Multipoint Analysis in Biological Production with Process Mass Spectrometry

The utilization of online process analytical technology (PAT) in the biotechnology industry has become a preeminent endeavor In recent years.

A number of fermentation scientists have utilized the reliability of Thermo Scientific™ Process Mass Spectrometers since the beginning of the 1980s in order to monitor the composition of gas streams into and out of fermenters and bioreactors.

When taking the first steps towards process control, it is not unusual for some to think that the only effluent needed is the measurement of oxygen and carbon dioxide and that enough accuracy can be attained using discrete measurement technology.

The variability of sparge gas remains consistent because of external biological factors such as people and trees, which inevitably alter the input to the instrument air system and depending on their position in the regeneration cycle, the all-pervasive twin-tower desiccant dryer systems will also either absorb or regurgitate CO2.

Only a precise comparison of effluent and sparge gas is appropriate to facilitate an accurate pre-screening for potential contamination. An accurate comparison is also needed to calculate information in real-time regarding the availability of nutrients and culture respiration.

The minimum requirements for suitable control are as follows:

  • Local support
  • All gas components must be measured
  • Operational reliability and simplicity
  • Automatic calibration of all components
  • High accuracy is needed to calculate meaningful metrics
  • Flexible analysis schedules and techniques
  • Measurement of sparge and effluent gases

Typical benchtop bioreactor.

Figure 1. Typical benchtop bioreactor. Image Credit: Thermo Fisher Scientific – Environmental and Process Monitoring Instruments

Source: Thermo Fisher Scientific – Environmental and Process Monitoring Instruments

Magnetic Sector
Analytical Performance
N2 N2 O2 O2 Ar Ar C2 C2
%mol %mol %mol %mol %mol %mol ppm ppm
Mean St Dev Mean St Dev Mean St Dev Mean St Dev
Day 1 78.0807 0.0028 20.9459 0.0026 0.9337 0.0003 396.84 1.31
Day 2 78.0767 0.0023 20.9494 0.0023 0.9342 0.0003 397.46 1.25
Day 3 78.0761 0.0024 20.9500 0.0023 0.9342 0.0003 397.34 1.28
Day 4 78.0798 0.0023 20.9469 0.0023 0.9337 0.0003 396.31 1.31
Day 5 78.0777 0.0030 20.9487 0.0028 0.9339 0.0003 396.76 1.34
Day 6 78.0741 0.0023 20.9518 0.0022 0.9344 0.0003 397.47 1.27
Day 7 78.0750 0.0023 20.9512 0.0022 0.9342 0.0003 397.23 1.30


Taking the first steps towards advanced process control

The process diagram shows a fully instrumented fermenter. Both liquid and gas-phase measurements are supplied in order to track a large range of process variables in real-time.

These data are input into the advanced process control (APC) system, which usually includes hybrid models made up of formal (linear) models and neural (nonlinear) network models.

The APC system supplies the set-points for multiple variables, which include control of nutrients and amino acids, and sparge content and flow, in addition to the conventional variables of pressure, temperature, agitation and pH.

The best situation for process scale-up and understanding is shown in this diagram, but there is a detailed amount of expense and complexity associated with this expansive method.

Due to it providing a considerable amount of extra value with moderate cost and minimum risk, the more common method is to add a multi-stream mass spectrometer. The Thermo Scientific™ Prima PRO can monitor 60+ fermenters without compromising sterility.

The Prima BT is a good bench-top solution for smaller-scale fermenters which are configured with 6 calibration ports and 15 samples. The complete gas composition measurements given by both models are accurate and easily incorporated into the APC system. Within one or two days of a start-up, huge improvements in process control can be seen.

Fully instrumented fermentor.

Figure 2. Fully instrumented fermentor. Image Credit: Thermo Fisher Scientific – Environmental and Process Monitoring Instruments

Supplying value during every stage of product development

For the complex manufacturing processes which are intrinsic to biotechnology advanced instrumentation is needed to optimize the clear path to the final product. The key to increasing profits is mitigating risk throughout the scale-up process.

The Prima PRO and Prima BT process mass spectrometers provide the accuracy and speed needed to facilitate timely corrective action and monitor process dynamics reliably.

The Prima platform technology helps to enhance yields, bring products to market more quickly, and increase profits. It also delivers a fast return on investment, from research and development to the final product.


Produced from materials originally authored by Thermo Fisher Scientific.

About Thermo Fisher Scientific – Environmental and Process Monitoring Instruments

We design and manufacture industry-leading products for Gas & particulate pollutants, Flow, gas and liquid measurement, Process analytical measurements, and Industrial Hygiene.

Technologies have proven to help customers improve efficiency, ensure process and quality control, maintain regulatory compliance, and increase worker safety.

Process mass spectrometers

Maximize product yield and increase profitability with process mass spectrometry analysis. Process gas analyzers are engineered to meet a number of challenging process applications in the petrochemical, iron, and steel, and biotechnology industries. Highly reliable and easy-to-own, Thermo Fisher Scientific process gas analysis technologies deliver faster, more complete, lab-quality online gas analysis and process analytics. Learn More

Process analytical technology/Biopharma

Process Analytical Technology (PAT) is a regulatory framework initiated by the United States’ Food and Drug Administration (FDA) that encourages pharmaceutical manufacturers to improve the process of pharmaceutical development, manufacturing, and quality control.

PAT aims to improve process efficiency by defining Critical Process Parameters (CPP) and monitoring these CPPs to stay within a defined limit, either in-line or on-line to maintain a product’s Critical Quality Attributes (CQA). Monitoring CPPs with process mass spectrometry gas analysis reduces over-processing, pinpoints contaminants, and increase product consistency. Learn More

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Industrial hygiene instruments keep your investments secure, your facilities compliant with local regulations, and your workers safe from leaking pollutants, gases, or toxic vapors. Make sure you have the most updated technology, with access to repair and calibration support to maintain reliable gas monitoring. With our environmental expertise, you can breathe easy knowing your company, workers, and neighboring communities have cleaner, safer, and healthier air quality. Learn More

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Online sulfur analyzers replace expensive and time-consuming laboratory sampling. Get fast responses and wide measurement ranges of trace sulfur and total sulfur in flare gas, liquid, and vapor for reliable emissions monitoring. Learn More

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Flow measurement and process control are critical aspects of producing, handling, and transporting hydrocarbons around the world. With our Thermo Scientific suite of flow computers and flow meters, we enable our customers to reduce cost, decrease lost material, automate, and monitor critical points in processes. From field to control room and upstream to downstream, our products provide greater control, confidence, and reliability. Learn More

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Last updated: Mar 26, 2021 at 11:00 AM


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