Increasing bioreactor repeatability and yield through mass flow control

Rotameters are widely used across laboratory and pilot scale bioreactors for volumetric gas flow measurement because they are low cost and relatively simple to use. Replacing a rotameter with a mass flow controller (MFC) however, improves the accuracy and reliability of gas flow measurement and control, ultimately increasing cell culture yield. By reducing dependency on manual processes, greater automation provides a cost-effective approach in the long-term. Tony Brennan explains how an MFC can increase bioreactor efficacy.

To maintain optimum conditions inside the bioreactor for the growing cells, the concentration of Oxygen, Nitrogen, Carbon Dioxide and air needs to be carefully controlled. Rotameters are widely used to monitor the flow of these gases because their simple design enables relatively straightforward measurement in a low-cost package.

Manual measurement is a drawback of the rotameter. The float within the device’s gauge is read by the human eye, and in the absence of round-the-clock monitoring, reacting to the reading introduces a lag. As gas levels fluctuate from their optimal points, the efficacy of the bioreactor process begins to decline. A rotameter is typically used alongside manual control over gas flow, so this puts reliance on a human hand to achieve the exacting control required to re-establish the optimum gas levels. Human intervention also requires additional time, a resource which is typically valuable in lab and pilot settings.

The importance of accuracy

The most significant constraint of a rotameter, however, is measurement accuracy. A rotameter is calibrated under prevailing pressure and temperature conditions. If these conditions change outside of the calibrated conditions inaccuracies are introduced into the reading. The reading may be more or less accurate, but rotameter measurement typically delivers less than ideal conditions for optimised yield and rate of growth. Reduced measurement reliability also impacts repeatability, which is crucial for upscaling production. This means it’s important that flow meters are unaffected by changes in pressure or temperature in order to maximise the cell culture yield.

As the process is scaled-up from a laboratory or pilot bioreactor to pharmaceutical plant development, discrepancies in accuracy and repeatability are magnified, ultimately impacting the efficacy of growth and total cell yield. As a result, it’s critical for smaller-scale research, from 100 ml to 50 L laboratory projects, up to pilot scale, ranging from 50L to 10m3, to be able to confirm accuracy at the outset.

Automation increases repeatability

The key benefit of replacing a rotameter with a mass flow controller is that accuracy and repeatability of measurement is constant, irrespective of conditions. This is because an MFC measures mass rather than volumetric flow, which is impacted by changing temperature and back pressure. Crucially, an MFC also provides continuous, automated control. This means that as soon as any conditional changes occur within the bioreactor, mass flow of the gases is adjusted to ensure the optimum levels are maintained for the most effective culture growth. By automating the process and removing human intervention, production consistency can be improved while digitally capturing all of the relevant process information which can be used to improve the quality.

Communicating with the bioreactor’s controller via a communications gateway, a constant data stream from the MFC can be recorded. This enables detailed analysis of the process, supporting repeatability as it’s scaled up. Repeatability is important as this saves time, and as a result, the cost of production, and this assurance means that production can be scaled-up more quickly.

The advantage of Bürkert’s 874X series MFCs is the connection of multiple control loops to a pre-configured gateway module available in a variety of industrial ethernet protocols, including Profinet, Ethernet IP, EtherCAT and Modbus TCP. While this approach optimises the performance-price ratio, it also simplifies system integration and enables MFC users to standardise on a single platform that can be used across the board with their customers.

Simple integration and compliance

To meet footprint and performance requirements, Bürkert can also provide customised solutions. This ranges from customised sub-assemblies through to bespoke manifolds, designed to meet space envelope requirements and provide specific functionality. This includes the integration of additional components, such as check valves, pressure transmitters and shut-off valves, as well as performance customisation, such as increasing the turndown ratio to values such as 1:100 or more. Increasing the span of the measuring range can reduce the number of MFCs required, minimising the space envelope and cost.

As a result of the flexibility of Bürkert’s EDIP internal bus system, combined with a gateway module that converts the signal into the user’s choice of industrial Ethernet protocol, this enables easy integration for the customer’s selection of components and functionality. Bürkert’s internal engineering expertise also manages customisation projects completely in-house, in addition to manufacturing valves and flow control components. This approach reduces development time for proof of concept and testing compared to the coordination of multiple third-parties to create a bespoke solution. Ultimately, the Bürkert solution ensures fast development and enables plug-and-play use, straight out of the box.

Bürkert’s MFCs achieve full pharmaceutical conformance, including FDA approval plus USP Class VI that confirms bio-compatibility. Bürkert devices also achieve the 3.1 materials certificate. 

While integrating an MFC requires initial capital investment, the improvement in accuracy and repeatability can increase cell culture growth rate, as well as total yield, long-term. For the pharmaceutical manufacturer, this means increased productivity, and for the bioreactor OEM, this provides a more compelling proposition for potential customers.

Tony Brennan, Industry Account Manager – Industrial Devices, Bürkert.