Bioprocess development demands a careful blend of biology, engineering, and strategic planning. To develop robust cell culture processes and scale them up effectively, scientists often rely on a combination of traditional tools, such as shake flasks, alongside modern bioreactor systems. 

However, how you leverage these technologies can significantly impact time to market, project costs, and overall success. 

In a detailed discussion with biotech entrepreneur and seasoned commercial leader Jens Bayer, several critical insights emerged regarding the roles of shake flasks, smart sensing technologies, and entrepreneurial strategies in the biotech industry. This article consolidates those insights and presents them in one cohesive narrative.

Bridging Science, Business, and Entrepreneurship

Jens Bayer has a diverse background, blending biotechnology, business management, and startup leadership. After studying biotechnology at RWTH Aachen University in Germany, he pivoted to a bio-entrepreneurship program in Stockholm, Sweden. This blend of science and business set the stage for his later involvement in upstream bioprocessing and the founding of a company dedicated to sensor innovations.

Entering Bioprocessing Through Academia

While studying at RWTH Aachen, Jens Bayer encountered professors and industry leaders focused on microbial processes and fermentation engineering. One notable figure was Professor Jochen Büchs, known for co-developing advanced microbial screening methods such as the RAMOS (Respiratory Activity Monitoring System). 

Through these academic experiences, Jens Bayer became increasingly interested in how small-scale fermentations—particularly in shake flasks—could be optimized for higher yields, better data collection, and easier scale-up.

Early Challenges in Scale-Up and Time Pressures

Jens Bayer quickly saw that bioprocess development is a marriage of biological complexities and engineering constraints. 

Teams must manage:

• Multiple Disciplines: Microbiology, molecular biology, and process engineering
• Stringent Timeframes: Rapid iteration under pressure to reach proof-of-concept, pilot, or commercial runs
• Budget Constraints: Rising costs for labor, materials, and advanced instrumentation

Moreover, the often-cited “valley of death”—the phase between lab-scale discoveries and commercial manufacturing—underscores how easily a seemingly solid project can falter if its small-scale data are not transferable to larger vessels.

The Longstanding Role of Shake Flasks

Despite the proliferation of advanced single-use bioreactors and automated mini-bioreactors, shake flasks remain one of the most commonly used vessels in both industrial and academic labs. They are inexpensive, easy to handle, and allow scientists to run multiple parallel experiments with relative simplicity.

Why Shake Flasks Persist

According to Jens Bayer, many industry professionals predicted years ago that shake flasks would soon disappear, overshadowed by more controllable reactors. 

Yet shake flasks remain ubiquitous because they offer:

1. Low Cost and High Throughput
   • Inexpensive to acquire.
   • Simple to set up and operate.
   • Allow scientists to test many conditions at once.
2. User-Friendliness
   • Minimal need for specialized engineering knowledge.
   • Straightforward cleaning or disposal (in the case of single-use setups)
3. Versatility
   • Suitable for a wide range of organisms: bacteria, yeast, filamentous fungi, mammalian cells, and plant cells, among others.
   • It is commonly used in microbial and cell culture applications, although the specific flasks or single-use formats vary.

The “Black Box” Challenge

However, shake flasks have inherent limitations. The flask acts like a black box in many workflows: scientists inoculate their cultures, place flasks on a shaking platform, and sample intermittently. 

Major difficulties include:

• Lack of Real-Time Sensor Data
  • No built-in pH or dissolved oxygen (DO) measurements.
  • Reliance on physical sampling disrupts growth conditions by stopping agitation or exposing cultures to contamination risks.
• Limited Process Control
  • No capability for controlling stir speed (beyond setting the shaker’s RPM)
  • No direct gassing strategies, as in a conventional bench-scale bioreactor.
• Potential Oxygen Limitations
  • High cell-density cultures can outstrip the oxygen-transfer capacity in flasks if volumes or RPM settings are not planned correctly.

Overcoming the Black Box with Better Awareness

Jens Bayer emphasizes that a lack of knowledge about oxygen transfer rates, or suboptimal filling volumes, often leads to false assumptions and poor reproducibility. Many labs do not treat shake flasks as mini-bioreactors but as quick, “good enough” tools. 

Yet thorough research on agitation speeds, filling volumes, and breathable seals (e.g., cotton plugs instead of aluminum foil) can help scientists approximate better reactor conditions and gather more reliable data.

People don't treat it like a bioreactor. They simply look at the biology. Put my cells and put my media in and I forget about it. They don't have the mindset of "now I'm running a small fermentation, now I should be really thinking of what do my cells need, how do I optimize this so that I get the maximum titer, that I get optimal results and that it becomes reproducible?"

Toward Smarter Shake Flasks

The desire to optimize and digitize shake flasks has led to innovations that aim to turn these vessels into mini-bioreactors. Jens Bayer’s company has worked on platforms combining sensor hardware, feeding technology, and digital software interfaces to gather real-time data and control key parameters.

The DOTS Platform

Jens Bayer and his team developed a multi-component system known as the DOTS platform. Designed to be installed on standard shaker equipment, it addresses core deficiencies in typical shake flask setups:

1. Multi-Parameter Sensor
   • Place a non-invasive sensor under each flask.
   • Uses backscatter signals at varying wavelengths to measure real-time biomass growth.
   • Incorporates fluorescence measurement for tracking protein production when using fluorescent tags (e.g., GFP)
2. Sensor Pills
   • Small, single-use chemo sensors that float freely within the culture.
   • Detect parameters such as pH, dissolved oxygen, and potentially various substrates.
   • Enable real-time readouts each time the pill passes over the sensor, reducing or eliminating manual sampling.
3. Feeding System
   • A module is placed on top of the flask to enable fed-batch operations.
   • It can respond to triggers such as DO spikes or pH changes and automate nutrient feed or acid/base additions.
4. Software Integration
   • Consolidates sensor data for immediate process visibility.
   • Allows set-point definitions, real-time monitoring, and potentially advanced automation or experimental design.

Operational Simplicity

Jens Bayer points out that this system aims to maintain the shake flask’s user-friendliness. Researchers attach the sensor tray once, place flasks normally, and insert sensor pills only if those specific parameters are needed. 

The single-use feeding cartridge avoids complicated cleaning steps. The overall setup takes 10 to 15 minutes, which is much simpler than installing and validating a full bench-top bioreactor.

Comparing Shake Flasks to Other Technologies

Modern labs have an extensive toolkit: microtiter plates (with or without robotics), specialized mini-bioreactors like the Ambr system, bench-scale stirred-tank bioreactors, wave bags, and more. Each has advantages and disadvantages. 

Jens Bayer suggests that the best approach depends heavily on factors like:

• Organism Type (bacterial, yeast, filamentous fungi, mammalian cells)
• Lab Expertise (engineering knowledge, experienced staff, budget constraints)
• Process Goals (screening, clone selection, optimization, or scale-up)

Situations Where Shake Flasks Shine

Jens Bayer notes that shake flasks are especially beneficial for:

• Preliminary Screening: Quickly comparing strains, clones, or media recipes
• Early Process Understanding: Gaining insights into growth kinetics and basic substrate consumption
• Seed Train Production: Preparing cultures before transferring them to larger reactors

Scientists might prefer single-use bench reactors or a system like the Ambr 15 for more advanced or detailed process control. However, those come with higher costs, steeper learning curves, and more complex validation requirements.

Potential for Scale-Up

Contrary to a widespread assumption that scale-up from flasks is always limited, Jens Bayer insists that it is possible in many microbial processes with proper oxygen-transfer knowledge and standardization. 

He references published studies showing that data from carefully managed flask cultivations can correlate well with bench-top or pilot reactor results. Of course, not every organism or molecule behaves identically, so labs must evaluate their needs and constraints.

Keys to Effective Shake Flask Experiments

Jens Bayer highlights a few strategies to ensure that shake flask experiments yield more meaningful data. He urges scientists to address fundamental parameters, treat the flasks like actual bioreactors, and remain open to modern sensor technologies.

Critical Considerations

1. Understand Oxygen Transfer
   • Low fill volumes (e.g. 10% or less of the nominal flask capacity)
   • High shaking speeds (250 to 350 RPM)
   • Gas-permeable seals instead of aluminum foil.
2. Adopt a More Engineering-Like Mindset
   • View the flask as a small fermentation system.
   • Develop protocols for controlling or at least measuring DO pH or nutrient consumption.
   • Recognize the variables that can invalidate results (e.g. repeated stops for sampling)
3. Leverage Available Sensors
   • Research the growing range of non-invasive or minimally invasive measurement options.
   • Use real-time data to reduce trial-and-error efforts.

Design of Experiments (DoE) and Data Integration

Many labs rely on DoE to accelerate development. With minimal sensor data, DoE can still help pinpoint crucial parameters, but the introduction of real-time insight transforms DoE’s power. For example, scientists can immediately adjust nutrient feeds or sampling schedules if a strain hits a stationary phase earlier than expected. A more dynamic, data-driven approach often saves both time and resources.

I would definitely recommend you to take a look at Oxygen, especially when you're working with E. Coli or other bacteria that grow quite fast, because that's the number one limiting factor that's probably also preventing predictable scale up.

Entrepreneurship and Building a Successful Startup

Beyond his technical expertise, Jens Bayer co-founded a company focused on sensor technology for bioprocess development. This entrepreneurial experience taught him numerous lessons about launching a startup in the biotech sector.

Founding a Company from University Research

Jens Bayer and his partners started their venture by leveraging academic projects and obtaining government grants, such as the EXIST scholarship in Germany. 

These resources allowed them to:

• Develop a minimal viable product (MVP)
• Refine intellectual property strategies
• Validate use cases with a small set of pilot customers

Following this initial phase, they secured seed funding from experienced investors, including a business angel with strong ties to the life sciences industry.

Overcoming Daily Challenges and Maintaining Flexibility

Jens Bayer observes that running a startup is like climbing a continuous mountain range of obstacles. Each day brings fresh challenges—production hurdles, contract negotiations, talent recruitment, or compliance concerns. 

Founders must:

• Stay Resilient: Accept that setbacks will occur and adapt swiftly.
• Remain Open to Changing Roles: Wear multiple hats, from technology development to sales pitches.
• Prioritize Team Cohesion: Recognize that success depends on collective commitment and complementary skill sets.

Sharing Equity and Avoiding “Stealth Mode”

Two key pieces of advice stand out:

1. Equitable Ownership: If multiple co-founders are involved, dividing equity fairly fosters long-term alignment and motivation.
2. Avoiding Stealth Mode: It can be tempting to hide a new concept for fear of idea theft. However, broad discussions with potential investors, partners, and customers usually yield faster validation and invaluable feedback.

Advice for Aspiring Biotech Entrepreneurs

According to Jens Bayer, scientists who have a promising concept but hesitate to start a company should consider these points:

• Balance Technical and Business Expertise: Pair up with a partner who excels at operations, fundraising, and market strategy.
• Respect the Role of Execution: A strong idea is crucial, but turning it into a market-ready product involves building prototypes, ensuring regulatory compliance, and managing finances.
• Network Early and Broadly: Connecting with mentors, angels, or venture capitalists can refine a business model and expand market awareness quicker than working in isolation.

Looking Forward—Future Innovations and AI Integration

As advanced digital tools and artificial intelligence continue to permeate biotech, Jens Bayer envisions further developments in areas such as:

• Automated Shake Flask Setups: Integrating sensors, real-time data, and feeding modules to allow “plug-and-play” optimization
• Better Oxygen Control: Introducing specialized ways to increase oxygen transfer rates—potentially bridging some of the historical gaps between flasks and stirred-tank reactors
• Expanded Data Parameters: Viable cell density, sugar consumption, and even morphological tracking for filamentous organisms may become standard in advanced shake flask systems

He also anticipates that AI-driven decision support, fed by large volumes of accessible fermentation data, will streamline optimization and reduce guesswork. Such automation and intelligence might empower scientists to solve more complex problems at reduced cost—especially relevant in synthetic biology, where new products promise to address environmental and human health challenges.

Final Remarks

Shake flasks remain a cornerstone in labs worldwide, from early research to certain stages of process optimization and scale-up. Despite their simplicity, numerous pitfalls await researchers who fail to appreciate fundamental engineering principles like oxygen transfer or controlling fill volumes. 

However, new sensor technologies and integrated platforms now allow these commonly used vessels to approximate many capabilities once reserved for larger, more expensive bioreactor systems.

Jens Bayer’s experiences underscore that an engineering mindset and an awareness of modern measurement and feeding tools can transform shake flasks into surprisingly powerful mini-bioreactors. At the same time, he highlights the entrepreneurial energy necessary to bring new devices and software platforms to market. Biotech ventures can scale solutions that tackle urgent global needs more efficiently by combining scientific knowledge, solid business acumen, and robust development processes.

Ultimately, the path forward for bioprocess development involves continued innovation in sensors and control systems and a willingness to adapt and learn from engineering fundamentals and real-world commercial demands. By staying flexible, data-driven, and collaborative, labs of all sizes can harness the strengths of shake flasks, advanced bioreactors, and everything in between to bring groundbreaking therapies and products to a rapidly changing marketplace and commercial scale-ups.

About Jens Bayer

Jens Bayer is a deep tech entrepreneur and seasoned commercial leader with a proven track record in the bioprocessing industry. He is passionate about how sensors and data can support scientists in synthetic biology and cell line development. Currently, Jens serves as the Chief Commercial Officer at Scientific Bioprocessing, Inc (sbi). At sbi, Jens is driven to digitally simplify bioprocessing with a focus on miniaturized smart sensors and software for bioprocess development and scale-up. 

Previously, Jens co-founded aquila biolabs, a German-based startup specializing in sensors and data analytics for upstream bioprocessing. Under his leadership, the company grew quickly and saw a successful exit, with the company being acquired by Scientific Bioprocessing, Inc. Jens holds a B. Sc in Biotechnology from RWTH Aachen University in Germany and a M. Sc in Bioentrepreneurship from Karolinska Institute and Royal Institute of Technology (KTH) in Sweden.

Connect with Jens Bayer 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. 
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