Big Tuna and automated buffer exchange: An interview with Unchained Labs

Please could you give our readers an overview of the main functions of Big Tuna?

Big Tuna enables automated buffer exchange and sample concentration in most biomolecule processing applications. Typically, exchanging buffers from one to another ends up being a bottleneck, requiring many steps and a lot of manual intervention. Big Tuna was designed to automate this process so that people can go and do other things.

Why are the concentrations of buffer salts pH, ionic strength, excipients and surfactants in a buffer solution so important?

The reason is very much tied to the sample itself. Biomolecules are very complex, and they have different folding stability and performance stability in the right solution. The right solution means that it is at an optimal concentration, at the correct pH, the optimal amount of salt and the optimal amount of surfactants and excipients.

Everything about that formulation needs to be right for that drug to be a product: it confers stability, and it ensures efficacy, which is critical for manufacturing, shelf life and finally delivery to a patient.

Since it’s so critical, formulation development and confirmation of stability is a huge part of the process in developing biotherapeutics like monoclonal antibody treatments.

For newer gene therapy vector molecules like lipid nanoparticles and AAVs, less work has been done on formulation stability. As those molecules become more frequently assessed for drug development, the understanding of stability is going to become much more critical in those areas.

What sets the Big Tuna machine apart from other similar devices?

Big Tuna can process many samples simultaneously in volumes of 100 µL to 50 mL, so there’s not an equivalent device. There are automated ways to do buffer exchange if you are running large sample volumes, and there are a lot of manual ways when you are working with lots of samples in small volumes.

Big Tuna bridges that gap where you can automate both a low sample volume and high sample numbers, while guaranteeing the benefits of walking away to do other things.

How many samples is Big Tuna capable of processing during an experimental run?

Big Tuna can process up to 96 samples at the same time, from 100 microliters to 450 microliters. For people working with slightly larger volumes, which is somewhere between 450 microliters and 8 mL, Big Tuna can process up to 24 samples at a time.

We have a new application on that system where you can reduce a much larger sample volume into a smaller volume. You could run up to about 50 mL per sample, 24 at a time, and concentrate that down to 8 mL of each sample.

Could you explain why the automation of these processes is so beneficial?

The two big reasons are that it’s faster, can be set up quickly, and can be run unattended. Other methods like centrifugation filters are quick to set up but you have to go back periodically to add buffer and check on them. Dialysis can be run unattended but is usually overnight and slower. The big benefits are you get your time back and get your samples processed faster.

Big Tuna also gives more control over the buffer exchange process. As we’re monitoring volume on Big Tuna, we’re able to account for samples running at different flow rates and still process them in the way the operator wants.

What would you say to users who worry that the automation of these processes will reduce the control?

People who are used to running a lot of buffer exchange know that for certain methods, some samples take longer, whether that is because of the viscosity of the sample, the concentration of the sample, the viscosity of the buffers used or even for unknown reasons.

We developed Big Tuna with that assumption in mind. We monitor more closely what is happening with each sample. Big Tuna stops the run at different intervals and checks the volume, ensuring that it is aligning with the customer’s desired method.

Then, we adjust the time of the next cycle, ensuring that we’re meeting that target and making sure the faster samples are not going to overconcentrate. We ultimately monitor much more closely than people would do manually, especially for multiple samples at once.

What was the mission behind the design of Big Tuna?

The mission was to free customers up from standing at the bench. A lot of valuable scientific time is wasted either waiting for a sample to be ready overnight or going back and forth to a centrifuge and doing easy manual tasks like looking at a tube, pipetting buffer and waiting.

The process was really designed to enable people to use their time more efficiently and to get their samples ready for their next task sooner. We listened to our customers to understand their process, and what is important to them when doing this work. We incorporated a lot of that into the design of the platform.

A big component of this is software. People normally do this work manually and do not have to work with an instrument other than perhaps to hit a few buttons. We wanted to make sure that even though this is an automated system, people could very quickly learn what they needed to do to set up their experiment.

This way, they could walk up to Big Tuna and feel comfortable setting it up every time.

Can you explain the process used by Big Tuna to remove buffer, and how this proceeds?

Big Tuna essentially mimics the process of centrifugation filters except you don’t have to be there. It uses ultrafiltration to concentrate the sample and diafiltration to exchange in the new buffer. From a customer setup standpoint, they add samples to a plate-based format instead of tubes and type in their desired final volume and the percent exchange.

Big Tuna figures out the time to run each cycle and dynamically adjusts based on how the samples are running.

Big Tuna uses positive pressure to filter, with orbital mixing. This process ensures the whole plate is exchanged uniformly and that the sample does not concentrate at the membrane, which can lead to membrane fouling or aggregation in other approaches.

After an interval of time, that process stops, and the volume of each sample is measured with a non-contact acoustic sensor. Big Tuna does a couple of other things with those numbers.

It figures out how much volume to add back to each sample, determines the percent exchange that has already occurred and estimates the flow rate. The latter number is used to estimate the number of cycles remaining and the amount of time to do the next cycle.

It tracks this throughout the process until every sample has reached the target exchange percentage and the correct volume. From a user standpoint, they put their samples in, and a couple of hours later, they come back, and their experiment should be completed.

Why is the customizability of Big Tuna's buffer exchange process beneficial to users?

You have a level of control in this process that you wouldn't necessarily get from using other methods. For example, in a high concentration sample, I can choose to only remove the small amount of buffer each time so that my sample doesn't over aggregate or over concentrate.

I can also account for large changes in the buffer properties by doing smaller volume removals each cycle.

For more dilute samples, I can run it fast to complete the process more quickly. I have a degree of control regarding the degree of buffer exchange and the volume of buffer removed in each individual cycle. You also have additional data available to you that you wouldn't necessarily have via other methods, such as the sample flow properties in the new buffer.

If you could tell potential Big Tuna users one thing to sell them on the device, what would that be?

Buffer exchange is a chore, that is usually used to get your sample ready for something else. Get your time back and free yourself up to do more important things. The added bonus is that you can do more samples at the same time and you can track what’s happening every step of the way.

Why was the name "Big Tuna" chosen?

All Unchained Labs products have "UN" in the name, are also meant to be funny. Big Tuna is a nickname for Jim from The Office and Bill Parcells. It has nothing to do with the buffer exchange process, it is just fun.

About Unchained Labs

Unchained Labs is all about helping biologics and gene therapy researchers break free from tools that just don’t cut it. Unleashing problem-tackling products that make a huge difference in the real science they do every day. That’s their mantra, their promise and they own it.


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