Acceleration of commercialization of biologics including the filing of a robust control strategy is of utmost importance for biosimilars up to new modalities. Digital twins capture CMC knowledge and allow multiple deployments. This contribution shows how end-to-end digital twins.

• Save 50% of experimental effort by incorporating drug substance specification when designing CMC control strategies for the process chain and
• Allow for the identification of critical process parameters, which influence the process chain holistically.
• Allow for prediction and control on process performance in real time application and therewith allow for real time release testing and avoiding batch failures.

In the slowly evolving landscape of bioprocess development and manufacturing, digital bioprocess-twins have emerged as potential accelerators. While advanced algorithms are at the heart of this endeavor, they are just one piece of the puzzle. The talk delves into key discussion points that are integral to this paradigm shift. The foundation of accelerated process development and automated process control starts with a clever experimental design, in-time data accessibility combined with powerful modeling algorithms. The talk will highlight the advantages of using hybrid modeling, while emphasizing the other critical aspects on his journey. Several industrial relevant upstream showcases for microbial and mammalian cell lines will be highlighted. Thereby, concepts to save experimental effort by up to 70% will be elaborated, and the modeling structure created in the late-stage development will be reused for real-time monitoring and control in the later stages. Additionally, a downstream optimization showcase for UF/DF/SPTFF will be highlighted.

• Lessons from history
• Viral testing; no one method is perfect.
• Viral inactivation and removal
• How does viral control differ for cell and gene products?

Expanded bed adsorption promised to revolutionize downstream processing by combining clarification and capture chromatography into one step. However, due to the reliance on a perfectly fluidized bed this technology faced significant issues including poor and unstable fluidization due to complex feed streams, fouling and ultimately bed collapse. This concept has been reimagined in the form of a stable, monolith structure containing an array of uniform self-supporting channels. Printed Monolith adsorption (PMA) is a 3D printed chromatography column capable of direct purification of biological molecules from both whole cell culture and crude cell lysate. This talk describes both the use of this technology on the purification of his-tagged proteins from crude bacterial cell lysates and antibodies from high density mammalian cell culture. PMA purifications show equivalent purity to a traditional downstream clarification and capture chromatography process while significantly shortening purification time by up to two thirds. Routine lab-based purification can be completed within one hour from cell culture to highly pure product. PMA has also reached pilot scale with column volumes of 1 L with discussion regarding reaching the next column size of 10 L for the future of preparative chromatography.

Improvement in cell culture titers has directed demands on process intensification to reduce the bottleneck in downstream manufacturing facilities. Accordingly, in-process volume during downstream operations has risen significantly, straining capacities on the downstream unit operations. To address these challenge inline ultrafiltration technologies for volume reduction as modification to platform purification technologies scheme seems promising. We evaluated competing technologies: one based on countercurrent flow channels with a built-in fixed retentate restrictor, and second one with traditional 3X membrane PES based ultrafiltration membrane cassettes with added retentate restriction by plate dividers. Lab study studies showed that 3 membrane configuration gives the best outcome and was used for estimation of flux mAb concentration at constant feed flow rate and mAb load. Factors impacting volumetric concentration factor (VCF) were also evaluated to assess SP-TFF fit to downstream process in manufacturing prior to the AEX (Q) step. Results suggested that both competing technologies perform similarly in terms of VCF, inlet TMP or residence time showed the greatest impact on the VCF factor, with no impact on the product quality seen. Studies suggest that SP-TFF can be implemented as a process intensification tool to reduce in-process volumes significantly and can be implemented without much changes to a purification platform. UFDF modelling was also performed using Dynochem in-built tools and with modified recirculation loop. Modelling study shows that the VCF impact due the viscosity modulation within 10-40 g/L mAB concentration range is minimal. This technology has the potential to be an efficient process intensification tool for the high titer mAB processes and for controlling in-process volumes.

• Substantially improved product quality.
• Significantly higher productivity.
• Markedly lowered costs.
• Appreciably lower footprint.
• Closed system, facilitating sterile operation.

Bridgewest Ventures is partnering with the government, researchers and entrepreneurs in New Zealand to change the status quo. By creating a decentralized model for accelerating the development and manufacture of cutting-edge therapeutics that could save patients lives, worldwide. Bridgewest is building an end-to-end ecosystem for biomanufacturing of CAR-T cell and cell therapies by creating and investing in start-ups which fit into the value chain. The incubated ventures are able to leverage the broader Bridgewest Group portfolio, creating a unique end-to-end CAR T-cell development and manufacture offering. “This ecosystem could cut the development of novel cancer immunotherapies from an average of 3 years to just 9 months and make it available in New Zealand at a fraction of the current cost”

• Approaches to reduce the variability and address scalability challenges of advanced therapies
• Demonstrating the consistent and scalable expansion of CAR-T cells from multiple donors in stirred-tank bioreactors
• Establishment of novel process control strategies to achieve cell therapy process intensification
• Role and scope for adaptive manufacture in the development of novel advanced therapies
• Integration and implementation of artificial intelligence and digital twins to support process modelling and cell therapy manufacture