Preparing for future bioprocessing challenges with the Cellca CHO Expression Platform

Therapeutic protein development and production is a very technically challenging, time consuming and expensive endeavor.

What are some of the challenges? There are numerous critical decisions that must be made with regard to mammalian cell line choice (CHO, NS0, etc.), appropriate gene and marker expression systems, cell culture medium and feed optimization, clone selection and scale-up strategies. Biopharmaceutical developers should be careful to choose options which deliver the following:

• Maximum protein titer
• Scalability (5L – 1000L)
• Long-term Stability
• Cost effectiveness
• Shortened development timelines
• No burdensome IP concerns

Why is it important and critical to understand these challenges? There are considerable economic considerations to be made; one should maximize financial budgets by minimizing expenditures on equipment and technologies required for in-house development and characterization of the therapeutic protein. It’s important to make efficient and productive investments in R&D; technology and process development requires highly trained and expert staff. There are also commercial or market considerations which will affect return on investments; to maximize IP and patent life the therapeutic protein must be developed and commercialized as quickly as possible to gain maximum market share in a highly competitive environment. First to market is paramount for biosimilar developers.

How has the CRO industry responded? “Turn-key” cell line development and bioanalytical testing CROs are currently open for business and accessible for outsourcing nearly all upstream, downstream and biomolecular analytical activities. Sartorius Stedim Biotech offer the most comprehensive, scalable and unique bioprocess portfolio to support Biosimilar development and manufacturing. With Sartorius Stedim Biotechs’ recent acquisition of Cellca (cell line development) and BioOutsource (bioanalytical and biosafety testing), there is now established a fully functional, and integrated CRO uniquely positioned to support clients development programs across the entire product lifecycle.

The result of outsourcing biopharmaceutical development and production to experienced CROs will have major positive implications for shortening the time to commercialization at significantly reduced costs.

To learn more about the industry leading Cellca CLD platform which delivers stable, high titre clones, (95% of projects have delivered titres >3.0g/litre) in a proven scalable fed batch manufacturing process in a cost and time efficient manner please join our talk by Dr. Brian Wendelburg at IBC Cell Line Development & Engineering Conference, San Francisco, 14th June at 1.25pm.

Author Bio:


Dr. Brian Wendelburg received his Ph.D. in Molecular Biophysics from the Institute of Molecular Biophysics at Florida State University. He then completed his postdoctoral training at the University of North Carolina’s Lineberger Comprehensive Cancer Center. His professional career has involved diverse roles in sales and business development activities at leading Biotech companies such as Cepheid, Affymetrix and Miltenyi Biotec where he gained a strong technical background in genomics, proteomics and cell and gene therapy applications. He joined the Sartorius-Stedim Biotech team in the spring of 2016 and is currently Sr. Field Marketing Manager for the BioOutsource and Cellca divisions.

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Cell Line Meeting Is Just Two Weeks Away - See Who's Attending

IBC's Cell Line Development & Engineering meeting is less two 3 weeks away, taking place on September 8-10, 2014 in Berkeley, CA. 

Don't miss your chance to network with these confirmed attendees who will share their experiences, successes and lessons learned for improving cell line stability, predictability, quality and understanding.  The list includes guests from:

-         -  Merck Serono SA

-         - GlaxoSmithKline

-         - Lonza

-         - Bristol Myers Squibb

-         - Eli Lilly

-         - The FDA

-         - Amgen

-         - Genentech Inc.

Check out the full list here.

If you haven't had a chance to review the 40 case studies and new data presentations on this year's agenda, check it out today.

Register to attend this year's event and gain the practical strategies, best practices and approaches you need to implement today's novel technologies for developing better expression systems for novel modalities and difficult-to-express proteins.  Now you can save 20% off the standard rate* as a reader of this blog.  Register here and use code XB14188BLOG.  

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Cell Line Development: MicroRNAs in a Commercial Process

A few weeks ago, we wrote about an interview with Dr. Niall Barron, who’ll be speaking at this year’s Cell Line Development & Engineering conference, in which he explained why researchers should be paying attention to MicroRNAs.  Given that an estimated 50% to 70% of all protein encoding genes are under the control of MircoRNAs themselves, it’s clear that these molecules should be peaking the interest of researchers.  But how can they be leveraged in the commercial sense?  We go back to Dr. Barron for the answer.

How might they be implemented by industry in a commercial process?

Dr. Barron: So, as I mentioned previously, there are two main approaches. Ideally, an industry would use this technology before going through regulatory submission. So, with a new cell line making a particular product of interest, a cell line would be manipulated stably by using something like the technology I just described. For instance, over expression sponge that would target the microRNA of interest, or indeed, over expressing a short hairpin that will mimic the microRNA of interest if over expression is desired. So, that forms a stable cell line that can act as the parent, into which the product gene or the transgene is placed and that would go through the normal regulatory process.

The alternative in existing process where full regulatory submission is not desirable would be to add either mimics or inhibitors, which are short molecules that are typically complexed with some kind of transfection reagent and that can be fed directly into the culture medium where it is transported across the outer cell membrane to mediate its effect directly in the process.

You can hear the complete interview with Dr. Barron here, or you can download the transcript included in our brochure here.

Get the latest from Dr. Barron and other industry experts at this year’s Cell Line Development and Engineering conference, September 8-10, Berkeley, CA.  Now, SAVE 20% off the standard rate*.  Register here and use code XB14189BLOG.

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Removing Bottlenecks in Cell Line Engineering

There are several known bottlenecks in generating mammalian cell clones to produce therapeutic proteins.  Dr. Nic Mermod, Director of the Institute of Biotechnology at the University of Lausanne, cites biological issues, such as transcription levels, as well as process issues, including the cloning and maintenance of many cells, as causes of these bottlenecks.  Dr. Mermod, who will be speaking at this year’s Cell Line Development & Engineering conference, has several ideas on removing said bottlenecks.  Some thoughts from this leader in the field:

What are the current approaches when removing such bottlenecks?

Dr. Mermod: The first bottleneck is transcription of the transgene. We have been working on the element called MAR, which can remove some of the negative effects of integration of the transgene into a non-favorable genetic environment. And other people are also working on other elements. That – for the MAR elements –allows to, pretty much, dampen some silencing effects and also to prevent oscillation of transcription, whereby you get the transgene active at all times within all cells.

So, that’s one way to alleviate low levels of transcription. Another way, of course, is to basically increase transgene copy number. That is to work on the recombination mechanism to allow your CHO cells to more efficiently integrate transgene, if you want to further boost the level up.

And then for basic protein metabolism and secretion, there are efforts by a number of laboratories to perform genomic engineering of the CHO cell. For instance, we have reengineered the human secretion machinery in CHO-M cells which allows to increase protein secretion of easy or difficult to express proteins; both of them. So, that’s basically the current approach that we and others are taking.

To check out our full interview with Dr. Nic Mermod, download the Cell Line Development and Engineering brochure.

We’ll have more from Nic at this year’s Cell Line Development & Engineering conference.  Join us September 8-10 in Berkeley, CA.  Save 20%* off the standard rate as a reader of this blog when you register here and use discount code XB14189BLOG.   

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Timeline Reduction in Cell Line Development

What are the most important attributes in developing recombinant cell lines?  For Alison Porter, Head of Mammalian Cell Culture R&D for FUJIFILM Diosynth Biotechnology, the list includes high titer, growth properties that are suitable for a manufacturing process and production of product with the correct characteristics.  The importance of these qualities can’t be overstated, however, achieving them in an efficient way is a priority as well.   We went ahead and got Alison’s take on how to improve some of these characteristics with a reduced timeline in mind.  Check out what she had to say:

What can you target if you want to reduce timelines whilst improving some of these desirable attributes?

Alison: To answer this, I’m going to concentrate on the idea of improving titer whilst reducing timelines. Probably, increasing titer is the most common goal when looking to improve desirable attributes further. When people are thinking about increasing titer over the past 20 to 25 years, the obvious and main contributor that comes to mind is, of course, design of media and feeds in particular.

But there are other contributors from the cell line development stage that can play a role in improving titer whilst reducing timelines. The host cell line, vector and the cell line development process itself. If, for example, we think about the cell line development process, introduction of improved screens can allow earlier selection of the best cell lines. By improved screens, I’m thinking about things like multi-well plate systems, which are operated in suspension mode and have feeds applied, and micro bioreactor systems. So, you hopefully end up using these as being both better at identifying cell lines capable of high expression and identifying them earlier on.

September 8-10, Berkeley, CA

To think about host cell lines, work can be done to develop new host cell lines with increased expression capability and you can also improve them with regards to growth characteristics - and that will also potentially help reduce timelines.

At FUJIFILM, we’ve actually been looking at all three of these areas recently – host cell lines, vector and cell line development process. Looking to further improve our cell line development capabilities.

To check out the full interview with Alison Porter, download the Cell Line Development and Engineering brochure.

We’ll have more from Alison at this year’s Cell Line Development & Engineering conference.  Join us September 8-10 in Berkeley, CA.  Save 20%* off the standard rate when you register here and use discount code XB14189BLOG.   

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MicroRNAs: Should Researchers Be Paying Attention?

According to Niall Barron, it’s estimated that somewhere between 50 and 70% of all protein encoding genes are under the control of MicroRNAs themselves.  That said, MicroRNAs are an important part of cell line development going forward.  Dr. Barron, who will be presenting on the topic at this year’s Cell Line Development and Engineering conference, believes these molecules should have researcher’s attention.  We were recently able to pick his brain and get some of his thoughts as to exactly why that is:  

Should biopharma companies and researchers be interested in MicroRNAs?

Dr. Barron: As I say, harkening back to this characteristic – which is their ability to influence the expression of lots of different proteins – one of the challenges in the past for engineering CHO cells is that we have to do it gene by gene. This is not proven to be particularly useful, although there has been some success in that area. So, with the ability to over-express or down-regulate individual microRNA, that opens up the possibility of changing the expression of multiple downstream genes or proteins. This really allows us to start thinking of about ways of engineering entire biological pathways within cells.

One of the other interesting aspects is that these molecules are not translated into proteins themselves. Therefore, as we know CHO cells, what we’re using them for is to over-express our product. Therefore, engineering something in there that will compete without over-expression is likely to be detrimental to efficiency. So, by using a microRNA as a tool, you reduce the translational burdens that you place upon the cell. We would hope that by doing that you are less likely to negatively impact on the expression of your product.

Finally, genetic engineering of CHO cells typically would involve a full submission to the regulatory authorities. Stably expressing CHO cells to up or down-regulate a particular microRNA would require that also, but there is the possibility of transiently transfecting them into an existing CHO cell line within the bioreactor, which would just be a process-related change in the same way that adding a feed of nutrients or something to a bioreactor is not considered a new cell line.

Download the brochure to check out Dr. Barron’s full interview.

Get the latest from Dr. Barron and other industry experts at this year’s Cell Line Development and Engineering conference, September 8-10, Berkeley, CA.  Now, SAVE 20% off the standard rate.  Register here and use code XB14189BLOG.

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