What are the key takeaways from this GEN Podcasts episode?

Key insights include: **Downstream bottleneck scale:** Downstream purification represents approximately 60% of total biologics production effort, yet has not kept pace with upstream gains. Upstream titers have risen from milligrams to 4–6 grams per liter, while downstream losses reach up to 30% of harvested material — making this the highest-leverage area for yield and cost improvement.; **Mixed-mode chromatography consolidation:** Mixed-mode and multimode resins use ligands with two or more simultaneous interaction mechanisms, enabling a single resin to replace multiple sequential chromatographic columns. By modulating the mobile phase rather than switching resins, manufacturers can merge two purification steps into one, directly reducing processing time, material costs, and yield losses per gram of drug.; **Universal buffer strategy:** Moving from single-purpose pH-targeted buffers to universal buffers usable across multiple process steps reduces the number of materials to acquire, store, and manage. Pairing this with prequalified, single-use buffer concentrates that plug directly into workflows — plus selective hydrophobicity-modulating additives — improves impurity clearance, column performance, and overall cost per gram.

What did Jared Brophy discuss on GEN Podcasts?

Avantor's Dr. Jared Brophy examines downstream biopharmaceutical purification bottlenecks, focusing on chromatography resins, mixed-mode technologies, buffer optimization, and digital analytics tools. Downstream processing accounts for roughly 60% of total biologics production effort, with up to 30% of harvested material lost across multiple purification steps. Key topics include: **Downstream bottleneck scale:** Downstream purification represents approximately 60% of total biologics production effort, yet has not kept pace with upstream gains. Upstream titers have risen from milligrams to 4–6 grams per liter, while downstream losses reach up to 30% of harvested material — making this the highest-leverage area for yield and cost improvement.; **Mixed-mode chromatography consolidation:** Mixed-mode and multimode resins use ligands with two or more simultaneous interaction mechanisms, enabling a single resin to replace multiple sequential chromatographic columns. By modulating the mobile phase rather than switching resins, manufacturers can merge two purification steps into one, directly reducing processing time, material costs, and yield losses per gram of drug..

How long is this episode of GEN Podcasts?

This episode is 20 minutes long. SignalCast provides an AI-generated summary so you can get the key insights in about 3 minutes.

GEN Podcasts

Resins Address Downstream Purification Concerns

January 3, 2023

20 min episode · 2 min read

Jared Brophy

Episode

20 min

Read time

2 min

Topics

Productivity, Product & Tech Trends, Philosophy & Wisdom

AI-Generated Summary

Published Mar 15, 2026

Key Takeaways

✓Downstream bottleneck scale: Downstream purification represents approximately 60% of total biologics production effort, yet has not kept pace with upstream gains. Upstream titers have risen from milligrams to 4–6 grams per liter, while downstream losses reach up to 30% of harvested material — making this the highest-leverage area for yield and cost improvement.
✓Mixed-mode chromatography consolidation: Mixed-mode and multimode resins use ligands with two or more simultaneous interaction mechanisms, enabling a single resin to replace multiple sequential chromatographic columns. By modulating the mobile phase rather than switching resins, manufacturers can merge two purification steps into one, directly reducing processing time, material costs, and yield losses per gram of drug.
✓Universal buffer strategy: Moving from single-purpose pH-targeted buffers to universal buffers usable across multiple process steps reduces the number of materials to acquire, store, and manage. Pairing this with prequalified, single-use buffer concentrates that plug directly into workflows — plus selective hydrophobicity-modulating additives — improves impurity clearance, column performance, and overall cost per gram.
✓Chromatography digital twins: Chromatography is well-suited for digital twin modeling because its underlying physics and biochemistry are well characterized. Manufacturers should integrate process data, stability data, and certificate-of-analysis variables to detect raw material variability that passes specifications but still affects yields — enabling tighter input controls and proactive process corrections before batch failures occur.
✓Affinity chromatography ligand evolution: Protein A remains the dominant and most costly capture step for monoclonal antibody purification. As biologics diversify into bispecifics, ADCs, Fab fragments, and FC fusion proteins, manufacturers should evaluate Protein L and novel Protein A presentations tailored to these formats, while using mobile-phase additives to improve affinity step efficiency and reduce cost per gram.

What It Covers

Avantor's Dr. Jared Brophy examines downstream biopharmaceutical purification bottlenecks, focusing on chromatography resins, mixed-mode technologies, buffer optimization, and digital analytics tools. Downstream processing accounts for roughly 60% of total biologics production effort, with up to 30% of harvested material lost across multiple purification steps.

Key Questions Answered

•Downstream bottleneck scale: Downstream purification represents approximately 60% of total biologics production effort, yet has not kept pace with upstream gains. Upstream titers have risen from milligrams to 4–6 grams per liter, while downstream losses reach up to 30% of harvested material — making this the highest-leverage area for yield and cost improvement.
•Mixed-mode chromatography consolidation: Mixed-mode and multimode resins use ligands with two or more simultaneous interaction mechanisms, enabling a single resin to replace multiple sequential chromatographic columns. By modulating the mobile phase rather than switching resins, manufacturers can merge two purification steps into one, directly reducing processing time, material costs, and yield losses per gram of drug.
•Universal buffer strategy: Moving from single-purpose pH-targeted buffers to universal buffers usable across multiple process steps reduces the number of materials to acquire, store, and manage. Pairing this with prequalified, single-use buffer concentrates that plug directly into workflows — plus selective hydrophobicity-modulating additives — improves impurity clearance, column performance, and overall cost per gram.
•Chromatography digital twins: Chromatography is well-suited for digital twin modeling because its underlying physics and biochemistry are well characterized. Manufacturers should integrate process data, stability data, and certificate-of-analysis variables to detect raw material variability that passes specifications but still affects yields — enabling tighter input controls and proactive process corrections before batch failures occur.
•Affinity chromatography ligand evolution: Protein A remains the dominant and most costly capture step for monoclonal antibody purification. As biologics diversify into bispecifics, ADCs, Fab fragments, and FC fusion proteins, manufacturers should evaluate Protein L and novel Protein A presentations tailored to these formats, while using mobile-phase additives to improve affinity step efficiency and reduce cost per gram.

Notable Moment

Brophy challenges the assumption that simply scaling up chromatography equipment solves downstream bottlenecks. He argues that reordering workflow steps — such as applying virus-inactivating detergent formulations before the chromatography capture step rather than after — can meaningfully improve overall process efficiency without adding new equipment or columns.

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Episode Transcript

Welcome to Gencast, a sponsored podcast series brought to you by Genetic Engineering and Biotechnology News. I'm your host, Jeff Pugaliskis. The demand for safe and efficacious biologics has accelerated exponentially in the past several years due to the tremendous success of some of the initial therapeutic offerings in this space. Yet along with this increased demand comes the need for innovative solutions to improve downstream production workflows, Eliminating purification bottlenecks and improving overall yields from chromatography steps can have a significant impact on the cost of the final product. Now in this second episode of Gencast with executive vice president of biopharma production at Avantor, doctor Jared Brophy, we dive into some of the challenges that bio manufacturers face during downstream purification and how addressing the traditional thinking surrounding chromatography resins and buffers can be extremely advantageous and immensely cost effective. Now keep listening if you wanna hear some innovative ideas to improve downstream purification processes. Welcome, everyone, to another episode of Gencast. I'm pleased to welcome back doctor Jared Brophy, the executive vice president of biopharma production at Avantor. Nice to be chatting with you again, Jared. Thanks, Jeff. Looking forward to being here. So, Jer, in our last podcast, we discussed some of the precautions and improvements for cell and gene therapies and how manufacturers can address many of those challenges. So make sure you check that out if anyone in the audience hasn't listened to that one yet. But in this episode, we're gonna stay in the realm of biomanufacturing, but switch gears a little bit and address an area that is very familiar to many members of the gen audience and an integral part of the bioprocessing workflows. And I'm talking about downstream purification, with a specific focus today on chromatography and the resins utilized during that process. So let's start off with a kind of basic but important question. Why is it vital to develop improved downstream purification processes? Thanks. Yeah. Well, I'll start with some general comments about the market and why that leads to the requirement for these improvements. You know, the global clinical pipeline across multiple therapeutic areas and categories continues to increase the power of biopharmaceuticals and in particular monoclonals continue to be felt across the whole clinical area. And even within that, we're seeing an increased diversity of antibody and antibody type drugs coming through. Biaspecifics, multispecifics, Fab fragments, FC fusion proteins, antibody drug conjugates. Each of these has some unique requirements. Each of these is some of these are are nascent technologies and and will require improvements in downstream process. And in general, you know, we have to be aware of cost and availability, especially with things like biosimilars. Biologics manufacturers are investigating ways to address, you know, productivity, efficiency, and downstream production by processing is is an area that's getting a significant amount of attention. We feel that downstream production currently encompasses about 60% of the total efforts of producing a biologic drug. So this is clearly …

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