[Solutions spotlight] A better way to measure critical attributes in bioreactors

In pharma, the use of gas analysis in fermentation bioreactors is critical for monitoring the health of a culture, and measuring small changes to oxygen and carbon dioxide concentrations at key phases of the process. Whether using continuous or batch fermentation for bacterial, microbial or mammalian cell culture expression, Thermo Fischer Scientific's gas analysis mass spectrometry product range provides precise off-gas analysis through every stage of fermentation. To learn more about the Prima BT and Prima PRO models, senior editor Meagan Parrish chats with Daniel Merriman, strategic marketing manager, Thermo Fischer.

Transcript

Meagan Parrish: It's no secret that the pharma industry has been feeling the need for speed in the last few years. When the world asked for vaccines and therapeutics to be developed quicker than ever before, the industry responded and hundreds of potential vaccines and treatments were ushered into clinical trials within months. But as we know, developing a new pharma product is just one part of a process that requires several major complex steps to be taken.

So once pharma companies had approved products, they then had to race into their manufacturing facilities to crank out doses as quickly as possible. And they couldn't just move fast, they had to be careful and accurate because the world gripped by the pandemic was waiting. And any misstep would mean that the world would have to wait longer. I'm Meagan Parrish and you're listening to a special solution Spotlight Edition of "Off Script," pharma manufacturing's podcast that goes beyond the pages of our magazine to discuss the issues that matter to the industry most.

In this episode, we're going to talk about the use of analytical tools for fermentation, a complicated and integral part of the manufacturing process for several biopharma products, including monoclonal antibodies, hormones such as insulin, and of course vaccines because in the wake of COVID-19, a new normal has settled over the pharma industry. Now that everyone has seen just how fast pharma companies can innovate and produce new products, patients are wondering why can't we always move at this pace? So although the emphasis on speed arose during the pandemic, that push to keep moving quickly isn't likely to abate any time soon. And in this new environment, manufacturers are looking for solutions that improve efficiency while maintaining quality and accuracy.

To help meet both of those needs, Thermo Fisher offers a line of mass spectrometers for gas analysis in the biotech industry. In pharma, the use of gas analysis and fermentation bioreactors is critical for monitoring the health of the culture and measuring small changes to oxygen and carbon dioxide concentration at key phases of the process. Whether a company is using continuous or batch fermentation for bacterial, microbial or mammalian cell culture expression, Thermo's gas analysis, mass spec product range, which includes it's Prima BT and Prima PRO models provide precise off gas analysis through every stage of fermentation from the lab to the pilot plant to scale up. And on top of that, Thermo's mass spec products work quickly and provide significant process control improvements that can be achieved usually within just a few days.

To learn more about the Prima BT and Prima PRO models, I'm joined today by Daniel Merryman, the strategic marketing manager at Thermo Fisher. Daniel joined Thermo Fisher way back in 1988 and has worked extensively in his career to advance the use of online mass spectrometry as a process analytical technology in the biotechnology sector.

Daniel, thanks so much for joining me today.

Daniel Merryman: It's a pleasure to talk to you today, Meagan. I'm really looking forward to our discussion.

Meagan: Let's go ahead and start with some background on these technologies that we're going to talk about today. I was wondering if you could describe the relationship between gas analysis, mass spectrometry and process analytical technology as defined by the FDA.

Daniel: Yes, I will. And the FDA itself supports the implementation of analytical technologies. When implementing PAT, users typically identify critical quality attributes that they wish to effect, typically attributes that might impact product yield or quality. The next step is to study through analysis critical process parameters that impact those quality attributes. And this is where online analysis comes in.

Gas analysis mass spec is one powerful tool for the study of these process parameters both directly by measurement of off gas concentrations, such as oxygen, CO2, maybe some other volatiles, and then utilization of that data to calculate parameters such as respiratory quotient. The goal is to use these process parameters then to effect a better control of the process that ultimately yields better outcomes. And that's really what PAT is about as far as the FDA is concerned.

Meagan: Yeah. And you kind of just touched on this a little bit, but I was wondering if you could tell me a little bit more about problems that pharma companies are trying to overcome when they're using this type of analyzer.

Daniel: Well implementation of online process monitoring as a fermenter bioreactor is not a trivial matter. If the intention is to perform online automated liquid phase sampling, these can be complex systems. Whether the analysis is done online or offline, measurements at the fermenter often requires high value analyzers, which are costly to use from a consumable perspective.

The intention of online gas analysis though, particularly by mass spectrometry is to make these measurements low risk so that they should be fully automated and able to provide process data that can reduce the dependence on offline testing, but also to produce that data in real time, without the need for manual intervention. So really, it's taking the measurements away from an arts line, a manual method and turning it into an automated online method.

Meagan: Yeah. And you kind of brought up the issue of cost in there, of course that's always a big issue, cost and efficiency for every company. So I'm wondering, are there not simpler or cheaper methods for this?

Daniel: Yeah, of course. For gas analysis there are, but they're not likely to facilitate the online measurements from a large number of fermenters. A mass spec could sample as many as 50 fermenters with a single system. And I should also note that the measurement precision of lower cost sensors typically rather quite poor compared to mass spectrometry.

But another advantage of mass spec which isn't available to other techniques is that mass spec can measure more than just simple oxygen, CO2 components. I think I mentioned earlier, other volatiles are typically measured in many processes. That's commonplace. Things like ethanol and methanol that are routinely measured in fermentation processes by mass spec. And that doesn't add any cost to the solution.

Meagan: Yeah. And speaking of costs, I mean, as you're kind of alluding to, mass spec can be known to be a little bit more expensive, but is it a cost effective solution in the long term? Is it the kind of situation where you pay more up front, but it saves you money over, you know, down the line?

Daniel: Yeah. As I said, a single mass spec could be utilized and often are for many fermenters from a single analyzer. So, cost per point comes down very quickly, but it's, as you said, it's not all about initial cost. Operating costs of mass spec is very low, but notably, you know, it's also the value of the measurements that's very high.

Meagan: Okay. Now, let's talk about integrating mass spec if a company goes ahead and decides that they want to use this kind of system. You've described it as being relatively simple and low risk. I was wondering if you could just elaborate on that a little bit more.

Daniel: Yeah. What I mean by that, measurements of spars gas and bank gas from fermenters and bioreactors by mass spec requires the mass spec to be entirely outside of the sterile environment. There's no interruption to the process or interference to the fermenter or bioreactor. These systems also provide a very reliable measurement method. So, they are in this sense also a low risk implementation.

Meagan: So, there are many different types of processes that are of course used in biopharma production. Can you tell me a little bit more about how this technology is suitable for those different types of processes?

Daniel: Yes. Generally, it's been applied to microbial and mammalian cell cultures for the development and production of many types of products. So, mainly pharmaceutical, but also it's applicable to agricultural products, bio-materials and biofuels. And the latter is there's a lot of interest in that.

Meagan: Wow. So, it's used in a lot of different industries it sounds like. And of course, in biopharma, there's a lot of interest in mammalian cell culture. So, tell me a little bit more about how this technology is applied in the same way for that.

Daniel: Yes, there are already some excellent studies on the use of online mass spec for cell cultures. In general, the measurements are similar to microbial fermentation, but mass spec has a very impressive linear range for the gases that are required to be measured. And that's especially useful in cell culture because the concentrations of the spars gas and vent gases can vary significantly. That is the oxygen, CO₂ concentrations can vary over a very, very wide range in concentration.

Also, mass spec is very precise and again, in cell culture, the changes in CO₂ and oxygen in the respiratory gas, those concentration changes can be very, very small. And mass spec is precise enough to measure those small changes reliably, whereas other techniques would not be able to.

Meagan: Okay, great. And I want to talk a little bit more about the broad advantages of using gas analysis, mass spec. Can you tell me what kinds of advantages companies have realized by implementing this solution?

Daniel: Yeah. If I could summarize the advantages that have been gained given the things we've discussed so far, I'd say it's to have this real-time insight into cell metabolism, that really enables the realization of PAT goals such as improving performance attributes, but also, you know, with a focus on prevention and minimizing of poor process quality. I'd say that's it. I would summarize it.

Meagan: But of course, every single process, it seems like, in biopharma production has its drawbacks and limitations as well. So, tell me a little bit about those limitations for mass spec.

Daniel: Yes. Well, one limitation, which is common to gas analyzers is that they need a minimum gas flow, but from the sample. So, there will be some processes and in fermentation and cell culture where the volume of the bioreactor is so small that it's impractical to use online gas analysis to monitor them. So, there certainly is some limitation in that respect.

Meagan: Okay. And of course, vendors for pharma companies, they're always looking at ways that they can innovate their solutions to make life easier for pharma manufacturers. So, tell me a little bit more about what's next for gas analysis mass spec.

Daniel: Well, I think solving the above limitation would be a good start, but I think from where we are today, I do see an expected increase in the use of this technology for mammalian cell cultures, but also an extension of many other types of products, which are made by fermentation [and] are likely to use gas analysis mass spectrometry. Something, for example, like green energy, I referred earlier to biofuels and biomaterials. So, I think that we will see continued extension of different applications that have fermentation or cell culture that are common to them.

Meagan: Okay, great. Well, that was all really interesting, Daniel. Thank you so much for calling in to talk to me and share your insights with me today.

Daniel: Well, you're very welcome, Meagan. And thanks for the questions. I enjoyed that discussion.

Meagan: Absolutely. You've been listening to a special solution Spotlight Edition of Off Script. Stay safe, everyone and be well

For more, tune into Off Script: A Pharm Manufacturing Podcast.