Protein A Chromatography – A look at where we have been and where we are going


In this podcast and accompanying article, we interviewed Jonathan Royce,  Business Leader, Chromatography Resins, GE Healthcare Life Sciences, about the evolution of Protein A including the latest developments in Protein A chromatography resins. We also discussed what the future holds for this purification mainstay and how it can continue to address the changing needs of biopharma.

Jonathan Royce has over 15 years of experience in the Life Sciences’ field and has held positions in R&D, process development, sales and marketing. Jonathan has a Masters’ degree in chemical engineering from Northeastern University and he resides with his wife and two children in Uppsala, Sweden.

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Show Notes:

We began the interview by discussing how Protein A has become an institution in monoclonal antibody purification and how it has evolved considerably since its first commercial use in the 1980’s. I asked Jonathan which advancements did he consider the most important. He began by describing some of the challenges that protein A has faced and overcome in the decades since it has been in use. He went on to identify the work around increasing alkaline stability of the ligand as the most significant. By applying this technology, proteins have been created that are almost as alkali stable as many chemical ligands. Without this development, it would have been difficult for protein A to remain the go to step in antibody purification.

Next we discussed why it has been so important for protein A to have continued evolution. He said that the industry has almost every five years had some kind of new challenge in terms of what is the rate limiting step, scalability, time, and volumetric scale. Had protein A remained the way it was in the early 80’s, other technologies would have replaced it. Protein A is a relatively costly resin class and generational improvements have led to better cost position and lower cost of ownership. It is also important for protein A to keep up with the other technologies that surround the protein A step to ensure it is well matched in terms of capacity and throughput.

Then we talked about how GE is furthering those advancements with the September launch of a next generation of protein A resin called MabSelect PrismA™. MabSelect PrismA is designed to respond to two main challenges – the mass throughput issue on the protein A step and continued improvements in upstream technology, i.e., rise in titers. PrismA’s capacity is well matched to upstream titers and high throughput. It was also designed to address the risk of a bioburden contamination on the protein A column. Since protein A columns historically have required cleaning with weaker CIP chemicals, they tend to be more prone to contamination. PrismA’s new ligand stability permits the use of stronger cleaning chemicals.

Next I asked Jonathan to describe how PrismA is different from the other MabSelect resins. He explained that it is a new generation ligand with a new agarose bead that employs new technology in the bead manufacturing process. It has a rigidity that supports very high flow rates. For the first time the resin was optimized in parallel, with the team that creates the agarose beads working with the team that engineers ligand stability. This enabled the teams to create the optimal situation for both.

I wanted to ask Jonathan about a concern that comes up regularly, protein A pricing and the significant contribution to overall cost. Jonathan said that the strategy at GE is to stay at the forefront of technology development. He said that follow on technologies don’t provide the long term benefits or additional cost reduction. The key is to look at current challenges and design a resin that address them at a price that provides savings. Then you start that process again with the next set of challenges. Every new generation of protein A resin leads to a better cost position overall.

I asked how GE addresses supply chain stability with products that have no other exact match. He said that they are well aware that many of the products offered are single sourced. Working to secure their own supply chain and ensuring that they will always be able to provide these products to the market is a top priority. This begins with securing a second supplier of agarose, facility investments in Uppsala and redundant manufacturing. It also means expanding manufacturing areas to stay ahead of market demand and maintaining full control of manufacturing processes.

I asked Jonathan to tell me what he saw as the next set of advancements for protein A. He said that there is a lot of activity  looking at converting the protein a step to continuous operation.  This would mean more protein A columns in the process than today, but smaller. Smaller means more opportunity for protein A to take advantage of pre-packed technology. These continuous process opportunities may require some custom versions. For example in 2015, MabSelect Sure PCC was created for continuous manufacturing. It offers higher capacity at higher residence times, which is a key parameter for high productivity in a continuous process.

With an increase in diversification of antibody structures in general, protein A will have to adapt to address these different target molecules. There is a potential for protein A to be offered in several tailored versions based on antibody structure or other types of ligands that address a bigger portion of the non-fc region containing antibody library. Advancements required are achievable with close collaboration between suppliers and end users to provide a more tailor fit solution.

Jonathan closed by saying that protein A is a fascinating area having been a relatively recent discovery, less than 60 years. It took a long time to see its potential in purification. Over the years, alternatives to protein A have been identified and work, but none offer the broad applicability and ease of use. So given its ease of use and its fascinating root in nature, protein A will continue to be an important part of antibody manufacturing in the future.

To learn more: MabSelect PrismA a next generation Protein A resin