How Platform Chromatography Changes as Purification Challenges Increase

malene.linderoth@peakbiotech.com (Malene Linderoth) — Fri, 19 Jun 2026 10:02:33 GMT

Platform-based chromatography remains a widely used approach in downstream processing, particularly in workflows originally developed for standard monoclonal antibodies. In these cases, stationary phase selection, mobile phase composition, flow rates, and pressure ranges were defined around a relatively consistent molecular profile.

As pipelines expand into newer modalities such as bispecific antibodies, viral vectors, and mRNA, the potential for downstream platform process limitations increases. The question is no longer whether platform approaches apply, but where the applicability of current platforms begins to change. This question is driven by differences in molecular behaviour, impurity profiles, and how these elements interact within the packed bed in the chromatography column, as this is where separation is physically realised.

This shift can be visualised as an expansion of the original platform design space.

Figure: Platform processes were originally developed within a defined molecular space. As new modalities emerge, they are applied across a broader and more complex range.

From Stable Platforms to Expanding Design Space

Chromatography platform processes emerged in the early to mid-2000s as a response to the growing commercial manufacturing of monoclonal antibodies. Built around Protein A affinity capture followed by ion exchange and hydrophobic interaction chromatography polishing, these platforms standardised operations for well characterised antibodies with predictable behaviour [1,4].

This supported research, process development, and manufacturing. Development timelines were reduced, technology transfer became more efficient, and teams could operate within a defined and validated framework. The platform was not only a sequence of steps. It was a defined operating space. Mobile phase and buffer composition, resin or media selection, flow rates, pressure ranges, temperature, and expected separation outcomes were all developed around assumptions that held for the original molecule set [1].

That logic remains valid. What has changed is the range of molecules now being processed within the same framework.

New modalities introduce different structures, impurity profiles, and interaction behaviour in liquid chromatography. As a result, the assumptions underlying the original platform are not always met to the same extent. Platform processes still provide a strong starting point but require more adaptation. This is not a reflection of incorrect process design. It is a consequence of a broader and more diverse molecular landscape [5].

As these differences become more pronounced, maintaining the flow, pressure, and packed bed conditions that the platform depends on becomes less straightforward. In many cases, this is driven by changes in mass transfer and binding behaviour, where larger or more complex molecules require longer residence times or lower flow rates to achieve the same separation performance [2,5]. The question therefore shifts. Instead of asking whether a platform process can be applied, it becomes more relevant to ask whether the required conditions can be established and maintained consistently.

This is where the chromatography column becomes relevant, as it defines how these conditions are realised in practice.

Where Chromatography Platform Processes Still Apply

For conventional monoclonal antibodies, platform processes still apply very well. These molecules were the basis on which much of modern downstream chromatography was developed, and they remain a clear example of where standardisation creates value. Their molecular size is relatively consistent, their impurity profiles are familiar, and their interaction with commonly used stationary phase materials is well understood. In these cases, chromatographic methods can be defined with a high degree of confidence, and the relationship between mobile phase, stationary phase, sample composition, and separation outcome remains predictable.

This matters because predictable behaviour is what allows a platform to function efficiently. In liquid chromatography, reproducibility depends not only on the chemistry of the method, but on the alignment between that chemistry and the physical performance of the column. When column packing is uniform, when bed stability is maintained, and when flow rates and pressure stay within the expected range, the process delivers the separation performance it was developed for. Peak shapes remain controlled, different components are resolved consistently, and purification supports both product quality and manufacturing efficiency.

In this environment, scale up is more straightforward because the column behaves within a familiar operating space. Flow rates can be maintained, pressure responds predictably, and the column supports consistent interaction between the liquid phase and the stationary phase. For process development teams, this means that methods can often be transferred across molecules with moderate adjustment, rather than extensive redefinition. For manufacturing, it means that throughput, compliance, and reproducibility can be planned with confidence.

This is one reason platform chromatography has remained so valuable. It provides a way to carry established knowledge from one process to the next. It supports robust purification in a downstream process environment where time, yield, and product quality all matter. It also supports regular column maintenance and long-term operational consistency, both of which contribute to stable manufacturing over time.

Where Applicability Begins to Change

The picture becomes more nuanced when the molecule set begins to expand. New modalities do not remove the value of platform processes, but they do change the conditions under which those processes operate.

Bispecific antibodies, Fc fusion proteins, antibody fragments, viral vectors, plasmids, and mRNA all introduce features that differ from the original molecules around which many platforms were developed. These differences may include broader impurity profiles, altered charge behaviour, larger effective structures, different diffusion behaviour, or more complex mixtures entering the column. They may also influence selectivity, detector sensitivity, and the relationship between sample size and separation efficiency.

In liquid chromatography this becomes visible through changes in retention behaviour and resolution. Mobile phase conditions developed for one molecular class may no longer provide the same separation for another. Stationary phase performance may shift when particle size, pore accessibility, or interaction mechanisms become more influential.

The implication is not that platform processes lose relevance. It is that they are applied across a broader range of conditions than originally defined.

For example, a platform developed for standard proteins may operate within a defined pressure and flow range when molecules diffuse predictably through the bed. With larger or structurally different components, the same column may operate closer to the edge of its intended range. Residence time may need adjustment, flow rates may require refinement, and separation performance may become more sensitive to packing uniformity and bed stability [2].

The process sequence remains intact, but the degree of adaptation increases. This reflects a shift in applicability rather than a failure of platform thinking.

What Changes in Practice When Platforms Are Used for New Modalities

In practice, applying established platforms to newer modalities requires more process adjustment.

Mobile phase conditions may need refinement to preserve selectivity when impurity profiles shift or when the interaction between the sample and the stationary phase changes. Flow rates may need to be adjusted to maintain separation across more complex mixtures. Sample size and loading strategy may require closer control as the window between acceptable productivity and reduced separation narrows. Detector sensitivity becomes more important when components of interest and impurities begin to overlap more closely, especially during development and early scale up work.

Additional purification steps may be introduced as processes are adapted to address changing impurity profiles and product requirements. A downstream process that originally relied on a well-established sequence may be extended to handle more complex or diverse molecules. Continuous chromatography may be considered where higher productivity or throughput becomes important, and different media types may be explored to support these changes. This is not because the original methods were inadequate, but because the process is now being applied across a broader range of conditions and functions.

This is the point at which the column deserves more attention. When the process operates within a comfortable zone, the column can appear almost invisible. As the process moves across a wider range of flow, pressure, sample composition, and separation requirements, packing uniformity, pressure response, flow distribution, and bed stability have a stronger influence on how much adaptation is required at the process level [2].

Platform Processes Depend on Defined Operating Conditions

A platform process is often described through its sequence of steps, but its performance depends on operating conditions.

Chromatography depends on whether the column can maintain flow, pressure, temperature, and packed bed behaviour within a defined range. Separation performance is therefore both a chemical and a physical outcome.

This relationship is illustrated in Figure 2.

Figure 2 Chromatography platforms are defined by operating conditions. The column determines whether these conditions can be realised in practice

When operating conditions remain stable, the process behaves predictably. Column efficiency is maintained, peak shapes remain controlled, and purification supports expected quality and throughput. When conditions shift, the process can still function, but requires more tuning [2,3].

This becomes particularly important in scale up. Many scale up challenges are not due to a flaw in the purification principle itself. They arise because the same process is being asked to operate under conditions where flow distribution, pressure, compression, or packing behaviour become more influential. At laboratory or pilot scale, certain effects can be modest. At manufacturing scale, the column plays a larger role in determining whether the process remains stable.

Reframing the Question

The traditional question in many organisations is simple: can the existing platform be applied to the new molecule?

That remains a useful starting point, but it is often not specific enough. A more precise question is whether the column can maintain the conditions that the platform requires for this molecule.

This change in wording reflects a change in mindset. Instead of focusing only on whether a familiar sequence of chromatographic methods can be reused, the team begins to examine the conditions under which that sequence remains effective. That includes pressure, flow rates, sample composition, impurity behaviour, packing response, and the interaction between the liquid phase and the stationary phase.

In process development, this means mapping not only the separation behaviour of the molecule, but also the operating window of the column. It means asking whether the column supports the required function across the expected range of molecules, rather than assuming that platform chemistry alone will define the answer. It also means recognising that equipment and process are closely linked in process chromatography, especially as the portfolio expands.

This reframing is useful because it does not reject platform thinking. It strengthens it. It clarifies what actually allows a platform to remain effective.

The Central Role of the Chromatography Column

The chromatography column is the physical structure that turns method design into real performance. It determines how the liquid moves through the bed, how pressure develops, how uniformly components encounter the media, and how stable the separation environment remains over repeated cycles.

Flow distribution is one of the first areas where column design matters. If liquid is not distributed evenly across the bed, the process will not deliver the same separation everywhere inside the column. That affects column efficiency, peak shapes, and ultimately product quality. In well behaved columns this may be barely noticeable. In more demanding columns or with more complex mixtures, it becomes much more visible.

Pressure is equally important. Pressure is not just a mechanical consideration. It directly affects what flow rates can be used, how throughput can be increased, and how the process can be carried across different molecule types. Particle size, bed height, column diameter, and materials all influence pressure behaviour. This means that the column is part of the purification logic, not just a container around it.

Packing uniformity also plays a central role. Uniform packing supports predictable interaction between sample and stationary phase, helping maintain reproducibility across runs. If the bed changes over time, if compression differs, or if local variations occur, then separation behaviour may also change. This can affect selectivity, yield, efficiency, and the amount of method adjustment needed from one campaign to the next.

Redefining Platform Design for Multi Molecule Portfolios

If the column defines the operating space, then the idea of a platform can also be defined in a more precise way.

A platform does not need to mean identical steps, identical mobile phase composition, or identical stationary phase selection for every molecule. That definition is often too narrow for today’s portfolios. A more useful definition is that a platform provides a stable operating framework within which different molecules can be processed reproducibly.

Under this view, variation is not necessarily a sign that the platform has lost value. Instead, some level of process development and refinement becomes part of how the platform is applied across a broader molecular range. What matters is whether the system still provides a defined and stable basis for that work.

This is where custom column design can become strategically useful without turning the discussion into one of one off engineering. The real value is not that a column is different for its own sake. The value is that column design can help define an operating space broad enough to support several related molecules while still maintaining efficiency, separation performance, pressure control, and reproducibility.

That creates a better balance between standardisation and flexibility. Instead of forcing every new molecule into a narrow framework, the system can be designed to support a wider range of process behaviour while remaining controlled. For companies working across several products or modalities, this can create practical support for both process development and manufacturing planning.

Why This Matters in Business Terms

The technical argument has clear business consequences. Drug development pipelines are becoming more diverse, but organisations still need manufacturing efficiency, compliance, reproducibility, and reasonable development timelines. A platform that only works for one narrow molecule type may provide limited support in a broader portfolio. A platform that is redefined around stable operating conditions can offer a more useful balance. This is particularly relevant when the column is designed to support a defined operating space across multiple molecules.

This affects development because fewer repeated adjustments are needed when the column and its operating conditions already support a broader operating range. It affects manufacturing because throughput, pressure handling, and equipment usage can be planned more effectively. It affects purification because separation performance can remain more consistent across molecule types when the operating space is intentionally defined rather than assumed. It also affects product quality because the system is less dependent on repeated fine tuning to compensate for physical variation in the column.

For organisations considering continuous chromatography, higher productivity, or multi product facilities, this way of thinking also supports longer term planning. It creates a clearer link between process, equipment, and expected portfolio evolution. It makes trade-offs more visible and more manageable. It also allows support decisions to be made earlier in development, before scaling up amplifies the effect of column behaviour.

Future Direction

Future trends in chromatography are likely to reinforce this shift rather than reverse it. As molecules become more diverse, and as the range of components and impurities in development expands, downstream process strategies will continue to rely on strong process understanding. At the same time, column design, packing quality, pressure handling, and reproducible operating conditions will become more central to how platforms are defined.

This does not reduce the importance of chromatographic methods. It places them in a more realistic context. Method development, stationary phase selection, mobile phase optimisation, and separation technique all remain important. What changes is the recognition that these methods depend on a physical system that must support them across the intended range.

In that sense, the future of platform chromatography may be less about fixed recipes and more about defined operating spaces. That approach is better aligned with evolving portfolios, modern scale up needs, and the growing need to handle a broader variety of purification tasks within one manufacturing environment.

Conclusion: Platform Processes Still Apply but Their Applicability Depends on the Conditions They Were Developed For

Platform processes still apply, and in many cases, they remain one of the strongest foundations for robust downstream process development. They continue to support efficient purification, reliable manufacturing, and high product quality when molecules behave within the operating conditions the process was developed around.

As the molecular landscape expands, applicability changes. More tuning may be needed. More attention may be required at the level of column behaviour, pressure, packing, flow, and separation efficiency. This is not a sign that platform thinking is outdated. It reflects a broader and more demanding process environment.

That is why the most useful question is no longer simply whether a platform can be applied. The more useful question is whether the column can maintain the operating conditions required for that platform to deliver the intended performance.

When viewed in that way, chromatography columns are not secondary details in the process. They are part of the foundation on which platform applicability depends.

References

[1] Jagschies, G., Lindskog, E., Łącki, K., & Galliher, P. (2018). Biopharmaceutical Processing: Development, Design, and Implementation of Manufacturing Processes. Elsevier.
[2] Harrison, R. G., Todd, P. W., Rudge, S. R., & Petrides, D. P. (2015). Bioseparations Science and Engineering. Oxford University Press.
[3] U.S. Food and Drug Administration (FDA). (2011). Process Validation: General Principles and Practices. https://www.fda.gov/media/71021/download
[4] Gottschalk, U. (Ed.). (2008). Process Scale Purification of Antibodies. Wiley-VCH
[5] DCAT Value Chain Insights. (2026). Bio-Pharma Outlook 2026: The Year Ahead.
https://www.dcatvci.org/features/bio-pharma-outlook-2026-the-year-ahead/