Introduction
As biopharmaceutical pipelines become more diversified, and development timelines shrink, the pressure on downstream processing (DSP) to keep pace and deliver optimal results has intensified. Monoclonal antibody (mAb) production dominated the industry and drove the optimization and standardization of highly platformed DSP technologies, most notably Protein A chromatography for capture and a standard suite of polishing steps.
These processes, while robust and regulatory-proven, were not designed to handle the molecular heterogeneity and specific purity requirements presented by new classes of therapeutics.
New biological modalities such as bispecific antibodies, drug conjugates, fusion proteins, viral vectors, and nucleic acid-based drugs have unique physicochemical profiles that challenge the capabilities of legacy purification solutions. Purification of these new biological modalities require tailored strategies, molecule-specific process development, and greater selectivity.
Compounding this are broader industry trends toward more efficient processes, heightened sustainability expectations, and the need for greater supply chain resilience.
The Evolving Landscape of Biologic Purification
Chromatography processes are the backbone of biologics manufacturing. The core mAb DSP platform, centered on Protein A affinity capture followed by polishing steps like ion exchange and hydrophobic interaction chromatography, is well-established. The synergistic progress in both upstream and downstream development created a golden era of streamlined mAb production. Dramatic improvements in cell line productivity and fed-batch culture strategies enabled higher titers (1). In parallel, advances in resin technologies, such as increased binding capacities, enhanced caustic stability, and better impurity clearance, allowed DSP to scale relatively efficiently without becoming a bottleneck. All of these efforts, combined with rigorous process optimization and platform standardization, led to highly predictable, low-risk manufacturing workflows that still support the rapid and cost-effective development of conventional antibody products today.
Contrasting this mAb manufacturing platform, there is a pipeline of new biological molecules. These new biological modalities such as drug conjugates, viral vectors, nucleic acid therapeutics, and novel protein therapeutics are challenging the capabilities of current purification technologies. These molecules span a broad range of sizes, chemical characteristics, and stability profiles, often deviating significantly from canonical IgG structures. Their physicochemical variations result in interactions with the purification media that are very different from those of traditional antibodies, often leading to less selective, lower resolution processes, and poorer overall performance. This suboptimal purification performance limits the effectiveness of platform purification strategies and often requires additional unit operations to achieve the desired purity (2).
The increasing molecular diversity also coincides with rising regulatory and commercial pressures. Manufacturers are expected to accelerate development timelines, reduce cost of goods, and maintain robust quality across clinical and commercial stages (3). As a result, DSP is becoming the bottleneck in biomanufacturing, especially as upstream titers improve and demand for flexibility grows. As biomolecules become more complex, solubility and aggregation problems become more common and difficult to resolve without significant yield losses. This phenomenon is common in new mAbs, and other recombinant proteins but also in viral vectors (4).
Limitations of Traditional Technologies
As previously mentioned, traditional chromatography media were designed and optimized with mAbs in mind, and they regularly fall short when used for newer biologics. Many of the legacy resins when used in the purification of new biological modalities suffer from limited binding capacity, suboptimal selectivity, and reliance on harsh elution conditions that can compromise product quality, recovery, and stability. Protein A resins are very effective for Fc-containing molecules, but their limited selectivity across product variants often results in additional polishing steps. Unfortunately, when the capture step is ineffective major yield losses are common, with some single chromatography steps losing up to 40% of the target product. These challenges are further compounded by the inherent sensitivity of many new biological modalities, such as bispecifics, fusion proteins, and viral vectors, to low pH or prolonged processing times (4, 5).
In these cases, the development of milder elution strategies and faster, more selective purification workflows could improve both yields and process efficiencies.
Time-to-market will continue to be one of the most valuable currencies in biopharma. The search for manufacturing solutions that are adaptable, fast, and effective is ubiquitous. Yet, developing tailored DSPs for novel biologics remains a significant challenge (6). New biological therapies frequently serve niche markets or launch with low production volumes, offering limited commercial incentive for resin suppliers to develop new, fit-for-purpose solutions. Also, the development and adoption timelines for new purification solutions are too slow, taking several years to enter the market at a large-scale process. As a result, manufacturers frequently rely on stacking multiple generic unit operations or betting on unproven solutions at their own risk. DSPs are heavily constrained by platformed infrastructure and pre-validated procedures, where any deviation can introduce regulatory risk and require a reasonable justification. Derisking new purification technologies should be done as a unified industry effort to accelerate innovation and speed-to-market.
Also, supply chain resilience is a constant concern. As COVID-19 and other global disruptions have shown, the bioprocessing sector is vulnerable to delays in raw materials and consumables, particularly for specialty resins that rely on limited manufacturing capacity, long supply chains, and low inventory materials. This goes to show how important it is to have robust, scalable, and flexible purification solutions that can support fast tech transfer and global deployment (7).
Designing the Next Generation of DSP Platforms
Innovating purification media requires more than just marginal improvements in binding capacity or column lifetime. It demands a rethinking of both the resin base matrix and the functional chemistry. The base resin must offer fast mass transfer, broad chemical compatibility, and low backpressure; ideally enabling both batch and continuous formats. On the other hand, ligands must be highly selective, chemically stable, and compatible with manufacturing-scale synthesis (8). As the physicochemical complexity of new biological modalities continues to increase, the need for flexible and economically viable platforms capable of simultaneously optimizing both base resin and ligands becomes increasingly valuable.
The most valuable innovations in purification will be those that bridge all phases of development, from R&D to clinical manufacturing to commercial scale. Future purification media must be high-performing, robust to scale-up, tolerant to real-world feedstock variability, and compatible with existing hardware and cleaning procedures to minimize barriers to adoption. While customization remains essential for addressing the unique demands of specific modalities, drop-in compatibility with platform processes is also critical, especially in contract development and manufacturing organizations, where a single facility may be required to purify dozens of structurally distinct molecules. As the fastest-growing biologic modalities continue to expand, many with annual growth rates exceeding 20%, the demand for versatile and efficient purification solutions is becoming increasingly urgent (9).
In this context, AI-driven design and computational tools could open new possibilities to speed up development, and quickly refine ligands and resin materials into best-in-class purification solutions (10, 11).
Critically, innovations in DSP must align with the acceleration of clinical timelines. Biopharma companies now often move from IND filing to commercial readiness within just a few years, a shift that intensified during the COVID-19 pandemic, where vaccine and therapeutic programs were developed, scaled, and approved in record times. Similar timelines are common across other high-need areas such as rare diseases and emerging infectious diseases, where regulatory frameworks support accelerated development paths. In these accelerated timelines, purification bottlenecks can slow progress or compromise product quality, highlighting the need for new purification media that can reduce process development times while maintaining regulatory compliance (12).
High-Impact Advances in Purification
When industry incentives and the right solutions align, innovation in purification media can deliver major societal benefits by driving manufacturing efficiency and expanding access to critical therapies. One of the clearest examples is the success of Protein A resins stemming from the large-scale bioprocessing breakthroughs in the 90s. Despite their high cost, Protein A resins became ubiquitous because they drastically simplified capture steps, improved yields, and were highly reproducible. In recent decades, a combination of performance, robustness, and regulatory confidence has unlocked their widespread adoption (13).
Similarly, mixed-mode chromatography resins demonstrated value by offering broader selectivity and tolerance to feed variability (14). These resins found traction in polishing steps, especially for challenging impurities or aggregates, and helped reduce the number of unit operations in some processes. A recurring challenge with mixed-mode chromatography is the need for custom optimization to find the best parameter space to operate during processing.
Though, there are also notable examples of promising technologies that failed to achieve broad adoption. An example is membrane chromatography, which clearly offers rapid processing, but over the years has failed to be integrated into bioprocessing infrastructure, either due to lack of compatibility or cost concerns. Similarly, specific affinity ligands and Protein A mimetics have struggled due to narrow applicability, unproven performance at scale, and regulatory uncertainties (15). In many cases, the lack of widespread validation, industry familiarity, and strong incentives to move away from well-established platforms have further discouraged adoption.
The key takeaway is that adoption is not solely driven by performance. Ease of integration, regulatory familiarity, supply security, and cost all play pivotal roles.
Outlook: Accelerating Innovation in Purification Materials to Meet Biomanufacturing’s Urgent Demands
As the industry continues to develop more complex biologics, innovation in purification media becomes essential. As addressed in this article, this innovation gap is evident when talking about new biological modalities, where conventional purification media is often inefficient. In recent decades there has been an increased interest in technologies that improve manufacturing process efficiencies without changing the purification media used, like continuous processing (16). These process intensification approaches are typically adopted later in the development process, and apart from significant improvements in process efficiency compared to batch-like processes they cannot unlock major purification improvements. As we consider new purification solutions, affordability and compatibility with future process intensification efforts should be addressed early in the technological development.
To meet current and future purification challenges, collaboration between resin developers, equipment manufacturers, and drug producers is essential. Early engagement during process development can ensure that new purification technologies are effective and can scale. This collaboration should also include regulatory bodies, as early-stage alignment on raw material specifications, extractables/leachables, and validation strategies can significantly de-risk and accelerate adoption (17). Sustainability is another growing driver. More efficient purification processes inherently deliver more sustainable operations by reducing buffer consumption, energy use, and waste generation. Unfortunately, many traditional purification resins rely on petroleum-derived raw materials and produce large volumes of solvent waste during resin manufacturing. New materials that improve resin manufacturing efficiency while also reducing environmental impact through bio-based polymers, extended lifetimes, or compatibility with green solvents will likely be increasingly favored by both manufacturers and regulators in the long run.
It is evident that the biological manufacturing industry is at a crossroads. Either we continue relying on existing tools that were not built for the complexity and speed of modern biologics, or we invest in novel purification platforms that can scale with innovation. From modular and selective ligands to adaptable and high-performance base materials, the possibilities are broad, but they require a bold commitment to change.
Finally, the future of biomanufacturing relies on our ability to purify novel molecules efficiently, economically, and at scale. Purification media is no longer just a consumable; it is a strategic enabler of the therapies of tomorrow.
References and notes
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