Genzyme Pioneering Continuous Manufacturing In Biotech

By Trisha Gladd, Editor, Life Science Connect

Batch processing has been the standard process for manufacturing pharmaceuticals for over 50 years. However, the lead-up to the patent cliff and then its aftershocks have motivated experts in the industry to take a second look at how they’re producing drugs. One process being looked at as a way to speed up production while also lowering costs is continuous manufacturing. The smaller footprint of a continuous manufacturing model also offers greater supply flexibility for companies who want to expand globally.

One company that has made significant progress in the development of a continuous manufacturing platform for large molecule drugs is Genzyme. I recently spoke with Jason Walther, a staff scientist at Genzyme, about the impact of continuous manufacturing on the industry as well as its potential. Walther works in late-stage cell culture development, which is responsible for process development, developing new technologies, working on new platforms, and transferring products from the research phase to manufacturing.

Trisha Gladd: Continuous manufacturing has been referred to as the future of the biopharmaceutical industry. Would you agree?

Jason Walther: Yes, definitely. It has a lot of potential for biomanufacturing. If you look at the history of other industries, such as the steel industry, there is a pattern where processing moves from batch to continuous as industries mature. We see that transition happening in the pharmaceutical industry with small molecule drugs. There has been some very interesting work coming out of the Novartis-MIT Center for Continuous Manufacturing. When you look at those trends, we definitely think that something similar will happen in the large molecule biopharmaceutical industry as well.

Gladd: What process unit operations still need to be developed, in order to have a truly continuous process in biopharma?

Walther: We have previously demonstrated fully continuous processing for a monoclonal antibody process through drug substance in bench scale. We definitely think something similar can be accomplished with other types of biologics as well. That said, we feel that a shift to continuous processing has the largest impact on the early unit operations—the bioreactor and the capture step. These operations often require large volumes and represent the most cost-intensive part of the process. By integrating these two steps and making them continuous, we can deliver the largest initial benefits. From there, we evaluate processes case-by-case to see if additional downstream steps can also be made continuous as well.

Gladd: Given that the footprint and all of the project sizes can get smaller with a continuous process, where do you see the cutoff of products that could be made continuously?

Walther: You can actually apply continuous processing to both low- and high-demand products. In our experience, the demand you can meet with a continuous process ultimately depends on how high you’re able to drive your cell densities in the bioreactor. If you’re able to generate high cell densities using continuous cell culture, then that really opens doors for what you can do in terms of production.

In typical fed-batch systems, you may average, over the course of the bioreactor, 15 million cells/mL, but there are many reports now demonstrating perfusion systems that can reach significantly higher cell densities. By increasing the cell density, you’re able to increase production per volume of bioreactor, and even with a 500- or a 1000-L disposable bioreactor, you can generate hundreds of kilograms of product per year.

Once you have a bioreactor at these high productivities, the process bottleneck shifts to the downstream side if you rely on traditional batch chromatography steps. This is where continuous purification technology comes into play – by pairing a continuous high-productivity bioreactor with continuous purification systems, we can remove the downstream bottleneck. We’ve been working to develop large-scale downstream operations that can handle, in a continuous fashion, these high productivities from our reactors.

Gladd: Where do you see the biggest impact of continuous processing?

Walther: Initially, I see the impact being made on products that already need to be produced with continuous processing in some form or another. In particular, there are certain products with limited stability that just can’t remain in a fed-batch reactor for multiple days waiting to be harvested. These less stable products already require some sort of perfusion technology to limit their time in the reactor. I see continuous systems impacting these particular products first, just because it’s an obvious entry point.

Gladd: Can a continuous process model survive the rigors of the FDA and tech transfer?

Walther: I think a lot of people have been concerned about the regulatory hurdles around a new mode of manufacturing. However, if you actually look at what regulatory agencies are saying, I think there’s a lot of positive conversation and positive discussion around continuous manufacturing. Janet Woodcock from the FDA, in particular, has called for continuous manufacturing in the pharmaceutical industry. I think, in general, the FDA and other agencies support these types of initiatives, because continuous manufacturing has the potential to improve our processes, products, and product quality.

As to tech transfer, I actually consider that a strength of continuous processing and not a weakness. Because continuous processes have smaller physical footprints than their batch counterparts, we can run manufacturing-scale equipment in our development labs using the same control/automation systems and eliminate scale up altogether when we transfer a process to a commercial environment. This can dramatically reduce tech transfer risk while speeding up timelines.

Gladd:  If the industry does move to continuous processing, it’s a different way of seeing the market. Do you think that’s going to lead to a change in the skill set needed in the industry or a greater demand of a different skill set?

Walther: The same basic scientific principles are required in both batch and continuous systems. Both batch and continuous bioreactors are still growing cells consuming the same types of nutrients and generating product in the same way. On the downstream side, we are still dealing with column chemistry, filters, membranes, etc. I think that there are certainly lessons and learnings specific to continuous systems that we will all need to go through, but I think the same general science and engineering skill sets will still apply.

Something that will change over time is the level of collaboration between upstream, downstream and analytical teams. I think that there is already, across the industry, lots of collaboration between these different groups, but when you actually physically integrate the bioreactor and capture steps, that means, by necessity, that the upstream and the downstream engineers and scientists will be talking more. Anything that happens in the bioreactor will have an almost instant effect downstream. In our labs, we’ve definitely seen even more collaboration across these different groups. Integrating the process has led to a deeper integration of our teams.

Gladd: What are the biggest challenges with continuous processing?

Walther: There definitely are problems to solve, but as we’ve worked through things, we don’t see anything that should be insurmountable. I think the largest challenge may be more around shifting institutional cultures. Batch processing has served the industry well, so it makes sense that we are careful to not leave that immediately. The question will be—can we convince our respective organizations and the biotech industry as a whole that continuous manufacturing is a viable option?