Customized Chromatography Media and Affinity Ligands: The Personalized Upgrade Path for Biopharmaceutical Purification Media

In the industrial chain of biopharmaceuticals, downstream purification directly determines the drug's purity, yield, compliance, and production cost. Public industry data shows that the cost of the purification stage in biopharmaceutical production accounts for 50%-80% of the total production cost, and biopharmaceutical purification media, as a core consumable of the purification process, is key to reducing costs and improving quality thanks to its performance and compatibility. Among them, antibody purification media are the essential core carriers for the mass production of mainstream biologics like monoclonal antibodies, bispecific antibodies, and fusion proteins.

According to data from Qianzhan Industry Research Institute, the domestic market for biopharmaceutical chromatography media is expected to reach 10.8 billion RMB by 2025 and 13.2 billion RMB by 2026. Globally, QYResearch reports that the global chromatography media market is projected to reach $1.951 billion in 2025 and $3.212 billion by 2032. However, as biopharmaceutical targets continue to innovate and processes become more refined, standardized generic media can no longer meet the demands of differentiated drug systems and complex production conditions. Custom chromatography media and custom affinity ligands are becoming the key to breakthroughs in the industry.

From the broad system of biopharmaceutical purification media, to the subcategories of antibody purification media, and then to personalized solutions for custom chromatography media and custom affinity ligands—this represents an evolution from "standardization" to "customization" and is the core direction for next-generation biopharmaceutical purification.

1. Four Core Concepts: The Hierarchy from General to Customized

In the biopharmaceutical purification system, the four core keywords are not just parallel concepts; they form a four-level progressive structure: "overall system—subcategories—customized products—functional core." Grasping this hierarchy helps understand the technical logic of the entire purification media industry.

Biopharmaceutical purification media—the fundamental base of the overall system. This is a general purification medium system covering all categories of bioproducts, including antibodies, recombinant proteins, vaccines, peptides, enzymes, and more. It includes various types of media such as affinity, ion exchange, hydrophobic, and gel filtration, serving as essential consumables from lab-scale research to GMP commercial-scale production. High biocompatibility, low non-specific adsorption, and a complete traceable quality control system are basic requirements, fully meeting process inspection standards from major regulatory agencies like NMPA and FDA.

Antibody Purification Media — the most established niche category. These are specialized chromatographic media designed for purifying drugs like IgG monoclonal antibodies, bispecific antibodies, Fc-fusion proteins, and antibody fragments. Centered on affinity chromatography media, they are supplemented with ion exchange and hydrophobic interaction chromatography media to form a complete antibody purification workflow. Industrially compliant antibody purification media must meet strict quantitative criteria: under standard 6-minute retention time, the dynamic binding capacity (DBC) should be ≥60 mg IgG/mL, resistant to regular CIP with 0.5-1.0M NaOH, and maintain ≥90% binding capacity after more than 100 CIP cycles. Ligand leaching should be kept extremely low to ensure stable and controllable large-scale production processes.

Custom Chromatography Media — process-adapted integrated media. These are bespoke purification media designed around custom affinity ligands, combined with careful selection of bead matrices, optimized ligand coupling processes, and controlled pore size and particle size. Customization covers ligand type, ligand density, matrix materials (agarose, polymers, composite matrices, etc.), pore and particle size distribution, surface chemistry modifications, pressure resistance, and cleaning durability, allowing precise matching to different feed impurities and GMP production conditions. Compared with standard media, custom chromatography media’s biggest advantage is precise scenario adaptation, effectively addressing personal process challenges like high impurity contamination, difficult elution, high aggregates, or excessive host cell protein (HCP) residues.

Custom Affinity Ligands — the functional core from the source. This is the key functional unit that enables specific binding and precise separation on chromatography media, directly determining binding specificity, dynamic capacity, alkali stability, and mildness of elution. Unlike generic recombinant ligands, custom affinity ligands can be designed and optimized based on the target protein’s structure, binding sites, and physicochemical properties, creating exclusive ligand sequences. Leveraging AI design and protein engineering, custom affinity ligands can enhance the binding interface for better affinity, modify essential amino acids for improved alkali resistance, streamline redundant structures to reduce non-specific adsorption, and thoroughly overcome the performance limits of natural and generic recombinant ligands.

2. The Three Main Core Barriers in Custom Filler Development

Three Barriers to Ligand Development

It sounds like customization is the trend, but why are there so few companies that can actually create custom affinity ligands and chromatography resins? The core issue lies in three major barriers.

First, the ligand design barrier: finding the "right" molecule is tough. The first and hardest step in developing custom ligands is identifying ligands that can bind to the target molecule with high specificity. Traditional methods include immune screening, phage display library screening, etc. These methods take a long time, are costly, and for some hard-to-drug targets, they might not even yield suitable ligands. For non-antibody targets, the options for ligands are even more limited.

Second, the engineering barrier: there's a big difference between something that "works" and something that's "ready for use." Finding a ligand with binding activity is just step one. Industrial-grade resins require: high loading capacity, resistance to strong alkali (remaining >90% active after 100+ CIP washes), low ligand leaching, batch-to-batch consistency, low cost expression… Each aspect requires engineering modification of the ligand. Traditional directed evolution methods may require screening thousands of mutants for just one property change, which can take years.

Third, the regulatory compliance barrier: the leap from lab to GMP production. Once custom resins enter commercial production, they must meet GMP standards. Suppliers need to provide a full quality system, including raw material traceability, process validation, stability data, extractables/leachables studies, and ligand leaching detection methods. Building this system requires extensive project experience and time.

These three barriers are why custom resins have long been expensive, slow to produce, and limited in choices—forcing many pharma companies to settle for commercial resins, even if they’re not ideal.

3. AI Dry-Wet Loop: A new paradigm for custom resin development

Facing these three challenges—ligand design, engineering, and regulatory compliance—the AI dry-wet loop approach is gradually solving them from three angles.

MatwingsVenus™ (Xiaowu™), an AI protein large model platform under Shanghai Matwings Technology, is exploring a new path for custom resin development: "AI-designed ligands → dry-wet loop validation → GMP-level production." The core idea: use AI to reduce the cost and time of ligand design, use the dry-wet loop to ensure successful implementation, and support GMP supply through a standardized system.

Ligand design: from 'screening' to 'design'

The traditional custom ligand development model is "build a library → screen → optimize," which is essentially a trial-and-error method. AI-driven design works differently: starting from the structure and functional requirements of the target, it directly generates or optimizes ligand sequences.

The MatwingsVenus™ (Xiaowu™) platform relies on a protein large model trained with 15 billion protein sequences and 6.5 billion high-quality data entries with environmental labels. It can handle two core types of custom ligand design tasks: targeted optimization of known ligands—if there is already an initial ligand (like a Protein A variant or a nanobody), the platform can simultaneously optimize multiple parameters such as alkali resistance, loading capacity, expression levels, and elution pH, delivering high-potential mutation proposals at once, reducing the traditional transformation cycle from months or years to just a few months; and de novo design of entirely new ligands—for new targets without existing ligands (such as specific bispecific epitopes or viral vector proteins), the platform can design entirely new ligand molecules with binding specificity based on the target structure, breaking the limitations of natural sequences.

Taking the alkali resistance modification of single-domain antibody ligands as an example: to develop alkali-resistant affinity resins for non-antibody therapeutic proteins, Matwings Technology used the protein large model to increase the alkali resistance of a standard non-alkali-resistant single-domain antibody by four times in less than a year, successfully applying it to a 5000-liter production line.

Performance verification: from "paper design" to "dry and wet closed-loop"

AI-designed candidate ligands need experimental validation to confirm performance. The uniqueness of the MatwingsVenus™ (Xiaowu™) platform is that it not only provides computational design but also integrates automated wet-lab verification. Once the AI completes a design, it can directly drive the automated experimental platform to carry out ligand expression, purification, activity testing, and resin coupling tests. The experimental results are fed back into the next round of AI optimization, forming a complete "design-verify-iterate" closed-loop.

This approach solves the common industry pain point where "AI-designed performance is excellent, but lab implementation falls short"—no matter how accurate the computational prediction, experimental data is needed for calibration; in turn, the data generated from experiments make the models even more accurate, continuously boosting the efficiency of customized development.

Mass production supply: from lab samples to GMP-grade resins

The ultimate value of customized resins depends on whether they can be stably and compliantly supplied to the production end. Leveraging standardized quality control systems and large-scale production capabilities, ligands designed by the MatwingsVenus™ (Xiaowu™) platform can be supplied in GMP-grade mass production, with strong batch consistency. Specifications can be flexibly customized from lab-scale trials to industrial-scale production, supported by complete quality documentation for clinical and commercial manufacturing.

4. Five high-value scenarios: burst points of customized resin value.

Applications of Purification in New Drug Development

The maturity of AI design capabilities has made it possible to provide customized solutions for high-difficulty purification scenarios that couldn't be effectively handled by general-purpose resins before. The value of custom affinity ligands and custom chromatography resins is now exploding in the following five types of challenging biopharmaceutical purification situations:

Bispecific antibody purification. Bispecific antibodies have complex structures and a variety of impurities. Traditional Protein A resins with low-pH elution can induce acid-mediated aggregation. Custom mild-elution ligands enable elution at higher pH, reducing aggregation risks. At the same time, designing specific capture strategies for their unique structures improves the yield and purity of the target product.

ADC drug purification. ADCs are highly hydrophobic and prone to forming aggregates, requiring strict control over non-specific adsorption to the resin. By customizing the surface charge and hydrophobicity of the ligands, non-specific adsorption can be significantly reduced, aggregate formation minimized, and product quality and process yield improved.

Nanobody/single-domain antibody purification. Nanobodies/single-domain antibodies lack the Fc region and cannot rely on Fc–Protein A interactions for capture. However, many camel-derived VHHs have framework regions homologous to the human VH3 family and can still be recognized by certain Protein A ligands (literature reports ~99% of VHHs can bind engineered Protein A ligands like Amsphere A3). For VHHs with framework regions that do not bind Protein A, or in cases requiring epitope-specific capture, custom ligands targeting unique epitopes or general VHH capture ligands (e.g., ligands against the second framework region of VHH) are needed to provide exclusive affinity capture solutions.

Gene therapy vector purification. AAV, lentivirus, and other gene therapy vectors are large, fragile, and sensitive to shear forces. Custom combinations of large-pore matrices and specific affinity ligands enable efficient capture under mild conditions, protecting vector integrity and improving recovery and activity retention.

Scarce recombinant protein purification. For some high-value functional proteins and enzymes, traditional multi-step purification is complex and low-yield. Custom affinity resins can achieve high-purity capture in a single step, greatly simplifying the process and reducing production costs.

From a broader perspective, custom resins are driving two deep transformations in the biopharmaceutical purification industry:

First transformation: from 'resin selection' to 'ligand design.' Previously, the first step in developing a purification process was 'buy a few resins and screen them.' In the future, it may become 'design a dedicated ligand first.' The core competitiveness of the purification process is shifting from 'experience in selecting resins' to 'ability to design ligands.'

Second transformation: from 'standard products' to 'solutions.' Resin companies are evolving from 'suppliers of consumables' to 'partners providing comprehensive purification solutions.' Whoever can deliver the optimal purification solution for customer molecules faster, more accurately, and more reliably will take the lead in next-generation competition.

5. Conclusion

The innovation of biopharmaceuticals will never stop, and the emergence of new molecules will only accelerate. Behind every new molecule, there is a need for a customized purification solution.

From generic antibody purification resins to bespoke chromatography media, from off-the-shelf ligand screening to AI-designed custom affinity ligands, biopharmaceutical purification is undergoing a paradigm shift from "standardization" to "personalization." The core driving force behind this shift is AI protein design technology—it makes customization no longer a "luxury that's expensive and slow" but something efficient, controllable, and affordable.

When every new drug can have its own "exclusive" purification resin, the efficiency and cost structure of biomanufacturing will undergo a fundamental upgrade. Domestic AI protein design platforms, represented by MatwingsVenus™ (Xiaowu™), are providing the self-controlled technological foundation for this upgrade.