Process intensification in biomanufacturing driven by advances in single use technologies

Single use technologies now represent the state of the art in biomanufacturing, but still the full potential of a broad application has not been tapped yet. One strategy that captures most of disposable benefits is process intensification. Here single use systems are optimized to achieve similar output levels as traditional stainless-steel facilities but at much lower capital expenditure, smaller footprints and faster implementation times. This presentation gives an overview on current approaches, describes the opportunities and limits of disposables and delivers recommendations to what should be done by suppliers and users in the near future

Scalable mRNA machine for regulatory approval of variable scale between 1000 clinical doses to 10 million manufacturing scale doses

The production of messenger ribonucleic acid (mRNA) and other biologics is performed primarily in batch mode. This results in larger equipment, leaning/sterilization volumes, and dead times compared to any continuous approach. Consequently, production throughput is lower and capital costs are relatively high. Switching to continuous production thus reduces the production footprint and also lowers the cost of goods (COG). During process development, from the provision of clinical trial samples to the production plant, different plant sizes are usually required, operating at different operating parameters. To speed up this step, it would be optimal if only one plant with the same equipment and piping could be used for all sizes. In this study, an efficient solution to this old challenge in biologics manufacturing is demonstrated, namely the qualification and validation of a plant setup for clinical trial doses of about 1000 doses and a production scale-up of about 10 million doses. Using the current example of the Comirnaty BNT162b2 mRNA vaccine, the cost-intensive in vitro transcription was first optimized in batch so that a yield of 12 g/L mRNA was achieved, and then successfully transferred to continuous production in the segmented plug flow reactor with subsequent purification using ultra- and diafiltration, which enables the recycling of costly reactants. To realize automated process control as well as real-time product release, the use of appropriate process analytical technology is essential. This will also be used to efficiently capture the product slug so that no product loss occurs and contamination from the fill-up phase is <1%. Further work will focus on real-time release testing during a continuous operating campaign under autonomous operational control. Such efforts will enable direct industrialization in collaboration with appropriate industry partners, their regulatory affairs, and quality assurance. A production scale-operation could be directly supported and managed by data-driven decisions

Potential of duckweed for swine wastewater nutrient removal and biomass valorisation through anaerobic co-digestion

Over the last decades, phytodepuration has been considered an efficient technology to treat wastewaters. The present study reports a bench scale depuration assay of swine wastewater using Lemna minor. The highest observed growth rate obtained in swine wastewater was 3.1 ± 0.3 gDW m−2 day−1 and the highest nitrogen and phosphorus uptake were 140 mg N m−2 day−1 and 3.47 mg P m−2 day−1, respectively. The chemical oxygen demand removal efficiency in the swine wastewater assay was 58.9 ± 2.0%. Furthermore, the biomass valorisation by anaerobic co-digestion with swine wastewater was assessed. Results showed a clear improvement in specific methane production rate (around 40%) when compared to mono-substrate anaerobic digestion. The highest methane specific production, 131.0 ± 0.8 mL CH4 g−1 chemical oxygen demand, was obtained with a mixture containing 100 g of duckweed per liter of pre-treated swine wastewater. The water-nutrients-energy nexus approach showed to be promising for swine waste management.info:eu-repo/semantics/publishedVersio

Advanced control strategies for bioprocess chromatography: Challenges and opportunities for intensified processes and next generation products

Recent advances in process analytical technologies and modelling techniques present opportunities to improve industrial chromatography control strategies to enhance process robustness, increase productivity and move towards real-time release testing. This paper provides a critical overview of batch and continuous industrial chromatography control systems for therapeutic protein purification. Firstly, the limitations of conventional industrial fractionation control strategies using in-line UV spectroscopy and on-line HPLC are outlined. Following this, an evaluation of monitoring and control techniques showing promise within research, process development and manufacturing is provided. These novel control strategies combine rapid in-line data capture (e.g. NIR, MALS and variable pathlength UV) with enhanced process understanding obtained from mechanistic and empirical modelling techniques. Finally, a summary of the future states of industrial chromatography control systems is proposed, including strategies to control buffer formulation, product fractionation, column switching and column fouling. The implementation of these control systems improves process capabilities to fulfil product quality criteria as processes are scaled, transferred and operated, thus fast tracking the delivery of new medicines to market

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

Process automation and control strategy by Quality-by-Design in total continuous mRNA manufacturing platforms

Vaccine supply has a bottleneck in manufacturing capacity due to operation personnel and chemicals needed. Assessment of existing mRNA (messenger ribonucleic acid) vaccine processing show needs for continuous manufacturing processes. This is enabled by strict application of the regulatory demanded quality by design process based on digital twins, process analytical technology, and control automation strategies in order to improve process transfer for manufacturing capacity, reduction out-of-specification batch failures, qualified personnel training and number, optimal utilization of buffers and chemicals as well as speed-up of product release. In this work, process control concepts, which are necessary for achieving autonomous, continuous manufacturing, for mRNA manufacturing are explained and proven to be ready for industrialization. The application of the process control strategies developed in this work enable the previously pointed out benefits. By switching from batch-wise to continuous mRNA production as was shown in previous work, which was the base for this study, a potential cost reduction by a factor 5 (i.e., from EUR 0.380 per dose to EUR 0.085 per dose) is achievable. Mainly, based on reduction of personnel (factor 30) and consumable (factor 7.5) per campaign due to the significant share of raw materials in the manufacturing costs (74–97). Future research focus following this work may be on model-based predictive control to gain further optimization potential of potential batch failure and out of specification (OOS) number reduction

Process analytical technology for precipitation process integration into biologics manufacturing towards autonomous operation: mAb Case Study

The integration of real time release testing into an advanced process control (APC) concept in combination with digital twins accelerates the process towards autonomous operation. In order to implement this, on the one hand, measurement technology is required that is capable of measuring relevant process data online, and on the other hand, a suitable model must be available to calculate new process parameters from this data, which are then used for process control. Therefore, the feasibility of online measurement techniques including Raman-spectroscopy, attenuated total reflection Fourier transformed infrared spectroscopy (ATR-FTIR), diode array detector (DAD) and fluorescence is demonstrated within the framework of the process analytical technology (PAT) initiative. The best result is achieved by Raman, which reliably detected mAb concentration (R2 of 0.93) and purity (R2 of 0.85) in real time, followed by DAD. Furthermore, the combination of DAD and Raman has been investigated, which provides a promising extension due to the orthogonal measurement methods and higher process robustness. The combination led to a prediction for concentration with a R2 of 0.90 ± 3.9% and for purity of 0.72 ± 4.9%. These data are used to run simulation studies to show the feasibility of process control with a suitable digital twin within the APC concept

Sensor technologies for quality control in engineered tissue manufacturing

The use of engineered cells, tissues, and organs has the opportunity to change the way injuries and diseases are treated. Commercialization of these groundbreaking technologies has been limited in part by the complex and costly nature of their manufacture. Process-related variability and even small changes in the manufacturing process of a living product will impact its quality. Without real-time integrated detection, the magnitude and mechanism of that impact are largely unknown. Real-time and non-destructive sensor technologies are key for in-process insight and ensuring a consistent product throughout commercial scale-up and/or scale-out. The application of a measurement technology into a manufacturing process requires cell and tissue developers to understand the best way to apply a sensor to their process, and for sensor manufacturers to understand the design requirements and end-user needs. Furthermore, sensors to monitor component cells’ health and phenotype need to be compatible with novel integrated and automated manufacturing equipment. This review summarizes commercially relevant sensor technologies that can detect meaningful quality attributes during the manufacturing of regenerative medicine products, the gaps within each technology, and sensor considerations for manufacturing

Depuração de efluente suinícola por Lemna minor e valorização energética da biomassa por co-digestão anaeróbia

Mestrado em Engenharia do Ambiente - Instituto Superior de AgronomiaOver the last decades, phytodepuration has been considered an efficient technology to treat agricultural wastewaters. Swine wastewater is rich in nutrients that can be used to grow biomass, producing a treated wastewater that can be used for irrigation and a biomass that may be useful for potential energy production by anaerobic digestion (AD). In this study a comparative polishing treatment assays were developed, at a bench scale, through Lemna minor growth in swine wastewater (4%) with similar concentration at a real scale last lagoon and Lemna minor growth in synthetic medium. The highest observed growth rate obtained in swine wastewater was 28.7 ± 2.3 g m-2 day-1 or 3.1 ± 0.3 gDM m-2 day-1. The highest nitrogen and phosphorus uptake rates in swine wastewater system were 140 mg m-2 day-1 and 3.47 mg m- 2 day-1, respectively. The COD removal efficiency was 60.0 ± 1.0%. Furthermore, an integrated approach was investigated assessing possible valorisation of biomass by anaerobic co-digestion of swine wastewater with Lemna minor. Results showed a clear improvement in gas production rate and methane specific production in 40% and 44%, respectively, when compared to mono-substrate digestio