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Next-generation biopharmaceutical downstream process

Periodic Reporting for period 3 - nextBioPharmDSP (Next-generation biopharmaceutical downstream process)

Reporting period: 2018-03-01 to 2019-02-28

The scope of the project is the optimization of downstream processing (DSP) for the production of Biopharmaceuticals. Biopharmaceuticals have been successfully used as efficient therapeutic drugs for many pathophysiological conditions since the first recombinant product, insulin, was approved in 1982. Despite its efficacy, accessibility is still limited due to extremely high costs. In the production chain, capturing and purifying still represents a major bottleneck. Consequently, improvements in this area produce substantial cost reductions and expand patients’ accessibility to highly efficient drugs. Another aim of this action is to cope with the changing manufacturing demands, by lowering its environmental footprint and moving to more sustainable technologies.
The project’s main objective was to implement a fully integrated continuous manufacturing platform based on continuous purification, viral clearance and final Ultrafiltration/Diafiltration (final drug substance formulation) process unit operations, in combination with single-use disposable techniques. All unit operations of monoclonal antibodies DSP sequence on manufacturing scale were integrated together with incorporation of advanced analytical tools (PAT - Process Analytical Technology analytical tools).
In specific work packages we focused on primary separation, where the removal of cells from product takes place. There the aim was substitution of the standard process for primary separation with the utilization of flocculants in combination with filtration or for fully continuous bioprocess (perfusion process) also implementation of tangential flow filtration (TFF). This resulted in substantial reduction of cost and in robust process for removal of cells from the product. In capture step development studies, we focused on continuous chromatography on protein A resin, where the main aim was reduction in size of the columns and reduction of need for expensive resin volume and highly improved productivity. For implementation of such process on manufacturing scale also single use continuous chromatography equipment was developed. Additionally non-chromatographic capture step alternatives, such as continuous precipitation, were explored as a future approaches for purification of biopharmaceuticals. Single-use disposable technology for all downstream processing operations was evaluated and flow-through approaches for polishing steps implemented, to remove impurities in a continuous way. Other options for processing of biopharmaceuticals in a continuous way were also implemented, such as continuous virus inactivation and different continuous UF/DF techniques as part of continuous final DS formulation approach. Best performing technologies were selected and implemented on large scale continuous and integrated process, where we achieved reduction in the size and number of downstream unit operations. In order to monitor and control the established process, advanced analytical tools for measuring impurities, product content and other parameters in real time or close to real time were implemented.
Large scale continuous and integrated process was successfully validated and showed many benefits. Most important ones were more efficient drug production processes, with reduced costs, and greater productivity, flexibility and competitiveness – ultimately leading to greater patient accessibility and lower burdens on healthcare systems. A second aim was to create a more sustainable process, with a reduction in the amount of consumables and water used, leading to reduced environmental footprint of the biopharma industry and reduced investment and operating costs for companies.
Main work performed within nextBioPharmDSP project is described below.

WP1 - Management:
- administrative, financial, scientific and innovation coordination successful
- 9 consortium meetings organized, 7 business plans prepared for main innovations

WP2 - Primary Separation
- Continuous perfusion bioprocess developed on ATF and TFF (scaled up and connected to DSP)
- Primary separation for fed-batch bioprocess: several options evaluated and flocculation (pDADMAC) + filtration scaled-up for WP7

WP3 - Capture Step
- Multi-column continuous chromatography (MCC) process developed and optimized and PC approach prepared
- IEX-PCCC process developed and optimized based on mechanistic modelling
- Continuous precipitation process on 2 TFF systems developed

WP4 - Continuous chromatography equipment
- Single use MCC system successfully developed and validated together with flexware assembly

WP5 - Disposable DSP
- Continuous low pH viral inactivation approach developed and confirmed and large scale equipment developed
- mAb flow-through template optimized and scaled up for WP7 and large scale equipment redesigned to fit selected process
- AEX, CEX and HIC type based membrane adsorbers evaluated
- Disposable UF/DF device and SPTFF approaches evaluated for continuous product concentration

WP6 - Advanced analytical tools
- AAT were developed for content and impurity monitoring (UV/Vis & FTIR PLS-based peak deconvolution models with flowVPE device, QCM), particle monitoring (FBRM and lab-on-a-chip)
- AAT successfully integrated in WP7 and validated

WP7 - Final process
- Technical run on large scale successful and some improvements/learnings implemented for validation runs
- Three validation runs on large scale performed successfully on 1000L bioreactor scale and connected and continuous DSP, with AAT integrated
- Process showed expected cost and environmental benefits and increased productivity

WP8 - Dissemination and exploitation
- Communication activities (newsletters, press releases, promotional video, webpage)
- Dissemination activities (presenting on 50+ conferences, 19 accepted scientific publications and 10 more in preparation, 4 general publications, 7 workshops)
- Exploitation – 7 business plans prepared for main innovations
- Communication and collaboration with main stakeholders and international initiatives and organizations important part of the project
The project will contribute to the KETs:
-The action is expected to develop technology building blocks representing real progress towards better health and enable a broader patient access to biopharmaceuticals.
- Creating new and breakthrough technologies will boost competitiveness, job creation and growth, as well as build more efficient and cost effective DSP (help to achieve the EU’s Industrial policy’s goals; EU’s global competitiveness - the reduction in required initial investments and in running costs enables fast diffusion of the technology; companies involved gain resources to reinvest in further R&D and job creation)

The project results should eventually lead to:
- Broader patients’ accessibility to highly efficient biopharmaceuticals;
- Smaller Health Care System burden;
- Highly efficient as well as more sustainable production processes;
- Reduced utilisation of materials (chromatography resins, buffers, water) will substantially decrease the environmental footprint of the proposed process;
- Further environmental benefits: large decrease in water consumption and reduction of relative CO2 emissions;
- Sizable reduction of required investments and operating costs (smaller buildings, lower facility footprint - reflected in reduced running costs and decreased energy consumption);
- Increased production flexibility when changing between different products;