Scaling Perfusion Technology from Lab Success to Manufacturing Reality

In an interaction with Thiruamuthan, Assistant Editor at India Pharma Outlook, Veerendra Kumar Reddy, General Manager, Enzene Biosciences, discusses how perfusion technology is transforming biologics manufacturing by improving productivity, reducing costs, and enhancing process flexibility. He highlights the advantages for startups, key scale-up and regulatory challenges, the role of automation and PAT, and how ecosystem maturity will drive wider adoption of continuous bioprocessing.

Veerendra Kumar Reddy is a biopharmaceutical manufacturing and continuous bioprocessing expert with over 20 years of experience in biologics development. Specializing in monoclonal antibodies, perfusion technology, and biosimilars, he has led process development, scale-up, technology transfer, and commercialization initiatives. He played a pioneering role in advancing continuous manufacturing at Enzene Biosciences, successfully driving multiple commercial biologics programs from development to market.

Given the growing interest in perfusion-based processes for biologics, how are companies translating lab-scale successes into commercially viable manufacturing strategies?

The strategy can definitely work, especially for startup companies that want to adopt perfusion technology.

The reason I specifically mention startups is that, for established companies, moving an entire manufacturing setup from a fed-batch model to a perfusion model can be a significant challenge. If a facility was originally established using stainless steel bioreactor systems, converting from a fed-batch process to a perfusion process becomes very difficult.

For example, many companies that were established 15–20 years ago may have built their facilities around 5 KL or 10 KL stainless steel bioreactors. For such companies, transitioning to perfusion technology would require major changes. They would need to redesign the bioreactor setup, modify the facility layout, undertake requalification activities, and address several operational challenges associated with existing stainless steel infrastructure. It is not a simple conversion and often requires a substantial overhaul of the manufacturing model.

On the other hand, companies that are already operating with single-use systems have a much better opportunity to convert from fed-batch to perfusion processes. The flexibility offered by single-use technologies makes this transition considerably easier.

Startup companies, however, have the greatest advantage because they can design their facilities around perfusion technology from the beginning. One of the key benefits of perfusion is the lower capital expenditure requirement, along with a significantly smaller facility footprint.

For example, when establishing a startup facility, the entire drug substance (DS) manufacturing setup, including both upstream and downstream operations up to the DS stage, can be accommodated within approximately 3,000 square feet. In many cases, no larger footprint is required. This provides a substantial advantage in terms of facility investment, operational efficiency, and scalability.

Therefore, while perfusion technology offers clear benefits from a manufacturing perspective, the commercial viability largely depends on the starting point of the organization.

Startups can adopt it much more easily because they can build their facilities around the technology from day one, whereas established companies with legacy stainless steel infrastructure face significant challenges in redesigning facilities, requalifying systems, and restructuring their manufacturing operations. These are some of the major considerations when translating perfusion technology from laboratory success to commercial-scale manufacturing.

Amid increasing pressure to enhance productivity and reduce cost per gram, what factors are accelerating the shift from fed-batch to perfusion systems?

Cost remains the most critical factor in biologics manufacturing because, ultimately, it directly impacts patient affordability. Whether a drug is developed using fed-batch or perfusion technology, the focus is on achieving the most cost-efficient manufacturing model.

Based on my experience across more than 20 perfusion-based projects, including several global programs and commercial product launches, perfusion technology can deliver approximately 40–50 percent reduction in cost of goods (COGs). For example, if a product manufactured through a fed-batch process costs around $100 per gram, perfusion technology can potentially reduce that cost to nearly $40–50 per gram.

The next question is how these savings are achieved. In fed-batch manufacturing, larger facility footprints and larger production bioreactors are required. For commercial production, companies often operate 5 KL to 10 KL bioreactors. A significant portion of operating costs comes from media and feed usage. Typically, feed constitutes around 25–30 percent of the total batch volume, and feed media is generally four to five times more expensive than basal media. In fact, media and feed alone can account for nearly 35 percent of the overall manufacturing cost.

In a 10 KL fed-batch process, approximately 7,000 liters may be basal media, while around 3,000 liters consist of feed. Since feed is significantly more expensive, it contributes substantially to overall costs. In contrast, perfusion processes use very low feed concentrations, often around 1 percent, while relying primarily on basal media throughout the run. Although perfusion requires a higher total volume of media over an extended production period, the lower dependence on expensive feeds creates meaningful cost advantages.

More importantly, the productivity difference is substantial. Consider a fed-batch process using a 10 KL bioreactor producing a titer of 5 grams per liter. Such a process may generate around 50 kilograms of product per batch. With perfusion technology, a 500-liter bioreactor can generate a similar quantity of product over a 30-day run. This significantly reduces facility requirements, material consumption, utility usage, manpower requirements, and operational complexity.

When evaluating the entire manufacturing ecosystem including full-time employee costs, consumables, facility maintenance, engineering support, utilities, and production resources, perfusion consistently demonstrates superior volumetric productivity.

The ability to generate equivalent or higher product quantities using substantially smaller bioreactors and infrastructure is one of the primary reasons why the industry is increasingly moving toward perfusion-based manufacturing. Based on real manufacturing data, these combined efficiencies typically translate into an overall cost advantage of around 40–50 percent compared to conventional fed-batch processes.

In the context of scaling perfusion processes, what key technical and operational challenges arise when transitioning from lab-scale to large-scale commercial manufacturing?

I think there are definitely challenges when transitioning perfusion processes from lab scale to commercial manufacturing, especially when adopting it as a new technology. Initially, we also faced several challenges, although today the process has become much easier because we have addressed many of them through experience.

One of the most critical challenges is the gassing strategy. Most bioreactors currently available in the market are designed for fed-batch processes. In a fed-batch model, cell densities typically reach around 25 to 30 million cells per ml, and the existing oxygen supply systems are generally sufficient to support those levels. However, in perfusion processes, cell densities can reach 80 to 100 million cells per ml or even higher, significantly increasing oxygen demand.

During scale-up, we observed that if cell growth exceeds manageable levels, the gassing strategy can become a bottleneck. Continuous sparging may no longer meet the oxygen requirements of the culture, leading to a decline in cell viability.

As viability drops, cell debris increases, which can affect the ATF system supporting the perfusion process. This may result in filter blockage and limit the duration of the run. Frequent ATF filter replacement is possible, but it increases operational costs, which is why managing cell density and gassing effectively becomes extremely important.

Another major challenge is scale-up methodology. Different approaches such as KLA studies, tip speed, and power number-based scale-up models are available. However, there is no universal approach that works for every molecule. Companies need to evaluate the specific characteristics of each molecule, often through engineering batches, to determine the most suitable scale-up strategy. What works for one product may not necessarily work for another.

Foam generation is another operational challenge. Since perfusion processes operate at very high cell densities, significant foam can be generated during cultivation. Controlling foam typically requires the use of antifoam agents.

However, excessive use of antifoam can create additional issues. As the culture continuously circulates between the bioreactor and the ATF system, antifoam can accumulate on the filter surface, gradually affecting filter performance and potentially leading to blockage over time.

These are some of the key technical and operational challenges companies encounter when scaling perfusion processes. While they can be significant initially, they can be successfully addressed through process optimization, engineering studies, and operational experience. In our case, after overcoming these challenges, we have been able to scale up perfusion processes successfully up to 1 KL.

Against the backdrop of evolving regulatory expectations for continuous bioprocessing, how are organizations ensuring process consistency, control, and compliance at scale?

From an Indian regulatory perspective, we do not see any major issues today because we have already launched four products in the market and have two more products in the pipeline. This demonstrates that the regulators understand the process requirements associated with continuous bioprocessing and perfusion technology.

However, the journey was not always straightforward. When we initially started in 2015 and approached the regulatory authorities for approval, our first molecule was rejected. We had to make multiple attempts, provide detailed explanations, and refine our regulatory strategy based on the feedback received. Over time, as regulators became more familiar with the technology and we strengthened our submissions, the approval process became much smoother.

From a global regulatory perspective, continuous bioprocessing is also gaining wider acceptance. Regulatory bodies, including the FDA, have issued guidance around continuous manufacturing and are increasingly supportive of integrated continuous bioprocessing approaches, including perfusion technologies connected with downstream processing.

To ensure process consistency, control, and compliance at scale, companies must demonstrate robust contamination control strategies, effective bioburden management, and strong process controls throughout the manufacturing cycle. Regulatory authorities expect comprehensive data that clearly supports product quality, process robustness, and operational consistency. Once these aspects are adequately demonstrated, regulators are generally supportive of these technologies because they can improve manufacturing efficiency and ultimately reduce costs for patients.

In our experience, the key requirement is generating sufficient supporting data, particularly for global regulatory submissions. As a CDMO, we work with clients across the US, Europe, and Asia, and several molecules are already progressing through clinical and regulatory pathways. We continuously address regulatory observations and requirements as they arise, ensuring that our processes remain compliant with evolving expectations.

Overall, I do not see significant regulatory barriers for continuous bioprocessing today. The focus is increasingly on demonstrating process control, contamination mitigation, and data-driven consistency, which are critical to achieving regulatory acceptance and commercial success at scale.

Considering the complexity of perfusion systems, how are companies optimizing critical parameters such as media consumption, cell retention technologies, and process stability?

This is extremely important because cell retention technology is really the backbone of any perfusion process. Today, many companies claim to have their own cell retention solutions to support perfusion manufacturing. Having evaluated and worked with multiple systems myself, including ATF, TFF, and several other platforms, I can say that selecting the right cell retention device remains one of the biggest challenges in process optimization.

When it comes to cell retention technologies, both TFF and ATF systems are widely used. However, each has its own limitations and advantages. Based on our experience, TFF systems often face challenges related to cell and product retention and typically support cell densities of around 60–70 million cells per ml. This can become a limitation during scale-up, particularly when higher cell densities are required to maximize productivity.

On the other hand, ATF systems offer a significant advantage. They can comfortably support cell densities approaching 100 million cells per ml, enabling higher productivity and ultimately lowering manufacturing costs. This is why optimizing the cell retention strategy is critical, as it directly influences productivity, scalability, and overall process economics.

Process stability is another key area of focus. We have successfully established stable perfusion runs for up to 40 days without major issues. Beyond operational stability, product stability is equally important, particularly for complex molecules such as bispecific and trispecific antibodies.

In traditional fed-batch processes, these complex molecules remain in the bioreactor for extended periods, often 13 to 14 days, where they are exposed to proteases, metabolites, and other potentially damaging components. This can negatively impact product quality, leading to degradation or fragmentation of the molecule.

Perfusion technology addresses this challenge effectively. Since the product is continuously harvested as it is produced, its exposure to proteases and toxic metabolites is minimized. As a result, product stability and quality are significantly improved, especially for complex biologics.

Media consumption is also an important parameter that companies continuously optimize alongside cell retention and process stability. The overall objective is to maximize cell productivity while ensuring efficient media utilization and maintaining stable long-duration operations.

For complex molecules, particularly bispecific and trispecific products, perfusion-based manufacturing combined with continuous processing offers a highly effective commercial strategy. In many cases, it becomes the preferred approach because it not only supports higher productivity but also delivers superior product quality and process consistency at scale.

As demand for high-volume biologics like monoclonal antibodies continues to rise, how is perfusion enabling higher throughput and facility flexibility?

One of the biggest advantages of perfusion technology is its ability to increase throughput without requiring significant facility expansion. For example, we initially operated at a 500-liter scale and have now scaled up to 1 KL. In a conventional fed-batch model, whenever demand increases, the only option is typically to increase reactor size or run multiple batches.

For instance, if a company is producing at a 5 KL scale and demand doubles, it may need to move to a 10 KL reactor. If demand continues to grow, it may require 20 KL, 30 KL, or even larger capacities. Alternatively, the company must run multiple batches, which increases operational complexity and facility requirements.

Perfusion technology offers a different approach through what is often referred to as a scale-out or scale-on strategy. Instead of continuously increasing bioreactor size, manufacturers can increase production by extending the duration of the run while maintaining product quality.

This is particularly important because fed-batch processes have a practical limit. Once the process extends beyond approximately 13–14 days, product quality can begin to deteriorate, potentially resulting in product loss. In contrast, perfusion processes can be operated for significantly longer durations without compromising quality.

For example, a perfusion process can run for 25 days, 30 days, 40 days, or even longer depending on production requirements. If demand increases, there is often no immediate need to install larger bioreactors or undertake major facility modifications. Instead, manufacturers can simply extend the production campaign and generate higher volumes from the same infrastructure.

To illustrate, if a process produces 40–50 kilograms of product in 30 days, and demand rises to 100 kilograms, production can be increased by extending the run duration rather than investing in larger-scale equipment. This provides exceptional flexibility in responding to market demand while minimizing additional capital expenditure.

As a result, perfusion technology enables higher throughput, better facility utilization, and greater manufacturing flexibility. By decoupling production growth from bioreactor size expansion, companies can meet increasing demand for high-volume biologics such as monoclonal antibodies more efficiently while maintaining consistent product quality.

With advancements in automation, PAT (Process Analytical Technology), and real-time monitoring, how are digital capabilities strengthening the scalability and robustness of perfusion platforms?

This is a very critical area for the future of perfusion technology. Supporting a fully connected continuous manufacturing process requires strong digital capabilities, and this is where technologies such as PAT, automation, and real-time monitoring are becoming increasingly important.

During the early stages of establishing perfusion platforms, we explored several PAT approaches. Around three to four years ago, we conducted experiments using Raman spectroscopy with the objective of implementing advanced process analytical technologies. However, because perfusion processes operate at very high cell densities, those early approaches did not provide the level of support and reliability we were looking for.

More recently, we entered into a collaboration with Rutgers University and have successfully established PAT capabilities that are better suited for perfusion-based manufacturing. These systems now support real-time monitoring of critical process parameters, including product titer, viable cell count, viable cell density, cell viability, and key metabolites. In addition, they can monitor important product quality attributes such as purity, aggregates, charge variants, and even glycan profiles.

These capabilities significantly strengthen process control because they provide continuous visibility into both process performance and product quality throughout the manufacturing cycle. Instead of relying solely on offline testing, manufacturers can monitor critical attributes in real time and take corrective actions whenever required.

We are also planning to implement these PAT capabilities in one of our commercial manufacturing batches in the near future. From a regulatory perspective, this is becoming increasingly important because authorities want greater assurance that continuous and perfusion-based processes remain under control at all times.

Since perfusion manufacturing is inherently dynamic, regulators are particularly focused on how companies ensure product quality, control bioburden risks, and maintain process consistency throughout extended production runs. Real-time monitoring and advanced PAT systems play a critical role in addressing these expectations by providing continuous process verification and quality oversight.

Going forward, I believe automation, PAT, and digital monitoring platforms will become integral components of perfusion manufacturing. In my view, by the end of 2026 or 2027, these technologies will be widely adopted across continuous bioprocessing platforms, enabling greater scalability, stronger process robustness, and enhanced regulatory confidence.

Looking ahead, what factors will ultimately drive widespread adoption of perfusion technology—cost competitiveness, regulatory alignment, or ecosystem maturity?

I believe all three factors—cost competitiveness, regulatory alignment, and ecosystem maturity—will influence the adoption of perfusion technology. However, ecosystem maturity will ultimately play the most important role.

From a cost perspective, the advantages are already quite evident. Based on our experience, perfusion technology can reduce manufacturing costs by nearly 40–50 percent compared to conventional fed-batch processes. This is a significant benefit, particularly as the industry looks for ways to make biologics more affordable while improving manufacturing efficiency.

From a regulatory standpoint, the situation has also evolved considerably. Regulatory agencies today are much more aligned with perfusion technology and fully connected continuous manufacturing approaches. In fact, when advanced tools such as PAT are integrated into these platforms, they further strengthen process monitoring, control, and regulatory confidence. Therefore, I do not see regulatory alignment as a major barrier going forward.

The real driver now is ecosystem maturity. If we compare the industry today with where it was five years ago, there has been a significant shift in how companies view perfusion technology. More organizations are recognizing its advantages over traditional fed-batch manufacturing, not only in terms of productivity and quality but also in terms of operational efficiency and commercial viability.

Recent discussions across the global biopharmaceutical sector indicate that a substantial portion of manufacturers are considering a transition from conventional fed-batch processes to perfusion-based manufacturing over the coming years. By 2030, it is expected that nearly 30–40 percent of the industry could adopt perfusion technologies in some form.

Ultimately, every stakeholder is focused on the same objective: reducing manufacturing costs while delivering high-quality therapies to patients more efficiently. Perfusion technology addresses both goals by improving productivity, lowering production costs, and enhancing manufacturing flexibility. As the ecosystem continues to mature—with better technologies, stronger expertise, and broader industry acceptance—I believe it will become the primary catalyst for widespread adoption of perfusion-based manufacturing worldwide.