologous processes than allogeneic processes. This is attributed to economies of scale achieved with scale-up for allogeneic cell therapy manufacture. This study can be used to predict the commercial FCI and facility footprint during early stages of process development

Integrated continuous bioprocessing: Economic, operational, and environmental feasibility for clinical and commercial antibody manufacture

This paper presents a systems approach to evaluating the potential of integrated continuous bioprocessing for monoclonal antibody (mAb) manufacture across a product's lifecycle from preclinical to commercial manufacture. The economic, operational, and environmental feasibility of alternative continuous manufacturing strategies were evaluated holistically using a prototype UCL decisional tool that integrated process economics, discrete-event simulation, environmental impact analysis, operational risk analysis, and multiattribute decision-making. The case study focused on comparing whole bioprocesses that used either batch, continuous or a hybrid combination of batch and continuous technologies for cell culture, capture chromatography, and polishing chromatography steps. The cost of goods per gram (COG/g), E-factor, and operational risk scores of each strategy were established across a matrix of scenarios with differing combinations of clinical development phase and company portfolio size. The tool outputs predict that the optimal strategy for early phase production and small/medium-sized companies is the integrated continuous strategy (alternating tangential flow filtration (ATF) perfusion, continuous capture, continuous polishing). However, the top ranking strategy changes for commercial production and companies with large portfolios to the hybrid strategy with fed-batch culture, continuous capture and batch polishing from a COG/g perspective. The multiattribute decision-making analysis highlighted that if the operational feasibility was considered more important than the economic benefits, the hybrid strategy would be preferred for all company scales. Further considerations outside the scope of this work include the process development costs required to adopt continuous processing. © 2017 The Authors Biotechnology Progress published by Wiley Periodicals, Inc. on behalf of American Institute of Chemical Engineers Biotechnol. Prog., 2017

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

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

Cost-effective bioprocess design for the manufacture of allogeneic CAR-T cell therapies using a decisional tool with multi-attribute decision-making analysis

Reimbursement pressures have resulted in an increased awareness of the importance of estimating and improving manufacturing costs for cell therapy products. This work describes the development and application of a decisional tool capable of computing the manufacturing costs for an allogeneic CAR-T cell bioprocess. The tool was used to facilitate a comparison of the impact on cost of goods (COG) from the use of different process technologies including T-flasks, gas permeable vessels, rocking motion bioreactors, an integrated processing platform, MACS purification and spinning membrane filtration technology. Seven different process flowsheets were compared and the economic drivers of manufacturing costs were analysed. COG per dose values were compared against a specified target selling price (TSP) to understand the feasibility of achieving a target COG as % TSP. Finally, a multi-attribute decision-making (MADM) analysis was conducted in order to allow preference of process design to be determined on the basis of qualitative and quantitative operational attributes, rather than COG alone. The flowsheet containing rocking motion bioreactors, spinning membrane filtration technology and a MACS purification platform was found to result in the lowest COG value. The MADM analysis indicated that this was also the preferred flowsheet when qualitative operational attributes were also considered. Furthermore, process attributes such as viral transduction efficiency and electroporation efficiency were found to be key process economic drivers

Integrated economic and experimental framework for screening of primary recovery technologies for high cell density CHO cultures

Increases in mammalian cell culture titres and densities have placed significant demands on primary recovery operation performance. This article presents a methodology which aims to screen rapidly and evaluate primary recovery technologies for their scope for technically feasible and cost-effective operation in the context of high cell density mammalian cell cultures. It was applied to assess the performance of current (centrifugation and depth filtration options) and alternative (tangential flow filtration (TFF)) primary recovery strategies. Cell culture test materials (CCTM) were generated to simulate the most demanding cell culture conditions selected as a screening challenge for the technologies. The performance of these technology options was assessed using lab scale and ultra scale-down (USD) mimics requiring 25-110mL volumes for centrifugation and depth filtration and TFF screening experiments respectively. A centrifugation and depth filtration combination as well as both of the alternative technologies met the performance selection criteria. A detailed process economics evaluation was carried out at three scales of manufacturing (2,000L, 10,000L, 20,000L), where alternative primary recovery options were shown to potentially provide a more cost-effective primary recovery process in the future. This assessment process and the study results can aid technology selection to identify the most effective option for a specific scenario