Is it possible to do real-time analysis of aggregates in downstream protein solutions?

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Eighteen BioPhorum Technology Roadmapping Phorum members (eleven end-users and seven supply partners) have joined forces to collaborate on a hands-on downstream proof of concept (POC) project. The practical POC work has just begun at Merck KGaA (Healthcare)’s Corsier-sur-Vevey site in Switzerland and will investigate the real-time analysis of aggregates content in protein solutions during the bind/elute cation exchange step of a mAb process. It will use multi-angle light scattering (MALS) analytical technology provided by Wyatt Technology.

Bind/elute cation exchange chromatography is typically used to control aggregates when purifying monoclonal antibodies. However, current pooling strategies are UV- or volume-based and not triggered by real-time measurements against critical quality attribute thresholds.

These strategies may result in yield and quality variations of the pools and need a safety margin built into the UV-based collection to maintain product quality. However, this leads to sub-optimal yields, which could be improved if the pooling was based on a real-time aggregate breakthrough.

As this is a common strategy for aggregate removal, demonstrating the benefits of pooling using a critical quality attribute rather than a conservative UV threshold is attractive to many companies. It has significant potential for increased process yields, fewer deviations and improved consistency of input to subsequent process steps, all resulting in a reduced cost of goods.

“We expect aggregate monitoring and control to be critical for many of our processes,” said Jonathan Souquet, Global Head of Process Sciences at Merck KGaA (Healthcare). “I expect that if the POC and implementation cycle of this technology by Merck were successful, it would be applied to a number of our processes, facilities, and production lines. Once the technology and capability are built into our development and production infrastructure, it can also be applied for different applications.”

Souquet added, “The path to implementing process analytical techniques beyond exploration and innovation has been limited to date, and the way this project has been structured has its sights on the value-generating implementation pathway.”

The project is a great example of how BioPhorum can help members and industry by gathering a team of world-class, multi-disciplinary experts to devise a solution and facilitate the actual development of a piece of technology. Participating member companies have designed the experimental studies, will jointly analyze the results, collaborate on tackling challenges, and ensure an industry-wide solution instead of an ‘n of 1’.

Moira Lynch, Senior Innovation Leader at Thermo Fisher Scientific, explained that the collaboration had significant benefits. “Technology providers like us often partner with their customers, but this is typically a one-to-one situation. BioPhorum provides a safe space for industry to speak openly about challenges and find solutions together. The broad perspectives included in the discussions make for more robust solutions.”

Gunnar Malmquist, Senior Principal Scientist at Cytiva, added that “the real value of BioPhorum’s approach is bringing together a team that has different resources such as the process understanding, availability of feed material, an opportunity to run the experiments, and someone who understands the analytical aspects. We know that it can be difficult to successfully bring all these elements together at the same time as a single company.”

Carrie Mason, Associate Director of Process Science and Technology R&D at Lonza, said that this activity could happen outside of BioPhorum, but it would not be simple. “I think the headwinds would be very strong. As a CDMO, we might not have the same weight behind us as companies with much larger R&D budgets that could have more influence with a vendor. The advantage with BioPhorumis that it levels the playing field so that even small or medium-sized biotechs or CDMOs can be influential.”

Building a POC using real-time MALS would create a game-changing process analytical tool, but what would the next steps be?

“If we see broad acceptance and the cost benefits of developing comparable process analytical technology (PAT) products for full-scale manufacturing turn out to be favorable, we will need to get to work developing them,” said Geofrey Wyatt, CEO of Wyatt Technology, whose company is providing the MALS technology for the POC project.

Mason added that it was tough to estimate the effect on implementation timescales, but “a new piece of kit that doesn’t tick all the technology readiness indicators might take two or three years before it’s in the development phase. If a technology created by collaboration already answers the feasibility questions, then development might mean it’s only 6–12 months before it would be ready to go to the next stage, e.g., a rollout in a GMP environment.”

With so many benefits, the POC project can be a giant step-change for industry, with collaboration at its heart. “The BioPhorum technology roadmap is reaching a consensus on the requirements for a novel technology that will benefit the entire industry, said Wyatt. “Added to this is working with vendors with unique capabilities to realize and implement that technology. This all holds a lot of promise for every contributing member.”

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