Bioprocess development in biotechnology, particularly within the context of mammalian cell culture, is a field that constantly evolves, driven by both scientific advancements and economic considerations.
The industry has made great strides in optimizing production processes, with perfusion technology emerging as a key area of focus. In this article, we'll explore the evolution of perfusion processes, the challenges faced by biotech scientists and engineers, and how perfusion is becoming a more sustainable and economically viable solution in biopharmaceutical production.
This concept is discussed in greater detail with Jochen Sieck in an episode of the Smart Biotech Scientist Podcast, hosted by David Brühlmann, founder of Brühlmann Consulting.
The Surprising Economics of Bioprocess Development
Why Media Costs Matter Less Than You Think
A common misconception in bioprocessing is that reducing the cost of media is the most effective way to lower overall production costs. However, Jochen Sieck, a leading expert in bioprocess development, argues that the media's performance plays a much more critical role in process economics.
By optimizing media to produce more products per unit, the overall cost base can be diluted, making media performance a more impactful factor than its initial price tag.
This insight challenges the industry's traditional approach, emphasizing the importance of quality over cost in certain stages of production.
The Journey to a Leadership Role in Biotech
From Novartis to Global Head of Media and Process Development
Jochen Sieck's journey in biotechnology began in 2008 when he joined Novartis as an intern in bioprocess development.
His passion for the field grew as he worked his way up the ranks, ultimately earning a PhD and an MBA. He became a lab head and later the Director Cell Culture Media and Process Development at Merck Life Science. at Merck Life Science. Reflecting on his career, Jochen credits his success to the mentors who guided him through bioprocess development challenges, particularly in the field of mammalian cell culture.
His journey underscores the importance of mentorship and the influence of early pioneers in bioprocessing.
Key Challenges in Bioprocess Development
Juggling Black Boxes in Mammalian Cell Culture
Mammalian cell culture is a notoriously complex area within biotechnology, rife with uncertainties. The growing understanding of cell behavior during bioprocesses is still in its early stages, and scientists are constantly grappling with multiple variables that can affect outcomes. For example, cell culture media often involve 50 to 100 different chemicals, each of which can interact unexpectedly.
Jochen likens the process to "juggling black boxes," where scientists can control the inputs and outputs but often lack full visibility into the system's internal workings. This level of uncertainty contributes to the conservatism in the biopharma industry, where the standard strategy is to err on the side of caution.
Despite these challenges, advances in cell line stability, better media formulations, and a growing understanding of bioreactor behavior have significantly improved process efficiency and product yields.
The Resurgence of Perfusion in Bioprocess Development
Perfusion's Historical Role and Modern Revival
Perfusion technology, which was once mainly used for non-stable products like Factor VIII, has seen a resurgence in recent years. Initially, perfusion was necessary because the protein yields of cell cultures were too low to produce sufficient quantities of drugs. However, as cell lines have improved and yields have increased, traditional fed-batch processes have become more popular due to their simplicity and efficiency.
In recent years, however, several business drivers—such as uncertainty in patient populations, multi-product facilities, and the desire for more flexible production systems—have shifted the industry back towards perfusion.
Modern perfusion processes, dubbed "Perfusion 2.0," are not the same as past ones. Today, perfusion benefits from improved cell lines, media, and technologies that make it a more flexible and cost-effective option, particularly in an environment where demand and product types can be unpredictable.
Sustainability and Cost Considerations in Perfusion
The Economic and Environmental Drivers for Perfusion
Sustainability has become a major concern in biomanufacturing, and perfusion processes are gaining attention due to their potential to offer more sustainable solutions than traditional batch processes.
However, one of the primary challenges of perfusion is its media consumption. Unlike fed-batch processes, where nutrients are added in controlled amounts during different phases of the culture, perfusion continuously flows media through the system, which can lead to higher consumption.
Despite this, perfusion's volumetric productivity advantage can make it more economical in the long term. By achieving the same level of productivity in smaller bioreactors, perfusion processes can significantly reduce the capital expenditure (CAPEX) required for large-scale stainless steel plants.
Furthermore, traditional stainless steel facilities' energy demands, especially the need for autoclaving, contribute to their environmental footprint. Small-scale, flexible perfusion systems, often using single-use technologies, present a more sustainable alternative.
Achieving More with Less: The Sustainability Paradigm
Biotech engineers and scientists always seek to "do more with less." In perfusion, this means optimizing the process to reduce media usage while maximizing product yield. Perfusion's sustainability advantage lies in its ability to produce more pharmaceutical products using fewer resources, contributing to both economic optimization and a reduced environmental footprint.
Navigating the Challenges of Biosimilars with Perfusion
The Impact of Process Choice on Product Quality
When producing biosimilars, the goal is often to replicate the quality attributes of the original product. However, switching between different process types can make this challenging.
For example, if the originator product was produced using fed-batch methods, switching to perfusion could lead to unintended changes in product quality due to differences in the cell line, media, or process parameters.
Jochen notes that it's easier to replicate a process when the originator and biosimilar are produced using the same technology, such as perfusion. If a biosimilar is produced using a legacy fed-batch process, the new perfusion process could yield different quality attributes, making the process transition more complex.
Optimizing Perfusion for Sustainability
Key Strategies for Lowering Media Consumption
Optimization strategies must focus on reducing media consumption while maintaining cell growth and productivity to make perfusion processes more sustainable.
Jochen emphasizes precision in media composition, ensuring that cells have the nutrients they need to thrive without overfeeding. This is particularly challenging in perfusion because the medium must support continuous cell growth and productivity without the luxury of reintroducing nutrients as feed, as is possible in fed-batch processes.
By refining media formulations to balance nutrient levels and optimizing cell culture conditions, the bioprocess industry can reduce waste, improve cost-efficiency, and boost sustainability without compromising yield or product quality.
In biopharma, in mammalian cell culture, you have to be comfortable to juggle black boxes. So you have a couple of systems that you don't have sufficient insight, but you can control the inputs and outputs, like in a black box model. But you have multiple of these, so you need to juggle. And I think that's a good picture to describe bioprocess development.
Optimizing Perfusion Media Production
The Challenges of Scale-Up
The shift towards perfusion bioreactors has become more common as cell culture processes evolve. Unlike traditional batch-based methods, perfusion allows continuous nutrient supply and waste removal, leading to higher yields and more efficient production.
However, scaling this process to large volumes requires sophisticated media production and storage solutions. Perfusion processes often require large tank farms to support bioreactors, especially when scaling up to industrial production levels. This necessitates automation in media preparation to manage large volumes efficiently.
The challenge is ensuring the medium retains its performance even when produced in larger quantities. Biotechnology teams have recently developed automated systems that handle media preparation with minimal human intervention.
A key breakthrough in this area is the successful automation of perfusion media preparation at the lab scale. This resulted from collaboration with academic institutions and industry experts, demonstrating that even more complex media formulations can be automated effectively.
The focus now is on scaling these systems to handle 500L production volumes, which represents a significant leap forward in the industry.
The Future of Media Optimization
The future of perfusion bioprocessing will likely see even more sophisticated media development methods. Historically, most cell culture media have been developed using batch-based techniques. However, as the demand for continuous processes grows, there is a need for media optimized specifically for continuous perfusion.
Recent advancements in high-throughput techniques have allowed researchers to experiment with semi-continuous and fully continuous perfusion operations, optimizing media composition in ways that traditional batch methods cannot achieve.
This will lead to media solutions tailored for continuous processes, ensuring that they support the specific needs of cells in a perfusion environment from the very start to the end of the process.
Scaling Up and Overcoming Bottlenecks
Scaling up perfusion processes presents its own set of challenges. Media preparation and management must be optimized to ensure consistent quality and supply.
Companies can start by using pre-configured perfusion media platforms or cell lines, which allows for faster deployment and fine-tuning of media formulations. As these processes are refined over time, biotech researchers will be able to increase both efficiency and cost-effectiveness.
Practical Steps for Developing Robust Perfusion Processes
Getting Started with Perfusion Bioprocessing
The learning curve can be steep for those new to bioprocess development, particularly in perfusion. However, various resources are available to help researchers navigate the process.
Here's a roadmap for those looking to develop robust, cost-efficient, and sustainable perfusion processes:
- Understand the Basics: Before diving into advanced perfusion technologies, it is crucial to understand the fundamentals of cell culture and bioprocessing. Various textbooks and publications, such as Perfusion Cell Culture Processes for Biopharmaceuticals by Moritz Wolf, Jean-Marc Bielser, and Massimo Morbidelli, can provide solid foundational knowledge.
- Start Small: Start with small-scale systems like spin tubes or small bioreactors. These systems allow you to test and optimize processes before scaling up. They also offer valuable insights into how media behaves in a continuous setting.
- Leverage Existing Platforms: Today, there are commercially available perfusion media platforms and cell lines designed specifically for continuous processes. These platforms allow researchers to start with a working solution and optimize it, reducing the time required for early-stage process development.
- Collaborate with Industry Experts: Engaging with experts in the field is crucial to navigating the complexities of perfusion. Industry conferences and workshops provide invaluable networking opportunities and feedback on your research. For example, organizations like ACTIP (Animal Cell Technology Industrial Platform) offer excellent opportunities for young scientists to present their work and receive feedback.
The Importance of Networking and Mentorship
Mentorship and networking are key factors in advancing one's career in biotechnology. Many successful biotech professionals have benefited from the guidance of seasoned experts who have experienced the trials and tribulations of bioprocess development.
As the field evolves, mentorship becomes even more crucial as young scientists try to navigate the complex landscape of biopharma.
Engaging with ACTIP
One example of how mentorship and networking can shape the industry is the ACTIP platform, which brings together experts in animal cell technology and biopharmaceutical companies.
The platform supports career development by allowing young scientists to present their research, connect with industry leaders, and gain critical feedback. ACTIP also facilitates collaboration during times of crisis, such as the COVID-19 pandemic, helping companies overcome industry challenges.
If you're an early-career scientist, consider the ACTIP fellowship award. It offers a chance to join the network and receive valuable insights from industry leaders.
If you're starting in bioprocess development in perfusion, sleeves up. What would be your first steps? I think this is really something where there is a lot of material out there in the academic area, in the minds of experts in the biopharma industry, and there's also decades of experience available with Perfusion, but it's not broadly available. So maybe that is a takeaway that I will have to discuss with my team.
Closing Thoughts: The Future of Perfusion and Media Development
The future of perfusion processes in biotech is filled with promise. The continuous development of smarter media preparation systems and optimized perfusion protocols will lead to more efficient and scalable biopharmaceutical production. As the industry matures, researchers and companies must stay agile, ready to adopt new technologies and methodologies that enhance performance while reducing costs.
The takeaway from this discussion is clear: the biotechnology field is moving towards a more automated, continuous future. By leveraging existing resources, collaborating with experts, and remaining open to new ideas, biotechnologists can navigate the challenges of scaling up perfusion processes and contribute to the next generation of biopharmaceutical production.
There are abundant resources and support systems available for those on their journey in perfusion process development. For those with experience, the call to collaborate and innovate has never been more pressing.
About Jochen Sieck
Jochen Sieck is the Director of Cell Culture Media and Process Development at Merck Life Science and Chairman of ACTIP. With over 10 years of experience in mammalian cell culture and upstream process development, he specializes in perfusion media and critical cell culture components.
He holds a PhD in bioprocess engineering from ETH Zurich and previously worked at Novartis on scale-down models and perfusion processes. Jochen has authored multiple publications on media development and is completing an MBA in Innovation and Technology Management.
Connect with Jochen Sieck on LinkedIn.
David Brühlmann is a strategic advisor who helps C-level biotech leaders reduce development and manufacturing costs to make life-saving therapies accessible to more patients worldwide.
He is also a biotech technology innovation coach, technology transfer leader, and host of the Smart Biotech Scientist podcast—the go-to podcast for biotech scientists who want to master biopharma CMC development and biomanufacturing.
Hear It From The Horse’s Mouth
Want to listen to the full interview? Go to Smart Biotech Scientist Podcast.
Want to hear more? Do visit the podcast page and check out other episodes.
Do you wish to simplify your biologics drug development project? Contact Us
