How to Take the Grunt Work Out of Cell Culture Development
Michael McSunas, Senior Bioprocess Engineer leading Culture’s effort in CHO cell culture, talks about the challenges of running cell culture experiments, and how biopharma companies can benefit from leaving their experiment execution to Culture.
Can you tell me about your background? How did your previous experience bring you to join Culture, leading our effort to expand into mammalian cell culture?
I’ve always loved life sciences, so I studied biochemistry at UCLA, where I got a master’s in biochemistry and molecular biology. I then looked for opportunities to use what I learned to make an impact, and decided making biological drugs seemed like the best fit. I was lucky to participate in Genentech’s Process Development Rotation Program (PDRP) where I rotated for two years learning about bioprocess development. I saw everything from upstream process development through purification and formulation, as well as analytical assessment of product quality.
I enjoyed cell culture because I like the idea that you reap what you sow - it’s like high-tech gardening or farming, but with less digging in the dirt. Genentech had a robust microbial and mammalian pipeline when I started, so I could have gone in either direction, but I preferred working with CHO (the workhorse for mAb production) because it involves a long, detail-oriented process that requires a lot of upfront planning. After you plan, you get to watch it come to fruition. This delayed gratification aspect continued to inspire me throughout my time at Genentech. During my eight years there I did a wide range of things, including engineering and screening clones, developing and optimizing CHO cell culture processes, managing execution of pilot scale, and managing Phase 1 and 3 clinical material generation in GMP facilities.
Having developed this expertise in CHO cell culture development, I also wanted to nurture my interest in building new things. The opportunity to work with Culture and lead the effort to adapt their fermentation platform to grow mammalian cells was perfect for me. In addition to my excitement about the engineering challenges, I was drawn to Culture's mission: lowering the energy required to execute what can be a high-effort, costly, time-consuming experiment. That’s why I’m so excited to be at Culture helping companies both small and large execute processes more efficiently.
How does Culture uniquely help small and large biotech companies?
Culture’s bioreactor system is valuable for smaller companies who would do more of their own process development if only they had the facilities. Building and managing a lab takes time, effort and money that many small companies don’t have. They need a partner like Culture in order to ramp up process development quickly without buying in-house bioreactors - or hiring the staff to run and maintain them.
On the other hand, at large companies, there are often bioreactor capacity constraints because there are so many programs that are competing for space internally. With limited capacity, these firms are forced to prioritize only some experiments rather than running all the experiments they know are necessary to optimize their manufacturing process and de-risk scale-up. With Culture, larger companies can use all the bioreactors they need without making compromises, which enables them to make better, data-driven decisions.
As someone who worked on the client side, what are the challenges involved in running mammalian cell culture experiments?
Cell culture is very sensitive to even small changes in inputs, and unfortunately the results of these sensitivities can reveal themselves quite late in a process. As a result, you have to be vigilant in monitoring and extremely detailed in planning. Because mammalian cells can be so sensitive, and because running a bioreactor to grow CHO cell culture is such a big time investment - it takes an average of 14 days vs. only a few for something like E. coli - it can be nerve racking for those two weeks. That’s why having good, robust systems and processes in place for risk mitigation is important. As opposed to microbial processes, where you may be able to quickly intercede during development if something goes wrong, you can’t really do that with mammalian. Instead, you set the course from the beginning and you most likely have to start over if something goes wrong.
Why do you have to start over if something goes wrong?
It’s usually because you’re developing a therapeutic with mammalian cell culture. Unlike other products that aren’t as highly regulated for safety, the product quality for therapeutics has to be within previous clinical safety experience to ensure patient safety, the most important thing of all. If your product quality is off, the whole batch might have to be rejected, and you just wasted a lot of money on this process. Because of that higher risk, there’s less room for error and larger costs associated with failure. That’s why it’s so important to mitigate risks.
How does Culture address this risk problem for cell culture scientists?
Culture helps solve this problem in multiple ways. First, we’ve developed extremely robust hardware, software, and operational procedures that give clients the confidence that their runs will be successful. Additionally, although our clients design their own process development experiments, Culture’s team of experts works as a partner to ensure risks are identified and strategies are put in place to mitigate them.
Culture also solves the problem of irregular bioreactor capacity needs. For mammalian cell culture, because experiments run for weeks at a time rather than consistently, there tend to be surges in capacity needs. With Culture's Guaranteed Capacity model, customers benefit from having bioreactors available all the time to accommodate these surges quickly.
Can you tell me more about the hardware and software capabilities you mentioned? How do they give clients confidence in the way their process was run?
With mammalian cell culture, you’re probably controlling the top side of a pH limit by sparging CO2 and DO with one of several possible strategies involving air and pure oxygen. You need to fully understand the relationships there and have the right control logic in place. Culture’s hardware ensures that we have tight control over the way gasses make their way into the vessel. We built our hardware (and rebuilt it) so that it’s quite precise. On the software side, we refined our control feedback loops, so they maintain oxygen and pH really well.
We run our vessels with custom-built automation tools and control software. Our team is laser-focused on running high-quality experiments that our customers design, so all of our attention goes to maximizing efficiency of operations to ensure consistent and reliable data. We've developed streamlined procedures, tickets and records for our team to enable us to run high-throughput experiments for many different customers. In mammalian runs, there’s a lot of micromanaging involved - you have to think about the vessel prep, gassing strategies, and all the other process parameters - but with Culture, all steps of the process always happen the same way, so you can be confident the process will run as planned. As the process runs, clients can monitor the data on our website in real time to make sure everything looks as expected.
Another really useful piece of Culture’s software is the data visualization tool that enables clients to make faster data-driven decisions. When you’re managing in-house bioreactors, there’s as much work that goes into doing the run and generating the data as analyzing the data. Culture makes it so much easier to analyze data compared to what clients are probably used to; you’d be surprised at how antiquated most systems for analyzing data are - even at established companies. While these companies aren’t really invested in software, it is a crucial piece of Culture’s platform, and it allows scientists to make faster decisions so they can turn around experiments more quickly in an otherwise slow process.
Coming from Genentech, how would Culture have been helpful to you in your role there or to your colleagues?
At the end of the day, for Culture’s clients and places like Genentech, running bioreactors is a means to an end - it’s not the main mission. Driving value for patients by developing powerful, lifesaving biotherapeutics is their mission. On the research side, Genentech hires amazing scientists to discover new drugs. On the process side, they hire talented engineers to develop and optimize processes to consistently make high-quality medicines for patients.
Precious resources - namely, talented scientists - are too often misspent running bioreactors. That’s why I think partnering with Culture for experiment execution and lab buildout makes perfect sense - this should be handled by a team that efficiently and dependably executes high-quality experiments as their primary focus. This way, process development scientists can spend more time actually developing processes and less time monitoring runs or handling samples. Culture helps biotech companies accomplish their true mission - serving patients.
Another way Culture can help is to provide access to a representative scale vessel earlier in development. Cell culture process developers have traditionally been forced to do early clone screening in shake flasks because there was no alternative - or rather, the alternative was costly or unavailable. Now, with Culture, they can opt to use Culture’s 250mL bioreactors - without building out their own lab - and get more directly process-relevant data instead of something less representative like a shake flask or a micro-bioreactor like the ambr15. Access to more bioreactor capacity at an earlier stage of development allows you to catch crucial data and information earlier, which can lead to better processes at scale.
What about Culture made you decide to join the team?
I always loved what Culture was doing; I love the idea of more efficiently executing experiments and extracting data, and I knew the biopharma industry in particular could benefit from that. I was also excited to work at a startup and join a team of experts working across functions and wearing many hats. Once I met the team, I was sold.
What are you most excited about for Culture (and our clients) in the near future?
I’m excited to start ramping up the number of customers we work with who are doing cell culture process development. I can't wait to see scientists improve their processes using our scalable and reproducible system. I’m also excited for customers to discover how much they can benefit from our data visualization software. I think the best process developers communicate results and conclusions effectively, and Culture’s tool lowers the activation energy for that. I know that customers will be pleasantly surprised by how easy it is to generate valuable insights quickly. Overall, I’m excited to share a tool with biotech companies that will help them continue their success and eliminate the grunt work of running bioreactors that’s involved in bringing life-changing products to market.
Read our white paper to see data showing how Culture has developed a reproducible and scalable 250mL bioreactor system for CHO cell culture.