Biopharmaceutical processes can require that up to six gases be delivered into fermenters and bio-reactors. Their rate of delivery into the reactor must be precise and accurate with minimal risk of contamination from ambient.
Traditionally, the control of gas delivery in biopharmaceutical applications has been based on volumetric flow measurement and control. This approach is strongly affected by variations in the pressure and temperature of the source gas.
This Application Note discusses the use of more accurate electronic mass flow control for gas delivery in these applications.
Biopharmaceutical products are medicinal products that are manufactured through the use of biotechnology. According to the Biopharma website, the predominant view within the US pharmaceutical industry is that the term “biopharmaceuticals” is used to designate “pharmaceuticals that are inherently biological in nature due to their manufacture using live organisms (biotechnology)” [1]. Biopharmaceuticals are distinguished from conventional, chemically synthesized pharmaceuticals by this difference in their mode of preparation. Vaccines, blood and/or blood components, allergenics, somatic cells, gene therapies, tissues, recombinant therapeutic protein and living cells are all produced as biopharmaceuticals.
Figure 1 shows a schematic of a typical biopharmaceutical fermenter. Air and other gas inlets to the fermenter vessel are shown. FIC denotes a Flow Indicator/Controller in the input gas line, required to measure and control the gas flows needed in the biopharmaceutical process. Up to 6 gases, including air, oxygen, nitrogen and carbon dioxide, may be required to promote fermentation, aeration, reactivity and enrichment in biopharmaceutical processes. Precise and accurate control of these gas flows is needed to optimize reaction conditions such as the dissolved oxygen (DO) content in the reaction medium, an especially important parameter in biopharmaceutical processing.
Within the fermenter, gases are delivered directly to the headspace and/or into the liquid reaction medium, as shown in Figure 1. Gases or gas mixtures that are introduced into the reaction medium generally employ a gas sparger to ensure maximum contact (and hence absorption) between the incoming gas or gas mixture and the liquid medium. Gas spargers (Figure 2) produce very small diameter gas bubbles
(0.5 to 10 micrometers) that result in high efficiency transfer of the contact gas into the liquid.
Figure 1 - Representative schematic for a typical biopharmaceutical fermenter system
Reprinted from ASME BPE-1-2014, by permission of The American Society of Mechanical
Engineers. All rights reserved. No further copies can be made without written permission.

Page 2
Application Note
Figure 2a - Gas inlet arrangement typically employed in a fermenter, including detail on gas sparger components [2]
Figure 2b - Gas sparging into a liquid medium [2]
Historically, gas flow into fermenters has been controlled using rotameters, Figure 3 [4] in which gas delivery is measured as volumetric flow. Rotameters must be mounted vertically with the smallest diameter end of the tube in the lower position.
The force of the gas flow lifts the float (Figure 3); as the float rises in the tapered tube, more gas can pass around the float.
The equilibrium vertical position of the float is determined by the balance between flow force and gravity. A vertical scale is calibrated to read the gas flow for a given tube taper and float density. The range of a rotameter can be changed by changing the density of float. Lighter floats rise to the maximum tube height under lower gas flow than do heavier ones.
While rotameters are mechanically robust and relatively simple to use, they are strongly affected by variations in the temperature and pressure of the supply gas. These conditions must be separately measured and accounted for to obtain accurate and precise rotameter measurements. Rotameters cannot be automated for data capture; the only possibility for data recording lies in manual observations by the operator.
This makes them ill-suited for use in automated processes that employ modern control schemes. The accuracy of rotameters is typically between 3 and 5% of Full Scale with repeatability of ca. 0.25% of Full Scale.
Figure 3a - Schematic of a conventional flowmeter [3] Figure 3b - Schematic of the flow tube, float and measurement scale showing the interplay of forces due to gravity and flow [3]

Page 3
Application Note
Electronic thermal mass flow meters (MFMs) and mass flow controllers (MFCs) are superior to rotameters in measurement precision and accuracy and in flow stability. As well, their electronic sensing modality and digital electronics make them usable as control components in modern process control protocols.
MKS Instruments’ thermal MFCs (Figure 4), unlike rotameters, measure gas flow as molar mass flow rather than volumetric flow. This approach provides a direct measurement of rate at which a molar quantity of gas is supplied to a process. Direct control of the mole ratio of reactant components, a parameter of fundamental importance, has obvious benefits in chemical and biopharmaceutical reactions.
Figure 4 - MKS I-Series General Purpose, Multi-Gas MFCs
(left: IE1000A, right: IE250A)
MKS Instruments’ I-Series MFCs are waterproof and dustproof. They are IP66 rated, designed for use in harsh environments where ingress of dust and liquids is a problem and hose-down of the instrument may be required. These environments include general biotech, biopharmaceutical and food and beverage production. The MFCs are manufactured in a clean room environment and all wetted materials are 316L stainless steel, ensuring contaminant-free gas delivery.
The design of the instrument hardware and firmware guarantees insensitivity to temperature and pressure variations in the gas supply making these instruments simple to deploy, with no ancillary measurements and compensations needed.
MFCs, incorporate advanced digital flow control electronics and a patented thermal sensor and mechanical design that ensures 1% of set point accuracy and repeatability of 0.3% of the gas flow reading. The accuracy and precision of the flow measurement, coupled with the highly repeatable control ensures that biopharmaceutical processes using I-Series MFCs are tightly controlled and that these processes can be replicated with relative ease.
I-Series MFCs are available in a variety of communication interfaces including Profibus, Analog and 4-20 mA. In addition MFCs can be operated via ModBus TCP/ IP via the Ethernet port located on all MFCs. They are designed as multi-gas/multi-range instruments, allowing users to change the gas type (e.g. between Ar, N
2
, O
2
and CO
2
) or
Full Scale flow range (as low as 5 sccm or as high as 250 slm) in <45 seconds using an on-board Ethernet interface and an integrated, JAVA-enabled web browser that requires no special software. This latter characteristic is especially valuable for reducing inventory burdens.
Biopharmaceutical production requires accurate and repeatable control of up to 6 process gases. The most effective way to achieve such control is through the use of electronic thermal mass flow controllers for control of the input flow rates for these gases. MKS I-Series MFCs provide an advanced solution for electronic mass flow control of gases in biopharmaceutical processing. They are both waterproof and dustproof (IP66rated) and can be washed down, an important feature for biotech applications. Their manufacture and materials of construction eliminate contaminants in the gas delivery path.
Flow control using the I-Series MFCs has state-of-the-art accuracy and repeatability that guarantees tight control and process transferability. The multi-range/multi-gas character of these MFCs enables rapid process adaptability and low inventory costs. These characteristics make the MKS
Instruments’ I-Series MFCs an ideal solution for the gas flow control requirements in most biopharmaceutical process.

Page 4
[1] R. A. Rader, BioProcess International, March 2007, pp 28-38; www.biopharma.com/terminology.html
[2] Mott Corporation Websites; http://www.mottcorp.
com/products/biotechnology-semiconductor/spargersbioreactors-fermentors.cfm and http://www.mottcorp.
com/newsletter/october07/1007_specialty.htm
[3] http://www.globalspec.com/reference/9771/349867/ rotameters-simplicity-utility
[4] Matheson Gas Co., Flow Measurement and Control
– Rotameters, https://www.mathesongas.com/pdfs/ products/flowmeter-product-line-overview.pdf
For more information on MKS Instruments I-Series MFCs, link to our web site: http://www.mksinst.com/news/NewsDetail.aspx?id=483
For more information on other MKS Flow Control Products, follow this link: http://www.mksinst.com/product/Catalog.aspx?catalogID=3
For a general catalog of all MKS Products, follow this link http://www.mksinst.com/
Application Note
MKS products provided subject to the US Export Regulations. Diversion or transfer contrary to US law is prohibited.
For further information, call your local MKS Sales Engineer or contact the MKS Applications Engineering Group at 800-227-8766.
mksinst ™ is a trademark of MKS Instruments, Inc., Andover, MA.
App. Note 10/15 - 8/15
© 2015 MKS Instruments, Inc.
All rights reserved.
MKS Global Headquarters
2 Tech Drive, Suite 201
Andover, MA 01810
978.645.5500
800.227.8766 (within USA) www.mksinst.com