Prepacked Chromatography Columns to Support Lean Manufacturing Efforts for Biotherapeutics

By: Laura Kronbetter, Senior Global Product Manager, Bio-Rad Laboratories

The rise of precision therapy approaches and personalized medicine has led to the growing global demand for targeted biotherapeutics which, in turn, require industries to accommodate large-scale production of increasingly complex molecules. At the same time, the fast approaching ‘patent cliff,’ which will see many of the world’s top selling drugs losing their patent protection and potentially expose an estimated $230billion in annual pharmaceutical revenues to generic and biosimilar competition between 2026 and 2030, is intensifying pressure on biotech and pharmaceutical companies to develop novel biotherapeutics rapidly and cost-efficiently.¹

Biopharmaceutical development covers a vast array of target molecules, ranging from therapeutic antibodies to cell and gene therapies, with product quality being the highest priority. Regardless of the therapeutic modality, the resulting biotherapeutic structure must be exactly as designed and of an exceptionally high purity level to ensure product efficacy and safety.

The Role of Chromatography in Biotherapeutic Purification

Downstream processing is an essential part of any biotherapeutic manufacturing process, involving the recovery and purification of target molecules from complex production mixtures. High-specificity chromatography tools such as resins, columns, and liquid chromatography systems are the mainstay of this workflow, especially in large-scale processes.²

During production, the process feed contains the desired target product, along with contaminant DNA, host cell proteins, protein aggregates, and other cell culture byproducts, necessitating advanced bioprocessing techniques to achieve effective separation and purification. Further to this, each product requires tailored purification strategies depending on the therapeutics’ molecular composition.

New biotherapeutics, such as those developed for precision medicine applications, are increasingly complex and diverse, leading to significant challenges associated with downstream processing. For example, the high bioavailability and specificity of monoclonal antibodies (mAbs) renders them as powerful therapeutic agents, and it is therefore critical for downstream purification to preserve their structural integrity and functionality.³ Protein A affinity chromatography is considered the industry-wide standard for the capture of mAbs, but the harsh acidic elution conditions required (typically pH 3.0-3.5) can cause protein denaturation, aggregation, and loss of potency, which can have a detrimental impact on the efficacy of eluted mAbs. The low pH can also damage the Protein A ligand, reducing the commercial lifetime of the resin.⁴

Building on the promise of mAbs, bispecific antibodies (bsAbs) are an emerging class of biotherapeutics that are engineered to target two antigens simultaneously, offering a stronger therapeutic effect, especially in cancer immunotherapy where multiple signaling pathways are at play.⁵ Given the similarities in their structures, purification strategies for bsAbs are often adapted mAb processes, although the distinct byproducts associated with bsAb production, such as half antibodies that fail to form the bispecific structure and other antibody fragments, require optimized methods to ensure their removal.^6,7 Additionally, bsAbs are more prone to aggregation than mAbs, further complicating purification.⁶

Challenges Associated With Large-Scale Chromatography

Many purification processes are initially developed at laboratory scale for use during the development of new therapeutics, which typically involves working with small sample volumes. Transitioning to manufacturing scale requires increasing downstream throughput without compromising product quality. This process is typically achieved by increasing column diameter while maintaining bed height and linear flow rate, ensuring consistent residence time across scales of operation. Other parameters such as volumes, processing times, and equipment will naturally change for larger-scale operations, necessitating further process optimization, as conditions that have been optimized for small-scale separations may no longer be suitable. These parameters are often dictated by the available resins, and whether they can be adapted to a commercial scale; for example, size exclusion chromatography operates in a non-binding mode and is typically limited by low volumetric productivity and sample dilution, making it less attractive for large-scale manufacturing than bind-and-elute or flowthrough chromatographic modes.⁸

Additionally, as novel biotherapeutics and upstream processes become more sophisticated, downstream workflows have expanded, often requiring multiple purification stages to remove a wider range of impurities and ensure effective product capture. This may result in production bottlenecks where manufacturing is delayed by inefficient downstream processes. Having multiple downstream steps can also negatively impact the reproducibility of separations and increase both time and cost requirements. With the additional purification steps, there is also the issue of column preparation, which often includes resin slurry concentration calculations, column packing, and testing.⁹ This can be a lengthy process involving regular review and monitoring to ensure consistent packing quality and performance between columns.

Process scale-up is about striking a balance between a researcher’s needs for rapidly manufactured biotherapeutic product at a high purity, with the financial implications of a longer, higher throughput chromatography workflow. This often necessitates a full review of the biomanufacturing process to identify areas for improvement and increased efficiency, and opportunities for new technologies to accelerate the most time-intensive aspects of chromatography.

Lean Manufacturing Workflows to Maximize Efficiency

The principle of lean manufacturing is to minimize waste within an industrial process in order to maximize output, while maintaining product quality. Waste in lean manufacturing is considered to be any process, product, or service that requires money and time, but does not add value to the desired product. Aside from byproducts and wasted materials, this could also refer to excess manual labor, under-utilization of resources or ineffective instrumentation.¹⁰

In the context of biotherapeutics, product quality, safety, and efficacy is critical, requiring streamlined downstream processing stages to ensure drugs meet regulatory guidelines, while maintaining operational efficiency. To maintain product quality at scale, purification processes have been optimized through advances in chromatography resins, column technologies, and instrumentation. Together, these innovations support flexible, high-throughput manufacturing workflows capable of meeting evolving market demands.

Mixed-Mode Strategies to Improve Purification Efficiency

Mixed-mode chromatography (MMC), also known as multi-modal chromatography, is an increasingly common tactic in pharmaceutical and biopharmaceutical applications that combines multiple interaction modes into a single step, enabling removal of a variety of impurities.¹¹ By streamlining multi-step processes, MMC can reduce time and costs associated with purification of therapeutics, with the financial benefit also passed onto the end user. MMC offers several advantages over single-mode chromatography, providing greater selectivity for a wider range of target molecules.

A notable example is ceramic hydroxyapatite (CHT), a mixed-mode chromatography medium that provides calcium metal affinity and cation exchange (CEX) interactions via calcium and phosphate functional sites on a macroporous ceramic bead.¹² Its unique selectivity enables removal of host cell proteins, DNA, and other process impurities, achieving a high level of purity. By combining multiple interaction mechanisms, MMC resins offer enhanced selectivity across a broad range of target molecules, including mAbs and antibody-drug conjugates, while enabling gentle separations that can reduce chromatography-induced aggregation under optimized conditions. CHT media has proven particularly valuable for bsAb purification, where product-related by-products often form a seemingly homogeneous mixture with the target molecule.

Prepacked Columns as a Standardized Solution for Downstream Processing

In addition to MMC resins, prepacked chromatography columns offer an attractive solution to many of the current bottlenecks seen in downstream processing steps for biotherapeutics. Critically, they offer broad applicability across development and manufacturing workflows, with a standardized design that ensures consistent and reproducible column packing (Figure 1). Combined with mixed-mode resins such as CHT, the benefits of prepacked columns are extensive, particularly for CMOs, where implementation can improve efficiency for any purification workflow:

• Ensure reproducibility while increasing purification capacity: Prepacked columns eliminate the need for column preparation, enabling consistent performance across workflows. Removing dedicated column packing areas also frees space, increasing manufacturing capacity and simplifying facility layouts.¹³
• Standardized quality standards help meet regulatory guidelines: The standardized nature of prepacked columns is a key advantage.¹⁴ Columns are supplied GMP-ready for use, manufactured with defined bed heights and diameters, and accompanied by comprehensive quality documentation, simplifying process setup, reducing labor requirements, and supporting GMP-compliant workflows (Figure 2). The FDA requires that all biopharmaceutical manufacturing processes, environments, and technologies comply with current GMP regulations, to ensure product safety, efficacy, and quality. In addition, standardized resin volumes help optimize resin utilization, improving operational efficiency. Together, these features enable reproducible and reliable purification performance across manufacturing and bioprocessing sites.
• Increased flexibility across purification requirements: Prepacked columns are available in a wide range of standardized sizes, each consistently packed with defined resin volumes, enabling robust process scaleup from laboratory to manufacturing scale. Vendors that manufacture both the resin and the prepacked columns can also provide documentation and warranties to support regulatory approval and technology transfer. In addition, prepacked columns are available with a variety of resin chemistries, allowing teams to select appropriate, prequalified column formats during process development or for future platform applications.
• Significant time– and cost– savings: In traditional chromatography workflows, substantial time and resources are required for column-specific activities such as resin preparation, column packing, packing verification, and associated documentation, often resulting in extended downtime. The use of prepacked GMP-ready columns eliminates these column-specific preparation steps and enables rapid column changeover within existing chromatography workflows. While standard equipment cleaning and validation requirements remain unchanged, prepacked columns reduce downtime associated with column handling and preparation, improving overall operational efficiency.

The combined effect of these key features of prepacked columns dramatically increases productivity while minimizing costs and maintaining product quality. This increased flexibility in production offers a further advantage to manufacturers, enabling delivery of wider product portfolios.

Prepacked columns are particularly beneficial in contract manufacturing organizations (CMOs), where speed and flexibility are essential to service delivery. By reducing manual labor associated with column preparation and streamlining column changeover, prepacked columns enable CMOs to scale chromatographic workflows efficiently while maintaining predictable timelines for biotherapeutic production.

Future-Proofing Biopharmaceutical Chromatography

The biotechnology sector is constantly shifting to meet increasing biotherapeutic demands, requiring more innovative solutions to increase process efficiency whilst maintaining high purities. The use of prepacked columns is instrumental in the delivery of rapid, flexible chromatography workflows, while the implementation of lean manufacturing principles is facilitating the development and manufacturing of high-quality biological products at a lower cost.

Purification processes must be designed to evolve with target molecule structure, as well as to meet capacity demand. Prepacked columns provide a modular, standardized approach that supports controlled process adaptation within established development, validation, and regulatory frameworks. By eliminating manual column packing and reducing column-specific preparation steps, prepacked columns can streamline operations and accelerate execution of approved chromatographic workflows. In addition, integration with automation platforms offers further opportunities to enhance process consistency and efficiency, supporting reliable and scalable production of high-quality biotherapeutics.

References

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10. The Welding Institute. What is lean manufacturing and the 5 principles used? Available at: https://www.twi-global.com/technical-knowledge/faqs/faq-what-is-lean-manufacturing. Accessed March 12, 2026
11. Zhang K, Liu X, Mixed-mode chromatography in pharmaceutical and biopharmaceutical applications. Journal of Pharmaceutical and Biomedical Analysis. 2016;128:73-88.
12. Cummings LJ, Frost RG, Snyder MA. Monoclonal antibody purification by ceramic hydroxyapatite chromatography. Methods Mol Biol. 2014;1131:241-251.
13. Scharl T, Jungreuthmayer C, Dürauer A, Schweiger S, Schröder T, Jungbauer A. Trend analysis of performance parameters of pre-packed columns for protein chromatography over a time span of ten years. J Chromatogr A. 2016;1465:63-70.
14. FDA. Current Good Manufacturing Practice (CGMP) Regulations. Accessed March 12 2026. https://www.fda.gov/drugs/pharmaceutical-quality-resources/current-good-manufacturing-practice-cgmp-regulations

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