Todd Przybycien on Precipitation As Antibody Capture

October 8, 2026

In the latest episode of Bioprocessing Unfiltered, Bill Whitford talks with Todd Przybycien about using precipitation as a continuous capture step for monoclonal antibody downstream processing, and why higher titers make the approach practical again. We dig into step change improvements in cost of goods, throughput, footprint, and sustainability, plus what it takes to control and automate a continuous process.

Join us to hear:

• Todd’s early downstream processing work and why “unconventional separations” matter
• Why precipitation was sidelined at low titers and why modern mAb titers change the efficiency
• How precipitation enables fully continuous capture and pairs with flow-through polishing
• Where the biggest gains show up, including dollars per gram, water usage per gram, and smaller facilities

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Covering both upstream and downstream processing, analytics, AI and digitization, cell and gene therapy and more, Bioprocessing Unfiltered is your insider's pass to the researchers tackling—and solving—the day-to-day challenges in the bioprocessing industry.

GUEST BIO

Todd Przybycien, PhD, Professor and Head, Chemical and Biological Engineering, Rensselaer Polytechnic Institute
Todd M. Przybycien, PhD, Professor of Chemical and Biological Engineering at Rensselaer Polytechnic Institute, received undergraduate degrees in chemical engineering and in chemistry from Washington University in St. Louis and Masters and PhD in chemical engineering with a minor in biology from Caltech. Todd started his professional career with Monsanto Agricultural Company where he worked in downstream bioprocess development for recombinant somatotropins for about two years. He then launched his academic career at Rensselaer Polytechnic Institute, where he worked for eight years, followed by another twenty years at Carnegie Mellon University, where he was a faculty member in the Chemical Engineering department and the Founding Head of the Biomedical Engineering department. In fall 2018, he returned to RPI. In summer 2025, he became the Department Head. Todd’s primary research interests are in the downstream manufacturing (purification) of biotherapeutics.

HOST BIO

William Whitford, Founder, Oamaru BioSystems
Bill is founder of Oamaru BioSystems with over 20 years' experience in biotechnology product and process development. He now publishes oral papers, print articles, and book chapters on such topics as ATMP process intensification, AI/ML tools, and net positive building economy in biomanufacturing. Recently, his work has been acknowledged in the 2022 APEX Award for Publication Excellence in the Technical & Technology Writing category and the 2023 ISPE Roger F. Sherwood Article of the Year award. He currently enjoys serving on such committees as the BioProcess International Editorial Advisory Board, and the chair of the 3SMAGNET Intersectoral Advisory Board. Bill has an h-index of 18 and an i10 index of 37.

TRANSCRIPT

Welcome And Guest Introduction

Welcome to the Bioprocessing Unfiltered Podcast. Each month we host conversations with the researchers and leaders tackling and solving the day-to-day challenges of the bioprocessing industry.

Hello, I'm Bill Whitford, and welcome to Bioprocess Unfiltered. Today I'm sitting down with Todd Przybycien. He's the professor and head of chemical and biological engineering at Rensselaer Polytechnic Institute. And we're going to be speaking about optimizing throughput, mass indices, and cost of goods in continuous precipitation-based MAB downstream processing. Welcome, Todd.

Thank you very much, Bill. Pleasure to be here.

All right. I

Todd’s Path Into Downstream Processing

thought to start off, you could talk about a little bit of how you got into this particular field and what your early goals were in it.

Yeah, I've been working in downstream processing since graduate school, where I started off and looking at, strangely enough, precipitation as a potential process for purifying proteins. And had a short stint at Monsanto, where I did some downstream processing work on bovine semanotropins and have been kind of fascinated and interesting, interested in downstream processing ever since. And in particular, trying to think of, we'll say, unconventional ways of performing the separations that drive downstream processing in hopes of driving us towards, we'll say, more sustainable manufacturing.

Well, that's interesting. You know, having the industrial experience then I'm sure is powerful in your scope, in your schema of envisioning uh these processes rather than being purely academic, that you you can see where the rubber meets the road and the practicality.

It was a really formative experience. And I thank my colleagues at Monsanto uh extremely. Uh, you know, you learned so much in graduate school uh and you know, some of the uh the theories, et cetera, but where the rubber hits the road is in manufacturing and in process development. And they really opened my eyes to the practical considerations and really the practical problems that are faced in downstream processing. Always knew I wanted to be an academic and I wanted to tackle those kinds of practical problems, to know that, yeah, maybe I could bring some insights, my knowledge of the literature, maybe some theory to bear, but to bear on something that had practical value and to solve a problem that needed solving.

Why Precipitation Makes Sense Now

We were speaking earlier, and I expressed that I've I've been hearing about precipitation in MAB for 30 years, and people have been rejecting it for various reasons. And you were explaining to me why it's different now and what you're doing. And so we have a technical audience here, so I think it'd be nice for you to go into what the the hesitations were and why you think now is a good time to uh promote it.

Yeah, precipitation is something that's old and is now new again. Folks that have been in the field for a bit will certainly be familiar with the Cohn fractionation process for plasma proteins. And one of the fractions that was of interest, of course, or was the antibody fraction. And if you think about blood has antibody titers anywhere between seven and 15 grams per liter. Well, you know, in the early days of monoclonal antibody production, titers weren't all that great. And so precipitation wasn't on the top of anybody's mind. Now titers have increased pretty dramatically. Now, five grams per liter is common, 10 grams per liter, fairly common as well, above 10 grams per liter. I'm sure there are plenty of places that are producing that and that just haven't talked about that quite yet.

So if I can add for the audience that that dilute solutions are more difficult to precipitate and less efficient. So as you get up to the levels we're at now, it's not only easier, but it's more efficient as a procedure.

Now it makes sense to think about. When titers were very low, you would have to add a truckload of precipitant of any type in order to reduce the solubility to get some sort of precipitate. Now there's plenty of antibody in solution and bulk separation techniques like precipitation start to make sense. So that's kind of one barrier that we've crossed that titers have made precipitation part of the conversation now, because again, there's plenty of historical uh process development that's shown it's very efficient when you get to higher titers. I think another barrier, of course, is the same barrier to all we'll say, capital I innovation, where you know we're not making incremental changes, but more dramatic changes. Clearly, the use of precipitation in biological processes, particularly if we're talking about high titer proteins like monoclonal antibodies, that's a new thing for the industry for a lot of folks. And being able to cross that bridge of saying, you know, we're going to go from what we know and what works really well to something that's very different, something that we don't have a lot of institutional experience doing, and something perhaps that regulators haven't seen in quite a while, which brings a lot of risk to it. So,

Innovation Risk And Regulatory Reality

so why bother doing this then? And I think the answer to that self-imposed question is that we're not going to be able to do things the way we've been doing things in terms of purifying high-value, high titer proteins like antibodies, the way we've been doing them, and expect to do that indefinitely. The resources required, the costs that are involved, kind of the supply and global demand issues don't really permit that to go on indefinitely. We need to be thinking about alternative ways of doing things so that we can meet future needs sustainably.

You know, in that discussion, it seems to me that there are many individual distinct reasons why people want to increase efficiency or or would change a process. Uh, you mentioned kind of the democratization of a product, that you want to get more product uh to more people. And you know, that that's more of a noble goal, whereas an individual company might be trying to save money. I mean, so there are many or sustainability, there are many different individual goals that would drive towards uh this efficiency that you're promoting with precipitation. My thought is that from a regulatory perspective, you you're you're a bit a bit hesitant. You're saying that people don't want to change and and uh you people are concerned about regulators, but it seems to me that precipitation is so tried and true that that might be an easy one to convince uh uh quality people and regulators to examine and accept.

Yeah, and I don't think that there is resistance from the from agencies side or from their point of view. I think they do welcome and are trying to welcome innovation. But it is clearly a risk for companies to take something that a process that they don't have great familiarity with, or we'll say long-standing familiarity with. That's a probably a better way of putting it, and to take something like that forward, because the risk is, well, you know, what are the unknown unknowns that we have in taking this process forward? What might we, what might we get asked? What might we have to demonstrate that we haven't considered? And that brings forth the possibility of delays, which are difficult for companies, innovator companies to digest. And perhaps where some of you know these types of innovations that move well beyond what we'll call platform type approaches, well-established approaches that everybody knows, understands, loves well, knows the path forward for those. You know, what's going to break the ice and move us to direction, again, of kind of capital- I innovation? And you have to have step change improvements. It can't be an incremental improvement. It's got to be a step change improvement in some metric of interest. You know, maybe it's a cost of goods metric, maybe it's a capacity or throughput metric, maybe it's a raw material usage metric or a waste generation metric, maybe it's a complexity metric where a radically new type of process or a very different type of process has a very different supply chain, and that could be beneficial. There are a number of different reasons I think that that would move you in the direction of, we'll say, a more radical change in a process. And one of the things that I've been appreciating more is since you know the FDA has really pushed continuous processing and has been pushing innovation and is trying to make it more convenient to innovate. That coupled with you know more recent big changes like the use, the rise of single-use technologies, et cetera. Capital I innovation is something that companies are grappling with now. They may not be implementing it in their manufacturing processes right now, but it's something that they're developing and maybe for clinical lots, et cetera. So just the willingness to now consider big types of process changes, like moving from a chromatographic capture step to a precipitation-based capture step. That's part of the conversation now. And it's not, you know, when you talk about these things, you're not immediately shut down or asked to leave the room. There's, you know, a willingness to engage and to think about this. It's a possibility. And that's exciting to me.

Are you

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It seems to me that precipitation fulfills most of those categories of potential improvements that you've described. So I'm thinking maybe if you could describe for us a little bit of a case study or a particular application of your of what you're doing, and then maybe then weave into that the potential for automation or or as you mentioned, these other innovations that we're driving for. Continuous is a goal, but maybe automation or where you think this could possibly fit into a more advanced application.

Sure.

Building A Fully Continuous Capture Step

So again, the the the big change that that I'm a strong proponent of is the consideration of precipitation as a capture step. So and that means precipitating your target species. And that makes sense again when titers are large enough that bulk type processing like precipitation or maybe extraction, those kinds of things makes sense. And as it turns out, a process like precipitation is best conducted in a fully continuous manner. So it kind of fits in with the move of the industry towards adopting continuous processing. And as a capture step, it can be run fully continuously as opposed to periodic continuous operation of very clever modes of affinity chromatography that are commonly used with antibody capture. So it sort of fits that paradigm and fits very nicely of moving into a fully continuous process. But it's a different way of thinking, though. In precipitating the antibody, you know, the goal there is to concentrate and take a big step in terms of purification so that the cleanup purification, the polish purification, can work efficiently. And there, in the process that we envision, you might have one or two flow-through chromatographic steps just to soak up the residual contaminants. So the thing that you're binding, the thing that determines the capacity of those polish operations are the trace components. You're not trying to bind all that relatively pure antibody. And so putting it.

Which is a whole different world. I mean, to bind the trace versus binding your product, yeah.

Now, to be very fair to so-called platform processes for monoclonal antibody production, there are individual flow-through steps, and that worked very well. Now, can we do all of the polish in a flow-through mode? Flow-through is inherently continuous. And if we can couple that inherently continuous polish with a fully continuous capture operation, we can run the whole process continuously. And then we can, you know, perhaps achieve the kinds of things that the regulatory bodies are interested in with continuous processes. And that is ensuring that you make the same thing all the time. The processes are running at steady state, you have the same quality. Every individual chunk of fluid that moves through the process has the same process history, the same experience, so that everything that ultimately goes into vials or bags or syringes, what have you, is the same all the time. And so that you can count on that. So I think there's strong motivation there. And again, the antibodies provide kind of the perfect jumping-off platform for this different type of process because of the high titers involved. And as other types of proteins, probably antibody-related species, will be next in line. Uh, they will certainly fit that kind of model for bulk type processes as well.

So you do see it applied to, for example, antibody drug conjugates or antibody fragments. It's as a possibility. I think so.

I think it would, I think it would fit very well because certainly the initial downstream for an antibody drug conjugate is the same as a monoclonal antibody. You'll have then a conjugation step and then further purification. And you know, as we saw at uh at this bioprocessing summit, you know, a nice talk on kind of continuous production and conjugation of of antibodies to make ADCs. So I think it's just it's a natural fit.

I'm curious, just in in hearing this, you speaking about it now, what's your vision on the benefit?

Cost Metrics Footprint And Materials

How what about reduction in square footage or cost of of not cost of goods, but cost of purification? I mean, do you see a 50% reduction or more or less? What if you could just itemize the particular advantages that you see precipitation provided?

That's a good question. I see potential advantages on a lot of fronts. Part of the work that we're doing in developing precipitation-based processes is to develop one of the grand challenges of can we make antibody type drugs available at very low cost globally? And I think this is a possible pathway towards achieving that because precipitation can be very inexpensive. The equipment is very simple. These are tubular contactors with static mixers and hollow fiber membrane units. So very inexpensive to operate. The precipitants themselves, we happen to use zinc chloride, polyethane glycol 3350. These are inexpensive and readily available materials. And these kinds of processes, precipitation processes, they work better and better as titer increases. So certainly the upstream processes are going in the right direction for us. But we can put our fingers on the scale here too. We can do pre-processing so that we pre-concentrate even farther. And as you concentrate and concentrate, now your footprint shrinks. And all the sorts of metrics that you start to think about is dollars per gram, usage of water per gram, usage of precipitate per gram, et cetera, all those scale directly with the titer and then with any pre-concentration that you do. So you can start to process materials with very promising metrics, cost metrics, raw material usage, et cetera. And as you concentrate, of course, your footprints uh shrinks, so your facilities cost, all of that moves in very promising directions. We're very excited about that.

Well, you know, a couple of things occur to me in your description that you didn't specifically mention, but uh it it implies that the sustainability of the process then is it would be increasing.

Sustainability And Global Manufacturability

Yes, very much so. And I keep on coming back to sustainability, and it it's something I think that we should all bear in mind. And I think unfortunately, uh folks immediately, when they think about sustainability, immediately go to the environmental implications, which are incredibly important and I'm passionate about. But the first level of sustainability is economic sustainability. If something can't be economically sustainable, the other aspects of sustainability, the environmental, social aspects of sustainability, they're not gonna happen. So we've got to check the economic sustainability. It's it's all you know three sides of a three-sided coin, if you will.

I think you get that from your experience in industry, that you know that no matter how good an idea is, if it if it's not gonna work economically, it's not, it won't be accepted.

Yeah, yeah, we're we're very sanguine about that.

Um another though is the it seems to me that this is transportable, that that in companies that that want to move internationally, uh sometimes there's a limitation in the local uh talent pool or or local regulations for particular chemistries. This seems pretty international and easy to to uh move around the world.

We we view that as as an aspect perhaps of of social sustainability. That you know, can this process be replicated and you know dropped into many different places? We believe it can for a number of reasons. Again, the equipment tends to be low complexity equipment. The raw materials have you know ready availability. You know, there's you know, certainly they have to be made to GMP specifications, so it's not as simple as you know, kind of off-the-shelf commodity chemicals. But that being said, these are commodity chemicals that are available at GMP uh standards. And the processes themselves, again, the equipment is simple, small footprint. It just seems to make a lot of sense that these are representative of the kinds of things that we could replicate in many different places so that we can be on the ground where a drug is needed, manufacture it in place. I know a lot of low and middle-income countries want to capture some of the value value chain of manufacturing and would insist on local manufacturing. And this can be done in a straightforward manner. And I think it's it's not a matter so much that it's the technological know-how that's a limitation, because there are plenty of very talented people available globally to run bioprocesses. It's you know, how crazy are the supply chains, how complex is the equipment, you know, prone to breakdown, that sort of thing. If you can simplify, I think we're going to be a lot better off, right?

And it certainly seems that the precipitation is simpler than, for example, simulated moving bed or these other advantageous but more complicated approaches.

Yeah. I think there's I'm of course biased because I'm really hoping that precipitation-based process can be part of the solutions that we need to make drugs sustainability. But I do think they are things are all pointing in the right direction in terms of their cost, complexity, ease of use.

Automation Models And Process Control

Well, maybe if we could finish up, where what's your vision of the future of this? What about automation and and how do you're in the middle of it now, things are looking good. I've read a couple of papers that you've put out. What do you think the final step is? That you're not there yet, but what will it look like?

Yeah, the automation is is an important component because we have run the process now with a number of different mabs, and the process has worked well. But I have this nagging feeling because the operational space of possibilities is vast, as it is for so many different processes. And we're not going to be able to kind of walk through this space in any efficient manner and explore all the unexplored nooks and crannies. What we're trying to do is to develop models for our system. I don't know if I'd go so far to say as digital twins, but certainly mechanistic models for a system focusing on the precipitation aspect and then couple that with automation and control hardware and software approaches to help us operate this process and walk it in real time towards even more efficient spaces and operating conditions. And I think that that I've I'm I'm hoping that that opens even further doors in terms of reduction in costs and material usage and able to intensify, ability to intensify the process. So we're very hopeful in that regard and certainly understand the imperative for continuous processes like the one we're trying to develop to be operated in a controlled fashion. I mean, that's that's important because we need to be able to find, track, and take action on disturbances when they happen and deviations. That's a very important part of continuous processing. And the idea of just a completely open loop continuous process is probably not one that's going to fly.

Well, G

Closing Thoughts On The Road Ahead

Todd, it's really been a pleasure chatting about how precipitation can replace some of the more expensive and sometimes difficult um processes downstream, uh, such as protein A. And um, well, thank you very much uh for attending.

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