Rethinking Bioprocessing

The shift from high-volume drugs to niche biologics requires a more than just expanded footprints, it demands smarter bioprocess controls, lower COGs early on in development, and cross-functional teams.

As biopharma pipelines transition away from traditional, blockbuster-style products and toward highly targeted, complex modalities, the industry’s approach to investing into bioprocessing is shifting. To explore how developers and CDMOs can de-risk process intensification, optimize capital expenditure (CapEx), and lower long-term cost of goods (COGs), The Pharma Navigator spoke with Christelle Dagoneau, Ph.D., Chief Business Officer at Prolific Machines, and Principal Consultant and Founder of CD BioPartners.

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Strategic Alternatives to Facility Expansion

TPN: When biopharma companies experience capacity constraints a common reaction can be to build bigger facilities; however, might companies be better served investing in process intensification technologies instead? What are the key considerations in such an instance for an executive, are there specific trade-offs to evaluate between investing in an expansion versus technology?

Dagoneau: In my advisory work with CDMOs and pharma companies, I have seen that the reflex to just build bigger facilities is fading, but still the industry has not converged into one alternative solution to capacity constraints. Currently, I'm seeing three paths being taken to resolve capacity issues.

A small number of pharma companies are adopting fully intensified continuous manufacturing from upstream to downstream, such as Merck KGaA and Sandoz. However, those examples are still quite rare.

There's a larger group of biopharma companies who have been equipping their traditional sites to run semi-intensified processes. So, a process with an N-1 perfusion seed train, to boost upstream productivity while retaining fairly classical purification trains, which is not a big change to the actual facility infrastructures. With this approach, companies can still amortize their CapEx, while also boosting productivity a bit.

And there's a new and third segment of companies, who are increasingly interested in the foundation of the productivity itself. Basically, these companies are looking into new cell line development technology, plus everything that goes around that, to lift the titer early to get a better process from the start. Then, of course, they adapt all the upstream and downstream around the new cell line output, because if more is produced out of a cell line, it may well be necessary to adapt a continuous train to manage that output. But these companies are focusing on the cell line first.

Underneath all three strategies there is one clear trend on new facilities, which is that everyone is going towards lower CapEx and, to a degree, lower operational expenditure (OpEx) through increased automation. For the vast majority of the industry, when designing new facilities, they are moving to smaller bioreactors — the 2,000 to 5,000 L single-use ones instead of the old 20 kL stainless steel bioreactors. But those smaller bioreactors can only meet large demands if you bring higher productivity cell lines in and have a high productivity process. This kind of evolution towards smaller bioreactor size, meaning smaller CapEx, more offsite, is generally seen in combination with the trend of higher productivity, so that you've got the most out of the two trends.

At the executive level, decisions are made depending on what may be fit for purpose. No single solution is going to fit all supply and demand for every molecule, but, currently, it is clear that the bigger stainless-steel bioreactors can still offer cost efficiency for the existing low productivity processes and for very large demand. However, this approach requires costs to be logged and is a pretty rigid setup in terms of infrastructure.

Actually, the highest leverage/lowest disruption lever usually relates to the cell line, which is why adjusting this impacts the foundation of the process. This layer is where we are focusing at Prolific to leverage light to control protein expression, also called optogenetics for those that know the technology platform, to boost titer and also create a high performing bioprocess. Using this approach it is also possible to adapt processes to the complexity of the pipeline of biologics that we are starting to see and that we're going to see more and more in the future.

Low-Risk Transition Pathways

TPN: What might a truly low-risk transition to highly intensified processes look like from an investment perspective? Is it possible for companies to scale up yield without having to overhaul existing facility infrastructure, which is expensive?

Dagoneau: The answer to this question will really depend on how far a company would like to go. If they’re trying to convert a traditional fed batch plant into a fully continuous perfusion based one, they’re essentially rebuilding the plant — so at high CapEx, high risk, because there are still, you know, some skills required to run that kind of facility, it's not low CapEx for sure. The low-risk path is the opposite really, leaving the existing infrastructure in place and moving the productivity lever upstream of the hardware and the bioreactors, so, into the cell line.

To take this low-risk approach with low CapEx, companies would need to keep their bioreactors, keep their process backbone, and maybe add a bit of continuous downstream only if the output demands it, but actually playing with high performing cell line to get a better output from the existing capabilities. And again, using Prolific as an example, that's exactly where the optogenetics platform fits.

Basically, the team has developed a light-controlled cell line, which can be manufactured into existing bioreactors by equipping them with what we call illuminators — LEDs. This approach can already help to double or triple titers, achieve a better pairing of multi-specific molecules, and control glycans, without having to rethink the infrastructure and build a new footprint.

If we look at the pipeline evolution, the multi-tons of drug substance that we saw some years ago for the big blockbusters, is kind of behind us: The future is going to be made of ADCs and multi-specifics, all fitting a more precise indication, so, smaller population of patients, which is going to mean smaller volume, but with more complex formats to develop and manufacture.

Therefore, companies are going to have really to rethink CapEx because they’re going to have to adapt to more complex molecules, smaller volumes, and with a bit more risk embedded in those pipelines. So, getting back to the point of setting up a flexible kind of smaller scale facility, currently, we are seeing a lot of facilities with 2–5 kL single-use bioreactors and companies leveraging high-performing cell lines so that you can meet both clinical and commercial demand.

Balancing Timelines, COGs, and Probability of Success

TPN: When introducing novel bioprocessing platforms, especially those integrating hardware, software, and bioengineering, how does that affect the risk-adjusted net present value of a pipeline molecule? Where do we see the biggest gains: in accelerating the timeline to clinical trials, or in drastically lowering long-term cost of goods (COGs)?

Dagoneau: Firstly, I would say that for me the risk is less about the adoption of new technologies but rather with continuing to use old tools that are not going to work for the next generation of biomolecules, both from a developability and COGs perspective. For instance, looking at the Prolific technology, our team has been doing extensive modelling and development to de-risk the scale up of optogenetic cell lines to make sure that what is a great new technology can really translate into commercial success. But, as is true for any new technology, the zero-risk approach does not exist. However, companies must consider that the downside of using a new technology is going to be minimal and far smaller than the upside, because if they take no risk, they’ll be stuck with old technologies and won’t be able to adapt to what is ahead.

So, in terms of biggest gains, I actually see two directions: as mentioned there is the timeline, but there is also the probability of success. Many existing complex molecules are challenging and are just sitting in pipelines or stuck in clinical development because the process required to manufacture them cannot be simplified. A great CMC package with a higher titer, a reproducible process, better chain pairing for multi-specific compounds, and better control of glycosylation for biosimilars, will help to make a challenging or stuck program be developable and will ensure that investors can improve their internal investments and won’t waste hundreds of millions in early clinical programs. So, accelerating timelines is a definite gain, because when you come with new technology, you actually unlock the developability and you can spend months/years on developability.

Secondly, the COGs, and this is becoming existential, it was not that important in the past, but it's increasingly important. There are a lot of molecules that, in the past, could have scraped through Phase I, but now is stuck in the middle of clinical development because no one wants to invest in a molecule that while promising with a huge market indication behind it, doesn't have a sustainable CMC process, a sustainable yield, or sustainable COGs. This scenario is not possible anymore in the current regulatory and reimbursement environment, it’s as simple as that. So, the COGs can kill the economics and that what ultimately, it's not yet palpable, but it will become more of a factor when it comes to blocking the funding via licensing.

We hear a lot about product quality and process robustness. It is key for pharma companies to ensure that the supply/demand doesn't have hiccups at the commercial stage. Again, this is exactly what we are trying to do at Prolific — develop those high titer cell lines with a controllable process that can scale and also address the manufacturing efficiency and cost efficiency from day one and not five years down the path when that can become a bottleneck to commercialization.

Overcoming Process Bottlenecks

TPN: Historically, dynamic control of cell lines has relied on expensive chemical inducers, which skew downstream purification costs and complicate CMC data packages. From a CapEx and OpEx perspective, how does shifting the control lever from chemical molecules to physical inputs (such as light or automation) change the cost structure of a therapeutic program?

Dagoneau: Given the fact that downstream processing can be a bottleneck, more companies are looking at implementing a bit of continuous processing downstream so that they can just manage the output. But, this being said, companies must manage when they have a big output because the reality is that for some complex proteins, companies are not going to generate 20 g/L, they will still generate 5 g/L like they were doing for standard mAbs 20 years ago. However, a key difference will be that those 5 g/L will be fine because as it will be a cytokine fusion or a  multi-specific, where, 20 years ago, production would have been at 0.5 g/L. So, that's where the continuous processing was needed for the larger outputs, but a lot of those new processing approaches, they're just going to basically transform very difficult to express candidates into sustainable molecules with a decent enough titer to go to commercial.

On the impact of chemical inducer cost — here, I'm pushing back a bit on the premise that the big COGs lever is to get rid of the chemical inducers — where light can help is on the CMC side because there’s no end user and it's going to help to clear the downstream and to better characterize the data package. But to me, that's even a secondary consideration.

The real lever is productivity and control. For example, taking a difficult to express protein from 1 to 4 g/L, if there is a decent commercial demand, it is possible to save USD 20–50 million a year on commercial COGs, just on the savings from drug substance manufacturing costs. So, basically the chemical inducer in that sort of example, is not going to be the big play.

Beyond the cost, is the control — controlling what's happening in a bioreactor — which can also help unlock some scale up that can be tricky for certain molecules and certain processes. Also, during tech transfer, when the operators, facility, directors, and so forth change, having the ability to control what's happening live in the cells can enable companies to still hit their critical quality attributes (CQAs) and specifications, which is worth its weight in gold. The industry spends millions of dollars on failed batches, so, the ability to control what's happening at a site at commercial scale or when a project is reaching commercial scale, is also of very high value.

Therefore, process consistency and product quality are, to me, as important to the pharma industry as the timeline acceleration and COGs. It is important to combine them all.

Building Multidisciplinary Teams

TPN: As modern bioprocessing incorporates synthetic biology, physics, hardware engineering, and machine learning (ML), how should companies invest in training and building teams to handle the new environment?

Dagoneau: Let’s say that for any company building a new technology, training and skill building internally is not optional, this is the condition for innovation. I think here modern bioprocessing sits at the intersection of synthetic biology, physics, hardware engineering, ML, and the mistake would certainly be to be to hire those as silos, so side by side. For me, the value is created at the interfaces.

So, when you invest into those skilled people and make them work across boundaries — basically having a biologist who can talk to the ML engineer, an engineer who understands biology — that's basically the fertilizer to get innovation. And this ideal is how Prolific has been built. Those skilled people are all working in their labs, but also gathering together to make the magic happen and combine the different layers of expertise into one platform and working as a team.

I would add that, generally speaking, and, again, this is true for Prolific or for any innovative company, no one should ever rest on their laurels. So, companies need to keep bringing new skills and new perspectives into their teams, and also should cross-fertilize expertise too.

Basically, speak with partners and customers, keep listening about the challenges and ambitions, so that there is a constant feed into the platform that will allow for the generation of the next level of innovation. In our environment, every six months or so we’re seeing new complex molecule formats to tackle, which keeps us training and ensuring that our people are connected and wired to manage the innovation required to handle the upcoming biologics development and manufacturing challenges.

The Long-Term Valie of Early CMC Integration

TPN: Looking ahead, what will differentiate the companies that invested wisely in bioprocessing today from those that played it safe? What does the ultimate smart investment look like in hindsight?

Dagoneau: I think the differentiator is going to be the ability to handle the new complex formats, so, to unlock their development, accelerate their time to clinic and market, while also combining that with a cost reduction objective earlier on. If you really look at what's happening today, you see that to move fast, most clinical teams at biotechs go with traditional toolkits — conventional cell line development, fed batch manufacturing, and so on — and the CMC consultants are very scared about using new technology because the goal is time to clinic, funding, and to demonstrate the drug/molecule is safe, and then they’ll see what is next.

However, the next stage is that even though those molecules are successful in Phase I/II, they arrive at Phase III as a high value asset with pharma looking at them and the poor CMC package (low yield, weak manufacturing process) falls apart. So, that's where I think the companies who will win tomorrow, are going to be those that won't treat speed and commercial cost as a trade-off.

Companies that combine all those aspects — to pick the best cell line, the best upstream/downstream approaches to unlock complex candidate developability — will be able to develop something that is sustainable and also of high value, not only the molecule and its efficiency, but also high value from a CMC perspective. While there is general agreement that CMC is key — particularly given the fact that CMC is listed as the cause of many regulatory rejections and failures to bring a product to market — it has still not fully translated into decisions made earlier on in pre-clinical candidates.

At Prolific, we are combining all those elements within one platform — bioprocess control, high productivity  to reach low COGs, speed — to enable our pharma partners to bring their early pipeline to the next clinical stage and ultimately to market and grant wideraccess to patients. At the end of the day, behind the process and behind any product, there are the patients, so that's what we need to keep in mind.

About the Speaker

Christelle Dagoneau, Ph.D., is the founder of CD BioPartners, a strategic advisory firm serving deeptech, biopharma, CDMOs and investors, with deep expertise in bioprocessing and biologics development. She has over 25 years in global business development and commercial leadership across emerging and large biologics CDMOs, including Senior Vice President, Global Business Development at Just-Evotec Biologics and senior positions at Catalent.

Christelle works at the intersection of next-generation bioprocessing technologies and the dealmaking that turns them into value — commercial strategy, high-value partnerships and deal shaping, due diligence and M&A support, COGS optimization, and interim leadership. She currently serves as interim Chief Business Officer at Prolific Machines, where she leads partnering and licensing for its optogenetics-based production platform.

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