A Discussion Regarding the Productivity in Downstream Operations

Brian Caine (left) and Jonathan Royce (right)
PHOTO BY LEAH ROSIN

At the Biotech Week Boston conference (24–28 September 2017), BioProcess International publisher Brian Caine had the opportunity to speak with Jonathan Royce, global business leader for chromatography resins at GE Healthcare. Their discussion covered current downstream challenges and the company’s next-generation chromatography resin.

Industry Challenges

Caine: What are the most critical purification challenges for biomanufacturers?
Royce: The bioindustry has seen more than a 100-fold increase in the productivity of cells. This means that downstream purification technology must continue to evolve and meet those productivity gains so that purification doesn’t become the rate-limiting step in a process.

Biomanufacturers today seek ways to use their existing equipment more effectively and even incorporate reusable raw materials more effectively. There is a lot of focus on finding ways to get efficient cleaning of chromatography resins and to ensure that they don’t get contaminated by bioburden so that end users get the value out of those resins that they expect.

Protein And Bioburden

Caine: What role does protein A play in purification efficiency?

Royce: I always think of protein A as being the “Holy Grail of antibody purification.” Many people look for alternatives to protein A, but it’s a molecule that has developed over millions of years of evolution to protect bacterial cells against our immune systems. It has a fantastic specificity for antibodies that’s very hard to match with anything we could engineer as an alternative. It also has enabled the market to reach a state in which an antibody can go from drug discovery into manufacturing in a short time.

But at the same time, protein A is becoming a rate-limiting step in many processes because of the increasing upstream titers. The amount of mass coming onto protein A columns is increasing. That means that in many cases, the efficiency of protein A is determining the efficiency of an entire manufacturing facility.

Caine: How does protein A relate to bioburden?

Royce: Bioburden is a main concern in downstream purification today. Some regulatory agencies have asked manufacturers whether they understand sources of bioburden, what is being done to control them, and whether they are testing for it sufficiently. Protein A is challenged in that area because of two main factors. First, the protein A step is loaded with all the cell culture nutrients that cells are grown in. So the load fraction coming onto the protein A step highly promotes bacterial growth. Second, the majority of protein A resins that people use today are somewhat susceptible to damage by sodium hydroxide, which is the most common clean-in-place (CIP) agent used today.

So the highest risk factor for a bioburden outbreak occurs at a step that includes the weakest chemicals to control those outbreaks. That means that in a risk analysis, protein A would stand out as probably one of the most susceptible downstream steps for bioburden contamination.

Introducing MabSelect™ PrismA

Caine: GE Healthcare has just introduced MabSelect PrismA chromatography resin. What makes it unique?

Royce: MabSelect PrismA resin comes from a big effort by GE Healthcare to address two of the main topics that we discussed. One is the throughput of downstream purification and trying to make sure that protein A is not the rate-limiting step in that process. The other is to ensure that protein A columns have a capacity that is on par with the other steps in the process.

Current cation-exchange resins have capacities for MAbs in the range of 80–100 g/L. Protein A historically lags behind that, and there’s no technical reason for that. We felt that it was important to bring protein A up into that same level in terms of capacity and productivity. At the same time, the MabSelect PrismA resin is also designed for the same CIP operations that are used in other steps in a process.

So we went back to the drawing board with the ligand. We have had the MabSelect SuRe™ ligand in our portfolio for over 10 years. It’s been a fantastic part of the story of MAb purification and the “platformability” of MAb processing, but we felt that we could do some additional work based on new technology to find ways to improve its alkaline stability. The new MabSelect PrismA resin has a stability from 0.5 to 1.0 M sodium hydroxide. That means that it can be cleaned with the same CIP solutions that customers are using for ion exchangers and hydrophobic-interaction chromatography resins. It also has capacities in the range of 80 g/L, which make it well matched in terms of capacity to the secondary and tertiary steps in a bioprocess.

Caine: How can MabSelect PrismA help biopharmaceutical companies produce more product with their existing platforms?

Royce: MabSelect PrismA is designed to be an ultrahigh-capacity protein A resin. If you have an existing facility where you have columns or systems in place, those columns and systems can now process much larger loads of antibody than what they previously could do. As upstream titers increase in your bioreactor, your downstream purification can handle those increased loads without having to make additional capital investments to buy larger systems or columns.

Using the MabSelect PrismA resin also opens a bigger window of operation for prepacked columns. Today the largest ReadyToProcess™ column that we have could harvest and purify a high-titer 2,000-L bioreactor. That’s something that we couldn’t do with any previous generation of resins in our portfolio.

As you start to increase capacity and thereby shrink the size of columns in your operations, you also get a lot of secondary effects such as smaller buffer tanks and lower consumption of buffer, which also can be important in terms of making sure that plant efficiency stays high.

Next Steps

Caine: What is next as far as helping companies reduce cost and decrease manufacturing times?

Royce: Going back to your first question about the diversification of the pipeline, I think there will be future opportunities for additional affinity resins that are more specific to the molecule types that companies are developing. There are more than 40 different constructs of bispecific antibodies, some of which can be purified by protein A. But some will require other types of affinity solutions. If you look even farther back in the pipeline, you can see that a lot of new types of therapies are coming, which will require totally new thoughts around production and purification. Some of those therapies are, for instance, too large to be sterile filtered. They are going to require more aseptic processing in the downstream area. Some are too large even to go into a chromatography resin. So there will be opportunities to work with membrane absorbers and other technologies that are less diffusion-limited than chromatography columns are.

I think we’re going to see continued development in the space around new technologies that enable those therapies to come to market and enable them to be manufactured efficiently and cost-effectively.

Learn more: