More efficient flow control for bioreactors and bioprocess systems

Cowritten by Alicat and Chip Stacy, AbbVie Senior Engineer of Digital Systems

As the need for potent and specific pharmaceuticals grows, pharmaceutical manufacturers have turned to biologics to meet the increasing needs and find treatments for complex and currently untreatable conditions including cancer and myriad genetic diseases. Biologics and biosimilars differ from conventional small molecule drugs in that they are grown in living cells, rather than manufactured using chemical processes. This growth is carried out in a controlled environment known as a bioreactor.

The bioreactor environment poses some unique challenges to process and automation experts. Bioprocessing techniques require sophisticated control schemes, specific materials, and complex gas control systems. As the organisms grow in the bioreactor, mass flow needs within the reactor can scale exponentially, more than in most common chemical and industrial processes.

Figure 1 shows a typical gas input schema for a global premier biologics manufacturer. Note that this design requires high-flow and low-flow lines for both oxygen and process air. This multiplicity of mass flow lines is required due to the limited controllable range of the mass flow controllers used. For example, the oxygen flow lines show one controller to be used for flow rates under 35 SLPM and another for flow rates under 100 SLPM. These flow ranges imply a controllable range of no more than 50:1 for the controller specified. Alicat recommended simplifying the design by using Alicat’s mass flow controllers, as shown in Figure 2. The latest Alicat mass flow controllers have a controllable range as wide as 10,000:1, far in excess of the 50:1 requiring a dual flow range design, and improved from the 200:1 previously available from Alicat.


Figure 1: Piping and instrumentation diagram for the original gas input schema of a bioreactor.
Figure 2: Simplified piping and instrumentation diagram for gas input into a bioreactor, using Alicat flow meters with high controllable ranges.


Bioreactors typically have feed pressures of approximately 50 Psig or less. Table 1 shows the flow rate error of a standard Alicat Bio-Series 10 SLPM (standard liters per minute) controller when turned down from 10 SLPM to 1 SCCM under typical conditions.

Desired flow rate  (SLPM) Flow rate error (SLPM) Error as % flow
10 ± 0.06 0.6%
1 ± 0.01 1.0%
0.1 ± 0.01 10%
0.01 ± 0.01 100%
0.001 ± 0.01 1000%
Table 1: Flow rate vs. accuracy for an Alicat BIOC-10SLPM mass flow controller.


Virtually any modern mass flow controller is adequate within the middle and top of its specified flow range, regardless of the measurement technology used. The Alicat mass flow controller discussed here, however, has a mass flow error of only ±0.6% at the top of the scale, and only 1% error at 1 SLPM. What enables the flow range simplification shown above is the high degree of accuracy at very low flows. An Alicat mass flow controller has an error of less than 10% of the desired flow rate at a turndown of 100:1. Even at a turndown of 1000:1 the error in flow is only ±0.01 SLPM for a 10 SLPM flow controller. The biologics manufacturer could therefore reduce the total number of flow lines needed for this design from 5 to 3 by using an Alicat mass flow controller with differential pressure-based measurement. This allows for a 33% cost savings in parts, construction time, and control systems for this portion of the bioreactor. Furthermore, this simplifies the design, increases redundancy, and decreases the number of potential failure points in the system.

Many of the above advantages are enabled by Alicat’s laminar flow measurement technology. In addition to providing very high controllable ranges, this technology is equally accurate for any gas controlled, with no need for imprecise K factors or other compensation techniques. This means fewer spare devices are needed, since any unit can work equally well with any gas, and at a wide range of flows. Changing gases via Alicat’s “gas select” feature is easily done from the device’s front display screen and buttons, or through analog, serial, or industrial communications. This can all be done with no loss of accuracy or need for recalibration.

Other mass flow controllers commonly use thermal measurement technology. While this method has stood the test of time (dating back to 1911), thermal units cannot respond quickly, as the sensor mass needs to change in temperature to change reading. While newer thermal designs respond faster due to predictive algorithms, Alicat’s differential pressure method can respond to control changes in 1 ms – over 1000 times faster than thermal units can respond. Thermal units are also sensitive to process water contamination, as the presence of water effects the measurement and calibration of the heated flow sensor. Alicat mass flow technology is relatively insensitive to and will not be damaged by transient contamination with water.

Alicat’s mass flow controllers and meters include additional features enabling superior accuracy and ease of use. Units can be calibrated in place or on-site, using available Alicat software and calibration standards, regardless of whether the units are controlled via analog, digital, or industrial communication protocols. Under these same conditions, an Alicat flow controller can also report multiple parameters simultaneously. For example, an Alicat flow controller can output mass flow, pressure, valve drive voltage, and temperature – all at the same time. For ease of troubleshooting and testing, units also have a full color TFT display built in. The screen can be rotated 180 degrees (enabling easy use with the Alicat device, which can be installed in any direction) and the devices can be controlled locally using buttons and the display screen, in addition to through your communication protocol.

Alicat’s controllers and meters enable simple and efficient designs. The Bio-Series includes options for a fully ASME BPE 2016-compliant design, certified USP Class VI elastomers, and your choice of industrial protocol. Choose the unprecedented controllable range in the latest Alicat mass flow controllers and meters to reduce your bioprocessing costs while increasing system performance and improving reliability.

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