Tipping the Scales: The Benefits of Continuous Bioprocessing

As cost pressures for drug developers persist, there is an inevitability that the industry will transition to continuous processes to overcome the limitations of traditional batch fed manufacturing.

For decades, the bio/pharmaceutical industry operated with a scale-up philosophy, which led to companies building increasingly massive facilities, housing large-volume stainless-steel bioreactors, to meet global demand for biologics. While this fed-batch approach provides the consistency and microbial security needed, it is also associated with a staggering cost and a lack of flexibility that left manufacturers with rigid, fixed-asset legacies.

Today, that paradigm is shifting from scale-up volume to scale-out intensity, and through continuous manufacturing, companies are discovering they can achieve the output of the large-volume bioreactors with much smaller footprints. To find out more about the evolution and benefits of continuous bioprocessing, The Pharma Navigator spoke with Russell Miller, Vice President, Global Sales and Marketing at Enzene.

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An Evolution Towards Continuous

TPN: Historically, there has been a tendency to equate scale with volume within the bio/pharma industry; however, this is now shifting towards intensity instead. How does continuous manufacturing allow companies to scale out rather than scale up, and what does that mean for the lifecycle management of a biologic?

Miller: When you're looking at capacity in the industry, historically, cost of goods has always been an important component of drug product manufacturing. With the original set of biologics, these were really good therapies, but they also required a fairly large dose: so, with that combination — a therapy that has a global impact and a requirement for a large dose — it’s easy to see how the industry scaled in progression for building out fed batch processes from 2,000 to 5,000 to 10,000 to 15,000 to 20,000 to 35,000 liters. And, in the initial days, perfusion was a good technology, it created products consistently, but the challenge in the early stage, from my view, is the microbial ingress, and that risk could be, and was, mitigated by moving to a fed batch process.

So, when looking at the risk mitigation strategies and the challenges, 20 years ago, fed batch just made a lot of sense. However, looking at the state of technology today, the growth of titers in cell lines, and the different tools that teams have available to them for manufacturing and intensified processes, there is a greater flexibility, and when you can utilize an intensified process, whether it's an N-1 intensification or a continuous manufacturing process, it is possible to create an output that is the requirement for a given therapeutic. Additionally, there is less of an impact on the capital outlay necessary to build out such plants, maintain the plants, and potentially there’s even more flexibility in how commercial supplies are managed. Therefore, the evolution of advanced bioprocessing points us in the direction of continuous.

Challenges of Traditional Approaches

TPN: Recent years have exposed the fragility of global supply chains, so, how does the compact/modular nature of continuous manufacturing enable a more decentralized manufacturing strategy that batch processing is unable to support?

Miller: One of the biggest challenges to 20,000, 30,000, 50,000-liter bioreactors is that they require a lot of skill, time and effort, and capital to put these facilities in place. I mean, while you could conceive of a design for what you would want to do, to implement that design can take anywhere from four to five years, and then you have to have a skill base available to be able to take advantage of it.

Additionally, we're not talking about USD 50 million, we're talking about USD 500/600/700 million. I guess if the plans were for just a 2,000-liter bioreactor or single use one, you might only need to spend a couple hundred million to put that facility in place, but that's still a lot of money! So, when you can utilize an advanced bioprocessing technology that has a much more compact footprint — whether it's 1,500 square feet, 2,000 square feet/150 square meters, 200 square meters — then you have a facility that is much more efficient, in space, it's much more capital efficient, and, depending on the actual process itself, you have scalability that offers output potential that might be the exact amount of material you would need for localized or regional manufacturing.

Then, if you can plug that facility in to a network that's already existing — meaning there is already a team of support in the background that's developed the process, validated the process, and can simply tech transfer it — you have enabled regionalized manufacturing to enable that country, that region, to support materials, especially in terms of crisis elements, such as those experienced during COVID, where they don't have to rely on these hubs of manufacturing that exist in Asia, or Europe or the U.S.

Now, that’s not to say that other places don't have biologics drug substance; however, there are a lot of countries that do not have it, and so, they're looking at ways of how to efficiently and effectively mobilize resources to create biologic drug substance capability in that region, in a way that makes sense, and that, frankly, is affordable.

The Biggest Gains

TPN: Beyond the obvious reduction in facility footprint, what are the other long-term efficiencies companies can gain through continuous manufacturing versus traditional batch processes? Are there any particular areas where the biggest gains are being seen, from your experience?

Miller: The biggest gain is if you can have an intensified process that operates in a 150 square meter or 1,500 square foot space and provides the same output as a 10,000-liter bioreactor. That efficiency drives directly down into cost of goods, and means that teams can take an existing plant, and can reconfigure it to an intensified process at a much lower capital outlay versus having to basically scrap a plant and do a rebuild.

What do I mean by that? If you have a 10,000-liter bioreactor, that's a stainless steel, fixed-in-place process, the only way that is changing is if you completely strip that process out. Now, if you have an advanced bioprocessing technology, such as our EnzeneX fully connected continuous manufacturing technology, that has modularity built into it, then you can essentially have one footprint, one very compact space, that can allow you to customize, more readily, your output demand with your commercial supply forecast. For example, if the output requirement is a 10,000-liter bioreactor, well, that means a 1,000-liter bioreactor in our system.

However, there's much more to consider because, especially if you're on a continuous platform where you've set the design space to be able to manufacture at 25, 30, or 35 days, not only can I customize my output based on my bioreactor size, I can further customize my output based on the time that I take to do that manufacturing.

There are multi-levels to advanced bioprocessing. When you have a 10,000-liter bioreactor, it's a fed batch process, that's a fixed asset, and it isn't changing unless you rip it out. And you get to make what you make in 20 days, plus or minus a day. So, you pretty much have a fixed output. When you have an advanced bioprocessing technology, like the EnzeneX platform, not only can you customize the bioreactor size to scale your output very quickly — these are single-use bioreactors, so they're roll-in, roll-out — you can also customize the output based on how long you manufacture. So, it's a lot of flexibility that you build into your future commercial supply, and honestly, lifecycle management.

Managing the Investment

TPN: The initial investment in continuous manufacturing infrastructure and the complexity of tech transfer can be daunting. For company decision-makers, at what point does the agility provided by continuous manufacturing outweigh the investment costs?

Miller: We're in a traditionalist and highly regulated environment, and when you bring something new into that environment, you have to help the regulators understand that you still have control of the process. There’s nothing crazy about that, it's just you have to make sure it's well-defined and that you have the right data sets to ensure that the regulatory agencies understand what you're doing.

In our case, for intense, advanced bioprocessing, there's literally nothing new in the component set that is different. Does it require a bit of a different skill set than a fed batch? A little bit, yes. I mean, it is necessary to have to upskill folks from how they manage a fed batch process with how they manage a continuous process. But, for a team that's already doing bioprocessing, that upskill is not super difficult, it’s actually fairly straightforward.

Enzene is in a unique position, because we actually run an academy in-house that incorporates full-on coursework, over several months, that helps people go from basic bioprocessing skills to advanced bioprocessing. So, that skill up, that investment is much more manageable.

Then, if the choice is about adding a 20,000-liter bioreactor manufacturing plant — a fixed asset, with an output that is never going to change — or to take an advanced bioprocessing technology — such as the EnzeneX platform that has modularity, output flexibility, and output scale, that aligns to being able to supply a product on a global market in the hundreds to 200s to 300s kilogram plus — the initial investment is an important element to recognize, but it's not insurmountable.

If I'm doing a comparative analysis on where my risk lies and my challenge points are for a team that already does, bioprocessing, that skill up is a small challenge versus the investment issue. So, I think it's important to recognize that it's a necessity, but it shouldn't be a limiting factor.

Need for Educational Engagement

TPN: You discussed upskilling, but industry is potentially facing a skills gap in the future for bioprocessing: so, from a leadership perspective, how can industry negotiate such an issue to ensure there are sufficient engineers and operators with the appropriate capabilities to manage continuous processes in the future?

Miller: We’re tackling this issue internally, because we recognize that there's a need to enhance the skill base for bioprocessing, and, I think, as an industry, what we can do is engage: Engage with university, engage at conferences, highlight what that demand profile looks like, help educate universities on what the skill set is so that they can define the programs for the industry need.

So, for us as industry and leaders, it's a little bit of education back into academia to help them understand what it is that we need, and once the universities understand that need, they're like, ‘oh, wow, okay, cool’. Now, there are universities all across the U.S., that have put this understanding in place for the small molecule space and it really just needs to be upgraded to support the bioprocessing arena, because as we move forward, the number of chemical entities coming into development are being dominated by new biological entities versus new chemical entities, and, so, advanced bioprocessing isn't going to go away, in fact, it's just going to get more innovative as time goes on.

Realizing the Benefits of Continuous

TPN: Looking ahead, do you believe that batch manufacturing could be seen as a legacy niche for specific modalities, or do you anticipate that batch and continuous processes will continue to coexist in a hybrid model? What do you think is the one factor that could finally tip the scales toward continuous manufacturing becoming the industry standard?

Miller: Well, I think anybody who's talked to me in any length of time probably knows what I think about that, but essentially, there’s thousands and thousands of liters of capacity in fed batch, and none of that's instantly going to go away. I think that capacity will be here, not indefinitely but certainly, for a period of time. Do I think that we will transition away from fed batch and utilize advanced bioprocessing? Absolutely. Without a doubt. There are too many gains to be realized.

For the folks that are holding on to fed batch being the gold standard, all I can share with them is the data. We have data, years of data, that demonstrate that we can take fed batch processes and put them into a continuous mode, and we can realize benefits of product quality, efficiency, productivity, reduction in cost of goods, which are only going to get better with advanced bioprocessing. It’s only going to be more challenging for fed batch processing in the future.

So, will fed batch go away? Yeah, it will. Is it going to go away tomorrow? No, it won't. We’re going to see fed batch for decades to come but there will be a tipping point where it will go away. I mean, when you look at drug pricing today, it's hard for everybody, because governments want prices to be moderated so patients have access, and you have all kinds of initiatives everywhere around that issue. You have to have more effective manufacturing, because the cost of therapy is going to come down, and that impact is also going to change the dynamic.

I think there's always a lot to say in continuous. As you can imagine, I think we have a fantastic technology platform, but the reality is that other teams are going to be coming up with other advanced bioprocessing, and I think that there's a lot of innovation ahead of us in the space, and there's going to be a lot of opportunities for folks to make a difference, and, ultimately, positively impact patients' lives.

About the Speaker

Russell Miller is the Vice President, Global Sales and Marketing at Enzene. Russell is a results-oriented business development leader with over two decades of experience driving growth in the pharmaceutical and biotech industries. His expertise spans analytical services, formulation development, and manufacturing, providing him with a deep understanding of the drug development process.

Spending over a decade at Catalent Pharma Solutions, he consistently exceeded sales targets and spearheaded strategic initiatives, including the successful reinvigoration of sales in the Northeast region and the design and implementation of a global Inside Sales Group. He has also held leadership roles at Vectura, ANI Pharmaceuticals, and Scotwork, consistently demonstrating his ability to establish companies as leading CDMOs, reinvigorate sales funnels, and streamline operations.

At Enzene, Russell's focus is on forging strategic partnerships and delivering solutions that exceed expectations, driving the company's continued success.

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