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The digital future of bioprocessing

Sponsored content | vrijdag 8 juni 2018

There is no way that the bioprocess industry can escape far-reaching digitalisation. It is not only a matter of replacing local PCs by web-based applications; all components of the process are linked and automated. The result is faster and better processes at less cost.

There is a lot happening in the industry. We now find ourselves in the fourth industrial revolution, or Industry 4.0. This is the trend of increasing automation and digitalisation in industrial production. The Internet of Things, the Cloud, artificial intelligence and machine learning being significant components. The main thing for bioprocessing and laboratories is the linking up of equipment, sensors and reactors. The automatically gathered data is used to make predictions and optimise the process.

‘One way is to make a digital twin’, says Sampath Kandala, director of digital product management & partnerships at GE Healthcare. Data is gathered continuously, for instance from a bioreactor in operation. Using that data, such as temperature, pH, mixing speed, etc., you train a model with the assistance of mechanistic and statistical models and machine learning. ‘This digital twin is more able to predict how the process will progress. For instance, you can obtain insight into cell density, product titre or glucose and lactose consumption. That makes it possible to detect faults in the process much earlier’, explains Kandala.

Central data collection

GE Healthcare already has a digital twin of a single-use mixer at production scale and is testing a prototype twin of a bioreactor. Implementation will still take some time, thinks Kandala, particularly because of the high investment involved. However, there are major advantages to be obtained by manufacturers. ‘You can use the data collected to speed up the development of drugs and production processes.’

In recent years enormous progress has been made in the field of linking up and automating systems. Before that, each device had its own operating program that was written exclusively by the manufacturer. And each program produced its own reports, for instance in Excel or a specific format of its own. ‘That’s all changing now’ notes Bert Lindemulder, manager at Infors Benelux. ‘An increasing number of devices are being integrated in the process. Data is gathered centrally and the software that regulates everything is becoming more and more web-based. This makes it much easier to team up with large groups, also in the international dimension.’ Infors developed the Eve software package for instance; a package that can not only control the user’s own bioreactors but also those of the competition, and various kinds of shakers, sensors and analysis equipment.

‘Faults in the process can be detected much earlier’

Erik Kakes, sales and marketing director at Applikon Biotechnology, also sees the benefits of a linked system. ‘Ten years ago, each device had its own package. It was one thing to be able to make a culture, but it took a lab assistant more than half his working time to analyse all the data. We now offer everything in a single package: Lucullus PIMS. Process Information Management System.’

It is important that user-friendly software makes such data accessible, says Jahir Kololli, product manager at Hamilton. ‘Customers don’t necessarily ask for the software itself; they ask for a solution. For instance: they simply want to be able to document the process and troubleshoot. Our ArcAir software supports the process.’ This software makes it easier for the operator to read out not only measurements but diagnostic data too. This means he is better able to anticipate the need for adjustments and consequently avoid unnecessary downtime. Kololli: ‘And with the off-line calibration tool you can substantially simplify and shorten the time needed to prepare an experiment. The software looks exactly the same on a PC, laptop, tablet or mobile phone, which means you don’t have to get used to the application on different devices. Starting up an experiment has been simplified, bringing down the number of steps involved from ten steps to four.’

Fast upscaling

‘Another major benefit of integrated software lies in the field of process optimisation’, says Lindemulder. ‘Users want to be able to design and plan an experiment simply. And that also includes process optimisation.’ The software helps users to design a series of experiments in which the various parameters can be adjusted. The processes are automatically analysed and a report showing the optimal process is the result.

Using the new software solution, V-Control (developed in collaboration with Emerson based on their DeltaV software), this optimisation also works between the lab and the production plant, says Kakes. ‘An industrial software package is usually more complex than a laboratory package and consequently more expensive. One of the main reasons being that you need to incorporate more safeguards in production. All systems are therefore duplicated, and data has to be securely stored.’

‘Customers don’t ask for the software itself; they ask for a solution’

In terms of usage, the Applikon V-Control package is the same for laboratories and production facilities. That makes it possible to rapidly scale up a laboratory-developed process for production, with no surprises. Kakes: ‘The formulas are the same, and therefore you can move quickly from laboratory, through pilot plant to production. That saves an enormous amount of time for our customers. You can also immediately test any improvements made in the lab during actual production because this is supported in the software.’

Problem solving is also easier given that the software centrally stores and analyses all the data. All data from the processes are contained in one and the same system. If anything goes wrong during production it’s easy to check exactly where the differences are with the lab experiment that did go well. This so-called audit trail and traceability is of immense importance, especially for biomaterials that must be produced in accordance with GMP and FDA guidelines, such as medical drugs and vaccines. Lindemulder: ‘All security measures are incorporated in the software. Everything is logged and the user can determine who has access to what.’

‘Flexible laboratories, such as GE Healthcare’s FlexFactory biomanufacturing platform, are now possible thanks to the aspect of automation in combination with single-use technology’, says Kandala. ‘Combined with an automation platform, monitoring and control of the process and data management have become much easier and we can now comply with the FDA regulations for audit trails.’

Monitoring the cells

Cell monitoring in bioreactors is also subject to constant improvement. Monitoring how the process in a bioreactor was progressing ten years ago meant taking readings chiefly with a pH meter, an oxygen sensor and a thermometer; in recent years advanced technologies have become more commonplace. The bioreactors of today are equipped with an HPLC, an IR or a Raman detector that record inline chromatograms or spectra. A microscope or other imaging technique monitors the shape of the cells and counts them. For instance, Ovizio, a spin-off of the Free University of Brussels, markets an imaging system that counts and analyses cells automatically and controls their quality. A biomass sensor measures how many live cells are still in the reactor.

All these options ensure a much better control of the bioprocess. Instead of first making the product and checking the quality after the process has finished, you can now check whether the quality is up to standard while the process is still underway. This makes it possible to intervene at an earlier stage and carry out adjustments if anything is not as it should be. To do this takes more than a pH or oxygen measurement alone. It is immediately evident after the process that the product, a vaccine for instance, meets the quality standard. In other words, the product can be taken to market much earlier. That does achieve a saving in cost, but for bioproducts it is also extremely important to ensure a fast time-to-market. Many products like vaccines only have a limited shelf life. The faster they reach the market, the more time there is to sell and use them.

Developments in sensors

‘Traditional sensors can still be developed much further’, says Kololli of Hamilton. ‘Maintaining pH sensors is becoming progressively more essential because the quality and lifespan of these devices have been greatly improved.’ Kololli believes many customers are unaware that proper maintenance can save them money. ‘pH is pH, is the general sentiment. But pH sensor maintenance is expensive, and many users still think they need to install a transmitter for each sensor.’

A transmitter is the amplifier that converts the analogue signal into a digital signal that can be read by the software. ‘Calibration and generating reports costs a lot of time and consequently money’, explains Kololli. That is why Hamilton developed the digital ARC sensor with an integrated transmitter and wrote a brochure to help clients understand that they can save almost half on their pH sensor. ‘It’s our duty to inform clients in this respect. There is little we can improve in terms of the pH measurement itself but this cost-saving aspect is becoming increasingly important.’

‘You can move quickly from laboratory, through pilot plant to production’.

Sensors are also becoming more highly developed, especially for single use. In this respect optical sensors are emerging. That works very well in respect of oxygen measurements. The measurement itself is based on fluorescence. The fluorophore, the part of the sensor that measures fluorescence, is located on the inside of the single-use bag and is immune to gamma radiation used for sterilisation purposes. The electronics are connected to the outer side of the bag and reused. Kololli explains: ‘We see that optical sensors are slowly replacing the traditional polarisation sensors because the measurement is faster, and in the event of lower oxygen concentrations more accurate than a traditional oxygen sensor.’

Hamilton is also working on these special sensors. In addition to an optical oxygen sensor the company has also developed a single-use pH sensor, the OneFerm. This has a single-use glass electrode inside the reactor bag. The costly electronics are located on the outside of the bag and are used repeatedly.


‘The emergence of single use has given the development of sensors a push. But these sensors are also being developed for smaller reactors: microreactors. This too is a present-day trend. Continuous processes are already smaller than batch processes. Production processes for cell therapies are even smaller still and more variation is possible’, says Kakes of Applikon. The concentration of cells in the reactors is constantly becoming higher, a so-called higher titre or cell density, so that more product can be obtained from a batch or process.  

This article was realised in collaboration with our commercial partners Applikon Biotechnology, GE Healthcare Life Sciences, Hamilton Bonaduz AG and Infors Benelux.

Join us on September 11th at the High Tech Campus in Eindhoven for the Single-Use Event 2018: the ultimate networking event in the world of (bio)pharmaceutical manufacturing, biotechnology and bioprocessing. Registration is now open!

Applikon Biotechnology

Applikon Biotechnology develops and produces advanced bioreactor systems, from laboratory scale via pilot plants to production facility. In addition to bioreactors Applikon Biotechnology is active in the fields of process control, process analysis and process automation. The company supplies its customers with total and reliable solutions for the bioprocess industry to contribute to a better quality of life. For instance, this year the company will market V-Control, the Delta-V automation solution designed for bioreactors in laboratories. Its headquarters are located at Science Park Technopolis in Delft with subsidiaries in the US and the UK and distributors in more than thirty countries.

GE Healthcare Life Sciences

GE Healthcare Life Sciences has wide expertise in many fields including medical imaging, medical drug discoveries and biopharmaceutical production technologies. It tries to help companies working with cells to make their production as efficient as possible. The company has an involvement in many projects on developing vaccines and gene therapy. With its FlexFactory it also offers a complete single-use factory installation that businesses can use. Last year, in association with other companies including Fujifilm Diosynth, this company developed these single-use bioproduction facilities.

Hamilton Bonaduz AG

Hamilton was originally an American company and now has a workforce of 1,400 worldwide and a large R&D and production location in Bonaduz, Switzerland. Among other things this company is engaged in robotics, high quality storage at low temperature and analysis equipment. It carries out much work on ways to make single-use and continuous analysis possible. Last year Hamilton launched a new version of the ArcAir software, a platform for controlling and monitoring the Hamilton Arc sensors.

Infors Benelux

Infors Benelux is a division of Infors-HT, a Swiss supplier of equipment for biotechnology systems. The company supplies, installs and maintains bioreactors, incubation shakers and bioprocess software for various companies located in the Benelux countries. It does this both for small-scale processes and large systems up to 1,000 litres. Infors Benelux’s specialism is supplying for R&D processes.