Scaling up phage production: Q&A with Cellexus CEO

Issue 84 | July 17, 2020
19 min read
Capsid and Tail

Want to scale up your phage production? The CellMaker is a single-use bioreactor designed to speed up and simplify cell culture and fermentation. It’s used by phage companies and labs around the world. Source: Cellexus.

This week, we interviewed Gavin Hands, CEO of Cellexus, about the company’s history of helping phage researchers and biotech companies scale up their phage production.

Gavin Hands, CEO of Cellexus

Gavin Hands is the CEO of Cellexus, a company that researches, develops and manufactures the CellMaker range of revolutionary single-use, airlift bioreactor systems.

Sponsor

Cellexus Sponsorship Logo

This issue was sponsored by Cellexus, which pioneers revolutionary, market leading single-use airlift bioreactor systems and technology.

Email [email protected] for more info.

Urgent July 16, 2020

Urgent need for Propionibacterium acnes phages for a patient with osteomyelitis

Phage Therapy Osteomyelitis

We are urgently seeking Propionibacterium acnes phages for a patient in Europe.

Ways to help at this stage:

  • By receiving the strain and testing your phages
  • By sending your phages for testing on the patient’s strain
  • By providing information on best practices for cultivating P. acnes and its phages
  • By helping spread the word about this request
  • By providing us with names/email addresses of labs you think we should contact

Please email [email protected] if you can help in any way, or if you would like further details/clarification.

Let’s make a difference,
Phage Directory

What’s New

Siân Owen (Harvard Medical School) and colleagues published a new preprint on a new prophage-encoded defense protein that simultaneously suppresses phage epidemics in a population (through abortive infection) and provides self-immunity to the prophage that encodes it. Here’s the preprint and a Twitter thread (full of microscopy videos!) by Sian that explains it!

Phage defense systemsPreprintProphage

James Gurney (Georgia Institute of Technology) and colleagues published a new paper on ‘phage steering’: when phages are used to push pathogens to evolve to be less antibiotic-resistant. They show that Pseudomonas phage OMKO1 effectively pushes P. aeruginosa to be more antibiotic-sensitive, even in the presence of antibiotics (and even after > 70 generations of continuous phage exposure)!

AMRPhage-antibiotic synergyResearch paper

Intralytix has been issued a US patent covering its Shigella phages and their various formulations and applications (US Patent # 10,711,252), including improving food safety and human health, maintaining healthy gut microflora by modulating a mammal’s microbiome, and reducing colonization in the gut.

Biotech newsIntellectual Property

Stanley Ho (University of Birmingham) has made a list of bioinformatics tools for predicting and identifying phages in metagenomes and metaviromes. See also this Twitter thread, where others have been sharing similar tools.

Bioinformatics ToolMetagenomicsMetaviromics

DBSCAN-SWA is a new tool for prophage detection, recently published as a preprint by Rui Gan (Harbin Institute of Technology, China) and colleagues. Preprint | Github.

Bioinformatics ToolProphage

Katja Šuster (Valdoltra Orthopaedic Hospital, Slovenia) and colleagues published a new paper in The New Microbiologica describing their use of phage K to speed up Staphylococcus detection in prosthetic joint fluid.

DiagnosticsProsthetic joint infectionsResearch paper

Oriana Flores (Pontifical Catholic University of Valparaíso, Chile) and colleagues published a new paper in Microorganisms showing the isolation and characterization of 13 phages with the potential to control Pseudomonas syringae pv. Actinidiae infections in kiwifruit plants.

Phage in agricultureResearch paper

Latest Jobs

Invitris is a new team out of TU Munich funded to spin off a phage therapy biotech company based on their unique synthetic phage production system. They’re looking for an additional team member at the intersection of microbiology and the clinic.
June Round (University of Utah) is seeking a postdoc to study phages in commensal populations of Clostridium.
Professor Lone Brøndsted (University of Copenhagen, Denmark) has an opening in her lab for a PhD student to work on a phage-host interaction project.

Community Board

Anyone can post a message to the phage community — and it could be anything from collaboration requests, post-doc searches, sequencing help — just ask!

Join us this coming Tuesday, July 21 for PHAVES 3!

Phage Directory

Our next PHAVES event will be Tuesday, July 21 at 11 AM Eastern, 5 PM CEST (GMT+2).

Piotr Tynecki of SLAVIC AI, the creator of phage.ai, will give a talk entitled "Boosting phage exploration by Artificial Intelligence: what could data science do for your research?"

Sign up here at seminars.phage.directory. If you’ve already signed up for the whole series, no action necessary! You’ll get an email closer to the date.

Wondering about the recap/recording of PHAVES 2? We will recap PHAVES 2 and 3 in next week’s Capsid & Tail.

Virtual EventArtificial intelligence

Pseudomonas Seminar Series

Cassandra Nelson, University of Maryland

Next week’s Pseudomonas Seminar will be held on Tuesday July 21th at 1pm EST. Our speaker will be Dr. Patrick Secor from the University of Montana presenting “The intersection of quorum sensing and Pf bacteriophage replication”. Register here.

Virtual Event

Seeking used phage equipment

Emmanuel Nnadi, Plateau State University, Nigeria

Are you changing lab or upgrading equipment? Consider donating used or old equipment to our phage lab to help us build our phage capacity. Email: [email protected]

Seeking equipment

Question for the community

Emmanuel Nnadi, Plateau State University, Nigeria

Would you consider a phage that has acitivity against Staphylococcus aureus, Staphylococcus capitis, Salmonella typhi, Escherichia coli, and Pseudomonas spp an asset or liability? Good phage or bad phage? Email: [email protected]

Q&A

Scaling up phage production: Q&A with Cellexus CEO

Profile Image
Phage microbiologist and co-founder of Phage Directory
Co-founder
Phage Directory, Atlanta, GA, United States

Jessica Sacher is a co-founder of Phage Directory and has a Ph.D in Microbiology and Biotechnology from the University of Alberta.

For Phage Directory, she takes care of the science, writing, communications, and business aspects.

This week, we bring you a Q&A with Gavin Hands, CEO of Cellexus.

This piece was sponsored by Cellexus.

Jessica: Can you tell us a bit about your background?

Gavin: My background is I’m an accountant. But the last thing I ever want to be called is an accountant. Some people call me an entrepreneur, but I don’t like that term either. I describe myself as an opportunist; I see an area where I can make a difference and I go for it.

How did you get started with Cellexus, and when was that?

I was working for a scientific toxicology business in Dundee that we managed to sell, and then quite naturally, my role was no longer required in 2017. So I put my network into overdrive and said, I’m now available for the next opportunity. What can I do? Within a week, a friend introduced me to a management advisor, who had a company in need of a new management team. Two other people got involved in this opportunity. And we looked at it and decided we’re just going to set up a new company and buy it. So Cellexus International was created in August 2017, and we acquired Cellexus Limited in October 2017.

What was so exciting about this opportunity? How did you know it was worth jumping into?

Funnily enough, I’d actually had dinner two years before with the managing director of Cellexus Limited, and he was telling me about what a great piece of equipment the CellMaker was. We’d also found a sales director with 30 years’ experience selling into the single-use bioreactor space. We talked to some users of the CellMaker system, who said that it was really good. But the company was run by a small team on a shoestring budget, and they were just running out of energy and looking at the wrong markets. So we put in better management processes and funding to take the CellMaker systems to market properly.

So let’s talk about the machine itself, the CellMaker. It’s a support structure with a bag inside, that essentially becomes a bioreactor. You throw that bag out and replace it, and then now it’s a bioreactor again, no cleaning. Is that right?

Our bioreactor bags sit in metal enclosures, with a seperate controller box that can sit underneath the lab bench, or on the bench depending on the lab space available. Our basic enclosure is 8 L in volume. You can fit two 8-L enclosures inside a standard fume hood, as one of our clients, Proteon Pharmaceuticals, originally set up.

And so your bioreactors are single-use, right? How does that work?

The single-use aspect is very simple. The CellMaker comes as a sterile ready-to-use bioreactor. It installs in minutes, is ready to fill, and has a quick change-over time between batches. It controls parameters like gas flow and temperature, so it’s easy to check on the process. It also records the variables used, so a standard process can be set up for reproducibility. And the clear side panels allow visual inspection during a run. In comparison, glass shaker flasks or stainless steel bioreactors have to be cleaned and sterilized between runs. And if you’re doing a GMP process, you have to validate that the vessels have been cleaned and sterilized, before you can reuse them. You also have to buy equipment for cleaning everything. And so you compare that to single-use plastic bags (though this has a bad connotation these days).

True, “single-use plastic” can sound bad. How environmentally-friendly are the bags?

It’s been proven that single-use is actually more efficient and better environmentally than the other systems. And it’s not only more environmentally friendly when you compare it to the amount of energy and chemicals that are added to the process, but it’s also a much more efficient use of time. You can change bags out and do your production in batches. You can take your bag out and put it straight in the fridge or take it for further downstream processing.

How do the contents get mixed?

In the CellMaker bioreactor, we use bubbles to agitate the mixture — we refer to it as airlift, and it can be any gas that your process requires. There are three other alternative methods of agitating the mixtures. Roller ball, which is just a spinning drum. It’s not very controllable. There is the rocking process such as the wave bioreactor, which is a square bag that sits on a rocking plate; it rocks backwards and forwards, but you buy a 10-L bag, and all you can do is put 6 L in it due to the wave motion. And then you’ve got a stirring process, which involves either an arm or impeller blades that spin around and turn the mixtures over; with this there is a risk of cell shearing. We use a fourth method, which is to bubble air or any gas or combination of gasses from the bottom of the bioreactor bag. As the gas bubbles up, it does the mixing, and the bag is designed to create a circular flow up to the top of the bag. So we believe our method is more gentle to cell cultures in comparison to the other methods, and it provides better oxygenation.

And you can control the temperature on the machine?

Yes, the controller will manage the temperature and the gas flow, and if you’re using a Plus controller it will manage the pH inside the bag and monitor dissolved oxygen. But the Regular CellMaker system, which is what’s needed for phage use, is a much simpler controller, less expensive, and the Regular bags are cheaper because they don’t have the additional sensors. The enclosures have heating and cooling plates, so you can accurately manage temperature to 0.1 of a degree. A lecturer at Dundee University, who was initially very skeptical, started using a Plus system for a trial and immediately loved it. He said, “you’ve created a mechanical womb!”, a phrase which has stuck with me, as the systems manage the temperature, dissolved oxygen and pH all from the controller, creating reproducible conditions.

As a former phage researcher, this sounds like something I really could have used. Is this something that research labs are purchasing, or who is buying this in the phage world?

In the phage world at the moment, it’s mainly biotech companies who are using it, because they’re scaling up phage production.

What kind of volumes is it designed for?

The 8-L bioreactor runs from 3-8 L, and our 50-L bioreactor runs from 10-50 L. And our one controller can run either an 8-L or a 50-L bioreactor. So if you start with an 8-L and then you decide that you’re actually moving up in volume, you don’t have to buy a new system — just purchase the 50L enclosure to scale up.

Are companies using this to prepare phages for clinical trials? Is this part of their GMP manufacturing setup?

The companies we’re selling to are mostly in the process of scaling up phage production for animal health applications. We have a customer in Portugal who is launching a clinical trial. So they’ve been under GMP for manufacturing. And Proteon is using our CellMaker as part of their phage production process, and also for their R&D projects. Rob Lavigne at KU Leuven is next to receive one of our CellMakers. We are really excited to be supporting his team on their phage projects.

Interesting, so biotech companies as well as research labs are using it. It’s exciting that this may be an option for labs.

Yes, we are aiming to make smaller bioreactor bags, which will sit inside the 8-L enclosure. That would reduce the minimum recommended working volume down to around 1.5 L, which would be a lot closer to laboratory bench research scale.

At what point did you realize as a company that phage was something you should focus on?

Well, the CellMaker was developed way back in 2008, and had been on many journeys in its lifetime. We took over the company and its existing customer base, and Proteon, a phage company, was one of the main customers. So we had to make a choice as we were changing manufacturing partners for our bioreactor bags; we had one last order to place with the previous manufacturers, which needed to last us to the point where we could have a new manufacturer up and running. We had to take a big risk as we were a new company with limited resources. We decided that we would produce the Regular bags for Proteon because we felt it was important for them; their orders grew quarter to quarter, and we were a critical part of their process. So we took the customer-centric view, deciding it was more important for Proteon to have bag supply than it was for us to get new customers in different areas. So we put all our marketing focus on phage, as our Regular bioreactor bags are the ones best suited for phage production.

Okay, so phage work has actually been integral to getting the company to where it is.

Yes, we saw Proteon’s demand growing, we understood that phage had come from Eastern Europe, we could see all the problems with antimicrobial resistance developing. The phage world seemed to be the area which was going to be the answer. That’s what my logic was. And then we came across Phage Futures in Washington in 2019, we were really enthused about the event, and the market. We decided that phage was something we were going to focus on and support, and that’s why we’ve gone to 12 different phage conferences in the last 18 months.

It’s exciting to see somebody addressing this key bottleneck for the phage world: being able to scale up phage production in a cost effective way.

Yes, we believe the CellMaker is really good for the phage community. Without knowing people’s processes, we’ve performed demos in laboratories, given the CellMaker a quick setup, and plugged in their process and their mixture. And we get between 20 and 30 times improvement in phage amplification over their expected results.

How about price point — I’m sure many are wondering whether this is within their budget?

One thing we’ve developed recently to help with costs is a rental model. There’ll be a minimum rental period, typically three months, and they would have to buy the single-use bags. If they decide they like the machine, we will credit 75% off the rental back against the purchase price.

Has the COVID-19 crisis made it hard to do new installations and provide support to customers?

When COVID-19 kicked off, we were concerned about travel and how to manage remote installations of the CellMaker. We had an inquiry from Cytophage in Canada, who decided to buy a CellMaker system. We’re about to perform a remote installation using FieldService24 technology. So Cytophage now has a headset that their engineer can wear; it has a camera and communications on it so that our engineer in Scotland can see exactly what is being looked at and be in direct contact during the process.

Also FieldService24 will give our customers a process for logging calls for an engineer; if a user has an issue that can’t be sorted through web chat or email and phone calls, we’d send out a headset so that there can be a live view of what the issue is (rather than sending an engineer out). This will lead to better support for our customers, and if this process does not resolve the issue, then we can still have the options to either carry out a service visit or have a unit shipped back for repair.

So people around the world can order the CellMaker?

Yes, we’ve been impressed at the level of inquiries that we’ve received; inquiries from Australia and from South America. And I’m on a call tomorrow with a professor in Singapore. So we have a worldwide base of potential customers, and we now have a system in FieldService24 that can support remote operators. We’ve also developed a network of eight distributors covering 12 different countries in Europe, and nanoscaleLABS in the USA.

What are some of the new improvements to the CellMaker that you’re excited about?

One thing I haven’t mentioned is our Dual Regular controller system. So this means that one controller will now run two enclosures — two 8-L enclosures, two 50-L, or one of each. An improvement we’ve made to our bioreactor bags is that they can now use an optical density sensor for in situ reporting. The sensor is a bit limited for OD below 1, so it may not be helpful for phage production just now. However for other cell cultures, like mammalian cell cultures, this will be useful.

We’re also testing a very exciting new technology that stimulates cell growth — it’s probably more for E. coli or mammalian cell culturing. In trials, cell cultures have grown in half the time, and produced 30% more antibodies. So we’re now looking to try this out with phage processes.

What’s next for Cellexus as a company?

Because our bioreactor bags are now ready to order and produce, we’ve started to grow the team here in Cellexus. So we’ve taken on another engineer to build up the engineering team, and we’ve set up outsourcing capabilities to scale up production of our CellMaker systems. We also have a new hire who is actually a phage scientist joining us in August. If everything goes according to plan, we could be up to 20 people by the end of next year.

Thank you so much for enlightening me and the rest of the phage community on your company’s story! It’s especially neat to hear about companies’ origins, and to see that they often grow from grassroots beginnings as well.

Yes, we are excited to better understand the phage community’s needs with the help of our new hire. As a phage scientist, he is better placed to support phage users and provide constructive advice on how best to use the CellMaker systems.


Rohit Kongari helped us produce this week’s article by helping us source articles for the What’s New section. Thanks Rohit!!

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