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Continuous Downstream Processing of Bioproducts

Periodic Reporting for period 2 - CODOBIO (Continuous Downstream Processing of Bioproducts)

Reporting period: 2021-02-01 to 2023-08-31

A manufacturing process for biological material consists of the actual production of the product (upstream processing) and product purification (downstream processing - DSP), aiming at releasing a highly pure product. The DSP usually consists of a series of consecutive steps and is mostly done in a batch-wise manner with minimal digitalization or automation. Real-time in-process control is limited and product quality or quantity are not analysed during the production. In the last decade the regulatory framework for manufacturing of biopharmaceuticals has provided guidelines that process development needs to take into account product quality already during production.
A transition to continuous processes has the prospect of better economics and reduced environmental footprint and is highly recommended by authorities but currently only a small fraction of bioproducts is produced in continuous mode.
A reason for the delay in implementation of fully continuous processes is the lack of experience with such new technologies and also the lack of skilled personnel able to develop and apply continuous processes
In recent years, the transition to continuous manufacturing has been recognized as the next step in further optimizing production processes in the bioindustry. Continuous manufacturing offers new opportunities to increase productivity, reduce environmental impact, improve product quality and consistency, and dramatically reduce manufacturing costs, making biologics accessible to a much wider population, including those in non-privileged countries. The significant reduction in the space required for the process will allow the manufacturing process to be carried out in a very small space, e.g. in a container, which can be transported to any location in the world and enable production of sophisticated biologics also in less-privileged countries. Continuous biomanufacturing is considered as a key enabler to arrive at a carbon neutral industry sector: it offers the possibility to enormously save resources such as water and energy and to reduce generation of waste.
The main objective of the CODOBIO project is to deliver creative, entrepreneurial, highly-skilled and innovative Early Stage Researchers (ESR) that are able to face the future transition challenges and to greatly contribute to the knowledge-based economy and digitized environment in manufacturing and society in general. In the proposed research programme, the most urgent questions in continuous DSP have been addressed:
- Process control and modelling of continuous DSP
- Miniaturization, scale-up and scale-down of continuous DSP
- Process design and development of integrated continuous DSP
From the results obtained by the CODOBIO consortium we conclude:
- that it is possible to scale down biomanufacturing processes by microfluidics and obtain relevant information with less material consumption
- that it is possible to define batches/lots based on mathematical models.
- that it is possible to establish a real continuous DSP with a non-interrupted product flow
In CODOBIO ESRs participated in extensive training sessions laying the ground for developing and applying novel technologies. The scientific trainings were accompanied by soft skill trainings equipping them with a set of skills that enables the ESRs to enter into their next career steps.
acib led work package 1 dealing with research work addressing the improved product quality and manufacturability when a process is rendered from a batch to a continuous DSP (NVSP, acib). Continuous integrated biomanufacturing allows the implementation of process control compared to batch processing. To understand the process a model must be developed (acib). Process models are also required to develop a model predictive control (MPC) strategy (EVON). To fully exploit MPC sensors are required and in particular sensors for product related impurities are not readily available (TUD).
WP2 led by IST dealt with the training of ESRs in the specific skills required for miniaturization and scale-up of continuous DSP and trained ESRs on different aspects of microscale bioprocesses, from mixing to miniaturized unit operations (acib, TUD). Focus was given to the development of mathematic models that translate data obtained in the miniaturized systems to lab, pilot and industrial scale equipment. Monoclonal antibodies were used as model systems for the continuous chromatography studies whereas enzymes were the model choice in the batch/continuous extraction studies (IST).
The aim of work package 3 led by POLIMI is to provide the ESRs with the theoretical and practical understanding required to design, develop, monitor and control continuous and integrated processes for the manufacturing of bioproducts. Specifically, this WP explored the integration of different DSP unit operations, not necessarily based on column chromatography (JUB), as well as the upstream and downstream section of a bioprocess. The justification for the activities of this WP came from a detailed economic analysis comparing traditional batch operations and continuous integrated processes, so that ESRs could properly identify advantages and drawbacks of each manufacturing approach (UCL). LU studied the design and realization of a laboratory-scale continuous DSP, implementing a model-based control strategy. Finally, POLIMI investigated the application of PAT tools for the in-line monitoring of continuous upstream and downstream operations, with specific focus on in situ Raman and infrared spectroscopy.
CODOBIO’s scientific work resulted in almost 30 open access publications in peer-reviewed journals. Two patent applications, a record of invention and some other exploitable results applied in industry came out of the project.
15 ESRs were trained to develop and apply continuous DSP. Their individual research projects led to recognizable results leading to innovation in the European biologics industry. Specifically, several devices, methods, processes and algorithms resulted from the project:
• Novel devices for real continuous DSP based on a moving belt adsorber or a fluidized bed riser adsorption system.
• A novel material to operate the adsorber.
• A small-scale buffer management system.
• A computer code for model predictive control of continuous chromatography, which can be used in conjunction with commercially available workstations.
• A millifluidics device for process development of continuous precipitation and flocculation.
• A microfluidic device for monitoring protein aggregates.
• A microfluidics device for measuring the equilibrium parameters of chromatography.
• A microfluids device integrating continuous upstream processing with DSP.
• A rational and model-based strategy to define batches in continuous integrated biomanufacturing.
• A continuous laboratory process for production of PHA.
CODOBIO also contributed to the ICH guidelines Q13 on continuous manufacturing of drug substances and drug products that has been adopted by the European Medical Agency and by the US Food and Drug Administration in 2023 by a rational and model-based strategy to define batches in continuous integrated biomanufacturing.
CODOBIO also contributed to structuring doctoral training at the European level. Parts of the teaching program have been used as best practice for designing the respective doctoral programs in the field of Bioprocess Engineering at the partners BOKU, IST and TUD.