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Bioprocessing in the Future: Single-Use and Continuous

Redactie | vrijdag 26 januari 2018
Analyse & Labtechnologie, (Bio)procestechnologie

A great deal is taking place in the bioprocessing industry. Plastic disposable drums are replacing the old-fashioned steel drums and traditional batch processes are being completely restructured. Five companies talk about the most recent developments in this industry.

Dictated by recent developments in molecular chemistry and biology, the bioprocessing industry and biopharma are engaged in a major transition. Researchers in laboratories around the entire world are using technologies like CRISPR-Cas9 to develop new processes, from personalised cell therapies to biofuel production. Both large and small-scale businesses are latching onto many of these new processes and subsequently trying to convert them into efficient production on a larger scale.

During this scaling-up process the bioindustry is more or less copying the well-established chemical-processing industry. And yet it is apparent that not all technologies can be duplicated one-on-one. In other words, a totally new approach and many new technologies and businesses are needed to tackle these challenges. A glimpse in the world of the bioprocessing industry and the most recent developments.

Disposable material

In cases where the traditional processing industry swears by enormous steel drums which can do their job for many years, these reactors appear to be a lot less efficient for use in biological processes. ‘When you work with bacteria you need to scrupulously clean the reactors’ says Jan van Diermen, director of Biotech Services. ‘Nothing may be left behind or the next batch could be ruined. And such a cleaning process costs a great deal of time and therefore money.’ That is why more and more companies are switching over to single-use, or disposable material.

Single-use reactors function something like your domestic rubbish bin: you buy a drum, line it with a bag and as soon as the reaction has finished you simply dispose of the bag. ‘But these bags can do much more than your domestic grey bag’, says Marcus Bayer, single-use manager at Hamilton. ‘Located at the upper side of the drum is a clip into which you click the bag as it were. That clip contains a number of sensors and electronics that help you monitor the reaction.’

‘Single-use material drastically shortens the time needed to take a product to the market’

Depending on your wishes you can add sensors such as a pH, dissolved oxygen or cell density sensor to obtain a more accurate picture of the reaction. Some of these sensors are again single-use and thus the risk of pollution is even less. But there are still some snags in that respect, points out Bert Lindemulder, manager at Infors Benelux. ‘The results of those single-use sensors are not always as good as those of the standard sensors. Plus the fact that it’s difficult to find materials that don’t leak into your reaction.’

Because of the system’s flexibility and the relatively low cost, single-use products are particularly useful for start-ups. ‘The investment required is substantially lower and start-up time shorter’, says Michiel Jansen, manager at PALL Life Sciences Benelux. ‘Single use enormously shortens the time needed to take a product to market given that you are then more flexible. That’s what makes it so attractive.’

In addition to the bags you also have single-use drums of up to 50 litres that businesses can use to test their first scaling-up operation. The largest single-use bag is currently 4,000 litres. But most companies use bags no bigger than 2,000 litres, comments Neil Ross, marketing manager at GE Healthcare. ‘You’re talking about plastic bags here. In a reactor of this sort a great deal of stress is put on the plastic during the stirring process. There is a limit to how much these bags can take.’

Apart from the limits in terms of size there is another major disadvantage to single-use: it generates a large volume of waste. And do businesses want that – especially now when we are gradually trying to make the world more sustainable? Van Diermen: ‘Waste is the biggest disadvantage of this system. Fortunately, a substantial amount of the single-use material is made up of recyclable plastic and therefore part of the problem is solved.’ Bayer does not expect that the extra amount of waste will be a critical issue for companies: ‘The advantages of single use, particularly the low risk of contamination, outweigh the aspect of extra waste. And recycling also negates the critical issue.’

Nonstop

Single-use materials today are being used more frequently in combination with another trend: continuous processes. That’s not always a good idea, believes Lindemulder: ‘For a continuous process your material has to be stronger and last longer. Single use is therefore not always suitable.’

But single use or not, in recent years an increasing number of bioprocesses have started to be continuous, almost all inspired by traditional chemical processing technology. ‘Continuous processing with cells is more difficult because it always stops at some point’ says Van Diermen. ‘The quality of your mixture then becomes too low or the cells die. But some cell lines can grow for months and therefore they are suitable for a continuous process.’ Ross also notes an increase in interest: ‘We see many customers wanting continuous processes. But it generally takes numerous technical adjustments making implementation difficult.’

However, businesses are not held back by that. The American Food & Drug Administration (FDA) even encourages businesses to switch to continuous processes. Ross understands why: ‘It makes it possible to produce more and therefore reduce costs. Ultimately that means cheaper medicines.’ But according to Jansen the higher production volume is not the main reason for businesses to make the switch: ‘First and foremost they want to be flexible. A modern-day continuous process makes it possible to start up with smaller volumes, generally using smaller reactors; it’s then easier to make adjustments.

‘It’s easier to make adjustments in a modern-day continuous process’

And again, start-ups find such a flexible set-up an interesting proposition, says Bayer. ‘You can adjust things faster and don’t immediately need a big factory. You have enough space to accommodate everything and the investment needed is low.’

It does cost money however, but it also makes it possible to connect the inlet flows to the reactor and constantly feed the cells and generate product. Yet all these processes are not completely continuous; batch elements are often needed. ‘Especially linking up the various cleaning stages at production scale is apparently still difficult’, says Jansen. ‘In fact you want to have continuous cleaning of your product, but that cannot be done without problem as yet. In other words, we expect that many processes will continue to be a combination of batch and continuous for the next few years.’

A glimpse inside the tank

During such a continuous process it is very important to keep a close eye on the reaction. That is why a growing number of businesses are asking for ways to monitor the cells 24 hours a day to enable them to check whether nothing has gone wrong. ‘The biggest challenge involved in implementing continuous processes is the analysis’, says Ross. ‘Cells are much less predictable than molecules; there’s much more going on in such a tank. That’s why we are trying to incorporate analyses – which are generally carried out separately – in the system.’

One of the important analyses is monitoring the number of cells. To get an idea of the density of dead cells you can measure the volume and weight. However, that only determines the dead cells and moreover it is not accurate. You can only really find out how the reaction is going if you know the concentration of living cells and not the dead ones. Hence many businesses use a cell density sensor. ‘These sensors measure the polarity of the cells in the mixture and are able to determine whether a cell is alive or not’, explains Van Diermen. ‘This gives you a more precise indication as to what is happening in your tank.’

Besides quantifying living and dead cells it is now possible to continuously measure variables such as pH and oxygen concentration. But Bayer thinks that this market will grow even further. ‘The trend of monitoring 24 hours a day has been going on for some time now but we see that our monitoring systems are becoming more popular. Apparently, a growing number of businesses want to know exactly what happens inside their reaction drum. And obviously we want to help them do just that.’

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


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!


Biotech Services

Biotech Services is a Dutch company engaged in the maintenance and installation of fermentation systems, bioreactors and various peripheral equipment. It is also an official agency for Solaris and in that role supplies companies with fermenters. Biotech Services is a supplier to numerous major players on the market and thus has a good overview of the developments in the bioprocessing industry. This company advises its clients for instance on the options available for continuous processing and assists them in setting up new processes.

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, the 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 OneFerm onto the market, a single-use pH sensor which is currently being brought into operation at numerous biotech companies. In collaboration with partners the company is integrating these products in production lines.

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 to R&D processes.

PALL Life Sciences

PALL Life Sciences has its headquarters in Port Washington, New York, and was originally a supplier of filters. Over the past few years the company has continued to develop and is now engaged in chromatography, single-use systems, bioreactors and mixers. With its wide-ranging portfolio, PALL helps its customers to produce new drugs, vaccines and pharmaceuticals. It is also highly involved in the optimisation of current processes, for instance by integrating chromatography and analysis methods into the system.

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