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Proven Mass Flow Performance for Bioprocess & Bioreactor Applications

Premier Control Technologies continue their support of the Bio-Tech Industries and following extensive voice-of-the-customer research they are proud to announce the latest Alicat Scientific BIO- Series of Mass Flow Meters/Controllers where modern design and solid-state construction provide solutions for many applications. They are specifically developed for: syngas production, Bioprocess/Chromatography, many types of bioreactors and bioprocess applications; biologics production, biosimilar development, biofuel production, nutraceutical development and much, much more. The new BIO-Series provides unmatched reliability, extreme flexibility and precise measurements in the world's only mass flow controller for bioprocessing.

The following studies consider the technological advances within three of the core applications:
Bioreactors - elastomer concerns and optimization
Gasification - creating Syngas and process improvement
Wastewater Treatment - an overview

Elastomer Concerns for Bioreactors

Biocompatible wetted materials are important to avoid contamination.
All Alicat BIO series mass flow meters and controllers use USP VI Elastomeric components exclusively. This means that every BIO series unit ensures that fragile bioreactions remain undisturbed by contaminants introduced by your mass flow control systems. This section discusses why this is a critical concern for professional bioprocess engineers and how we address it.

Bioprocessing has very specific requirements for wetted materials in order to avoid contamination of the bioreactor environment. The main potential contaminants are materials outgassed from elastomers, typically adsorbed onto elastomers during polymerization. While outgassing most commonly occurs under vacuum conditions, it can be a concern in any situation where a pressure drop is present (such as gas input lines for bioreactions). A number of studies have demonstrated outgassing from elastomeric components under a variety of conditions. Outgassed components are of concern as they are thought to be inhibitory towards microbial growth and have been shown to have toxic effects in whole animal studies.

The ASME Bioprocessing standards call out for specific materials used in construction of bioprocessing equipment. While mass flow meters typically lie outside of the sterile boundary, and should not have contact with the final product, it is still good practice to follow the BPE-2016 standards. Many high performing mass flow meters utilize elastomers to take advantage of the material's superlative sealing properties, which result in lower leak rates and higher precision mass flow measurement. Mass flow meters also require rigid materials (ranging from inexpensive ABS plastics to exotic stainless steels) for their flow bodies and process connections. Outgassing is a concern, as outgassed components would likely pass through sterilizing filters and are a potential source of process contamination. Therefore the BPE-2016 standards are often applied to mass flow meters, regardless of their position relative to the sterile boundary. 316L stainless steel can be used for elements in the flow path, including flow bodies and laminar flow elements. Less frequently considered, but of greater potential concern are the elastomeric components used in high performance mass flow meters.

To avoid the impacts of outgassing, only USP Class VI elastomers with good permeation resistance should be used. Outgassing is only able to occur after materials have first been permeated - so resistance to permeation is the critical factor in preventing subsequent outgassing. Marco rubber and plastics has published a nice comparison of permeation rates of common elastomers indexed with commonly used gasses. Additionally, elastomers used should be FDA certified. USP Class VI FDA certified elastomers have minimal reactivity and are certified safe for hygienic use. Finally, only certain corrosion resistant elastomers are recommended by the BPE-2016 standards. While several types of elastomer are available, Viton brand FKM (Fluoroelastomer ASTM D1418) meets the BPE 2016 standards, as well as being available in USP Class VI FDA certified form. Viton branded FKM also carries the implicit guarantee of Dupont's high quality manufacturing standards. Vitons' outstanding sealing characteristics, permeation resistance, high performance and available certifications make it a logical choice for these applications.

It is also good practice to use only Animal-Derived Ingredient (ADI) free products in bioprocessing. This avoids another potential source of contamination, as well as being an ethically sound practice. Choosing a mass flow meter which meets these requirements for compatibility should be an important part of any purchasing decision - and helps avoid potential contaminations of bioprocesses.

Optimizing Bioreactor Production
Bioreactors are used in a growing number of applications, from producing bio-adaptive medicines or environmentally friendly fertilizers and pesticides, to brewing beer, refining ethanol and treating wastewater. The increase in biologics production and single use reactors has led to a need for even greater precision and flexibility in instrumentation.

Alicat Scientific's broad range of mass flow
controllers simplifies and streamlines your bioreactor development lifecycle. Using one family of instruments with your choice of communications protocols, you can test conditions at 100 sµlm and then take the same accuracy and precision through the ramp-up to pilot plants and full-scale production at 5000 slpm. Built without hot wires, these MFCs can handle the ingress of liquids without being destroyed, making them well-suited to laboratory experimentation and continuous production use.

Maintaining Consistent Gas Delivery to the Reactor

Though the industrial applications for bioreactors are diverse, all rely upon the consistent delivery of air, oxygen, carbon dioxide and/or nitrogen to achieve and maintain optimal growth rates in the biomatter medium. Alicat's Gas Select feature allows you to use any Alicat Mass Flow Controller (MFC) to control these gases without sacrificing measurement accuracy, which in turn reduces the need to maintain separate inventories of gas-specific MFCs when ramping up to production. If you are adding or removing bioreactors on the same gas line, you can set the Alicat to maintain a constant pressure throughout the line while still monitoring or totalizing mass flow.

Standard backlit integrated displays make setup and data collection in the lab, or troubleshooting in the plant, easy and straightforward.

Controlling the Head Space
In certain reactions, when the oxygen in the head space above the biomatter medium is maintained at a higher pressure, the oxygen molecules more easily interact with the biomatter below. This condition can be achieved by using an Alicat Backpressure Controller at the outlet of the bioreactor to maintain an elevated pressure within the reactor. If you also want to monitor or totalize the outgassed mass, an Alicat mass flow controller can be configured to control the backpressure while at the same time measuring the flow through it. Alternatively, you can introduce additional oxygen directly into the headspace via a micro-flow mass flow controller running at mere milliliters per minute.

Monitoring & Recording Bioreactor Gas Output
Applications like methane production or hydrogenation benefit from comparing the mass of gas added to the bioreactor with the mass that has been outgassed. User-selectable units of true mass and optional totalizer firmware make it easy to compare these numbers without the cumbersome conversions from standardized volumetric flow rates.

Alicat COMPOSER Gas Select/Mix Calibration firmwareAlicat COMPOSERTM Gas Select / Mix Calibration Firmware allows the user to correct the flow rate on the fly as gas concentrations change or sent gas composition updates in real time from your gas analyzer. Even when outgassing occurs at atmospheric pressures, the very low pressure drop of Alicat's Whisper Series MWBs will not induce backpressure whilst quantifying outgassed mass. When your output is markedly peaked, the wide operating range of all Alicat MFCs will let you capture both the peak flow rates and the leading or trailing edges when flow is almost nothing.

Reduce Costs with 0.1% of Full Scale Accuracy
With protocols for bioprocessing now firmly established, there is an increasing focus on reducing the cost of producing biologics, biosimilars, mABs and other modern medicines that require bioreactions. Producing these pharmaceuticals promises to revolutionize treatment of many difficult diseases, especially modern scourges that have been resistant to small molecule-based therapies. Focus on cost reduction and improved speed has centered on two promising developments: so- called "single use" bioreactors and "continuous" bioreactors.

Reduce costs with 0.1% of full scale accuracy

Single use bioreactors lower costs by reducing the time and materials for sterilization and cleaning between production runs. In a conventional bioreactor, all material in contact with the bioreaction requires extensive and thorough cleaning and sterilization to prevent contamination. These processes in turn require extensive use of corrosion-resistant stainless steel and other resistant elastomers and materials. The use of these costly materials is a major driver in construction cost for new facilities. Single use reactors, by contrast, use disposable bags to contain biomass during the reaction. Rather than sterilization, many of the components of these systems can simply be discarded in between runs, reducing initial material costs and time required in between batches. Alicat helps meet the challenge of these systems by offering fast, flexible mass flow control at an affordable price. The COMPOSER feature means that their modern high speed controllers can function for multiple gasses with ASTM traceable accuracy (including, Air, CO2, and Oxygen - over 100 in all). Controllers can then be moved between systems as needed, providing redundancy at lower price points. Additionally, single use reactors are often used to "scale-up" processes. The high turndown ratio of Alicat's Mass flow controllers (up to 10:000 to 1 in some cases) mean that flows from a few sccm up to slpm ranges can be accommodated with the same mass flow controllers - allowing the mass flow control to scale with the reactor size.

Continuous bioreactors have been described as the "holy grail" of biologic production. These reactors are still a developing technology, but the promise can provide a bioreaction that allows for production over extended periods of time. Instead of typical reactions which are carried out for weeks to months - these bioreactors are designed to run for months to years. As with single use reactors, this would greatly reduce the cost per run. This is accomplished by dramatically extending the time of production between sterilizations. For this promise to be realized, homeostasis needs to be achieved by extremely accurate and responsive control of conditions within the reactor. Alicat can help overcome this challenge by providing extreme accuracy, responsiveness and control for your gas flow needs. Alicat's controllers have an astonishing mass flow accuracy as low as .1% of full scale and unbeatable repeatability of +/- .02% of full scale readings. Additionally, Alicat supports a variety of protocols and connections to ensure compatibility with your preferences. A custom-built, high accuracy mass flow controller with this level of precision is typically available less than two weeks after ordering!

The speed of biologics development and bioprocess production continue to advance with lower costs, higher speeds and greater flexibility. Mass Flow Controllers should offer the same.

Gasification Flow Control
Alicat Scientific Mass Flow Controllers can be used in multiple areas of the gasification process: combustion, clean-up reactors, safety, & quality control. Get more precise syngas production, redundancy between units and extremely fast control. Alicat's MCR controllers, with near- frictionless Rolamite proportional control valves, can rapidly & precisely control flow rates up to 5000 SLPM. With accuracy of +/- 0.8% of reading + 0.2% of full scale, precise composition can be ensured.

Gasification is a process by which biomass or fossil fuel is converted into carbon monoxide, hydrogen and carbon dioxide (syngas or synthetic gas). According to Carnot's Theorem of Thermodynamic Efficiency, the syngas produced is more energy rich than organic fuel in its combustion due to higher combustion temperatures. Furthermore, syngas can be used directly in gas engines, kilns, boilers and thermal oxidizers. In some parts of the world, syngas made from biomass is thought to be less expensive than fossil fuel and can be directly substituted in most applications. Furthermore, the quality of the syngas produced depends on the composition of the reaction, which ultimately relies on precise control of oxygen or air entering the gasification chamber.

Gasification Flow Control

Syngas can be created from a feedstock of biomass, municipal solid waste, medical waste and even hazardous waste. While the amount of pollution created depends upon the feedstock, syngas burns cleaner than fossil fuels and has much lower emissions of greenhouse gases.

Creating SyngasCreating Syngas
Syngas is typically created from three major components: carbon, oxygen and steam. The carbon and steam are created by heating the fuel, and the oxygen is added exogenously. The oxygen introduced will interact with the steam and carbon to ultimately create a mixture of hydrogen, carbon monoxide and carbon dioxide. The particular composition of the syngas is dependent primarily on the amount of oxygen added
to the system. Too much added oxygen will result in a higher concentration of carbon dioxide, and a correspondingly lower concentration of carbon monoxide. Such a mixture lowers the overall quality of the syngas and limits its applications.

Gasification ChamberDue to the large size of most gasification chambers, a large flow rate is typically required. A large mass flow controller is a precise way to combine the high flow rates needed with the accuracy required to create syngas with an ideal composition. Alicat's MCR-series controllers use near-frictionless Rolamite proportional control valves to rapidly and precisely control flow rates up to 5000 SLPM. With an accuracy of +/- (0.8% of reading + 0.2% of full scale range) extending to these high flow rates, precise composition can be ensured.

Improving Poor Batches

Improving poor batches
While the flow rate of oxygen can be precisely controlled, sometimes the concentration of syngas components is not as expected due to unforeseen variations in the feedstock or experimental setup. To combat this issue a simple quality control check can be inserted. When the quality of the syngas is less than ideal, usually by a creating a larger percentage of CO2 than is desirable, an Alicat Mass Flow Controller can be used to add propane to the mixture, rather than requiring a lengthy full system restart. This new mixture will more closely match the chemical properties of the desired composition and can be used in most applications. This compensation can be done easily via serial communication with the controller and integrated into an existing quality check program.

Additional Refinements

Additional Refinements
After the syngas has been created, a cleanup reactor may be used to remove undesirable tar particulates. Particulates are often removed using cyclonic separation. In a cyclone separator with secondary input, oxygen is sprayed through nozzles to create a vortex. The particulates will be unable to follow the tight curve of the vortex due to the increased inertia caused by their larger density. An Alicat Mass Flow Meter with high accuracy can ensure that particulates of the right density are separated efficiently by tightly controlling the oxygen flow. The syngas can be further cleaned with oil or water scrubbing to remove residual tar.

Safety First!

Safety First!
When working at such high temperatures with potentially combustible materials, purging the system quickly is sometimes necessary. A safety shut off system can easily be configured with a mass flow controller to flood the chamber with nitrogen. These controllers can be built with a CSA Class 1, Division 2 (ATEX zone 2) area classification to ensure that local fire safety regulations are being met and the mass flow controller is suitable for the operating environment.


Syngas produced by this method can be used for hydrogen fuel cells, power generation, transportation fuels, etc. A common secondary product from this process is "biochar". Biochar properties can be successfully predicted utilizing the van-Krevelen diagram. Biochar typically has hygroscopic properties and is highly useful in soil amendment, due to its inherent water retention, porous nature and utility as a carbon source. When operating at higher temperatures, gasification will produce liquid stone and metal instead of biochar. These resulting products can be used as construction materials or high density filler and have been proven to be non- leaching.4

Alicat Scientific Mass Flow Controllers can be used in multiple areas of the gasification process: combustion, clean-up reactors, safety, and quality control. The precision and versatility of these units allows for more precise syngas production, redundancy between units and extremely fast control. After all, the quality of the syngas produced is dependent upon accurate and repeatable flow of oxygen into the gasification chamber.

Aerobic vs Anaerobic Wastewater Treatment: An Overview
Conventional wastewater treatment consists of three distinct steps - primary, secondary and tertiary. Primary treatment involves the removal of solids by sedimentation or flotation. Secondary treatment involves the removal of organic matter through microbial decomposition. Finally, tertiary treatment is any additional treatment that the wastewater might have to undergo if it is reused, recycled or discharged to the environment. After the primary effluent leaves primary treatment, it is introduced into a specially designed bioreactor where the organic matter is utilized by microorganisms such as bacteria (aerobically or anaerobically), algae, and fungi (aerobically).

Aerobic vs Anaerobic Wastewater Treatment

Figure 1: Aerobic Treatment Principle

The selection of the secondary treatment may depend on several factors like nature of wastewater, chemical and biological oxygen demand (COD & BOD), energy demands, treatment time, investment, operational and maintenance costs, sludge production, space requirements, desired effluent quality, and microbial concentration. An optimum configuration would, more often than not, utilize a combination of these two technologies.
Aerobic treatment is typically applied to efficiently treat low strength wastewater (COD <1000 mg/L) when the treatment requires the presence of oxygen. Whereas, anaerobic treatment is typically applied to treat wastewater with higher organic loading (COD >4000 mg/L).


Figure 2: Aerobic Treatment Principle

Aerobic treatment utilizes oxygen and bacterial biomass to assimilate organic matter and other pollutants like nitrogen and phosphorus into carbon dioxide, water, and other biomass. On the other hand, anaerobic treatment, as the name suggests, breaks down organic impurities in the absence of oxygen to produce methane, carbon dioxide, and other biomass. Mass flow controllers and meters are critical to achieve fast, accurate and stable flows of air and oxygen in an aerobic process. Mass flow meters can be used to monitor fast, accurate and stable flows of methane and carbon dioxide in an anaerobic process.

Table 1 summaries the key differences between aerobic and anaerobic processes

Table 1 summarizes the key differences between aerobic and anaerobic processes:

Aerobic treatment has some distinct advantages over the anaerobic treatment process. These include reduced odour (due to non-production of hydrogen sulfide or methane) and better nutrient removal efficacy (facilitating direct discharge into surface waters or disinfection). However, Aerobic treatment does also have several disadvantages. Oxygenation is an energy- intensive process severely increasing the overall energy consumption, utility and maintenance costs of this process. Solid wastes that the microbes are unable to digest often settle out as bio- solids. These bio-solids require appropriate disposal adding to the utility and maintenance costs. Anaerobic treatment processes, on the other hand, have a number of advantages over aerobic treatment processes. The biogas produced during an anaerobic treatment process can be used as a source of renewable energy (natural gas/methane) also produces very low sludge that is de- waterable and fully stabilized for disposal. This makes it less expensive, simple and flexible when compared to most aerobic treatment processes.

Since both of these methods have their own advantages and disadvantages, often a combination of anaerobic and aerobic treatment processes are employed to achieve efficient treatment of wastewater. The wastewater going into the aerobic reactor will often undergo pre-treatment in an anaerobic reactor to fulfil wastewater standard discharge requirements in an energy efficient and cost-effective manner. In the past few decades bioreactor usage in the course of wastewater treatment has moved from an exotic, new technology to a standard process. A key strategy for optimization of these systems is to measure input and/or output gasses in order to understand and control the process efficiently. The precise usage of aerobic vs. anaerobic processes depends on factors unique to each facility and metering of mass flow is essential to understanding how best to utilize available tools to provides an optimal treatment regimen.

Reliable, Adaptable and Compatible Flow Control

Flexible configuration, customized for your needs. Everything you need, nothing you don't.
* Built with your preferred industrial protocols and Pharma 4.0 in mind

* FDA-grade elastomers prevent contamination

* Backflow tolerance with zero calibration drift

* Gas Select feature enables exchange of controller gasses without re-calibration or loss of accuracy

* 316L stainless steel for durability and stability, with a lifetime warranty

* Wide range flow rates and compatibility with multiple gasses eliminates unnecessary piping

* One family of instruments from lab, to pilot, to production

* 200 to 1 turndown reduces ranges required

* Gas Select reduces spare inventory

* Durably withstands ingress of liquids

* Low pressure drop models for working with low pressure differentials

* COMPOSERTM gas recipe system for matching outgassing compositions

* Profibus, Modbus, EtherCAT, EtherNet/IP, DeviceNet

* LabVIEW drivers

* Control pressure while measuring mass flow

For more information, please contact :

Andy Mangell - Sales Director

Premier Control Technologies Ltd.
Unit 1 Oaktree Business Park, Philip Ford Way, Wymondham, Norfolk, NR18 9AQ
+44 (0)1953 609930 (ext 742)

August 2019

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