The Engineering Behind Lisure ICPC

In biopharmaceutical downstream processing, chromatography system specifications are often presented as a collection of individual numbers: maximum flow rate, pressure rating, gradient accuracy, pH accuracy, conductivity range, or dilution ratio.

But these specifications are not independent.

A high-performance chromatography system is an integrated fluid-processing system. Its achievable dilution ratio affects the required flow-control range. Flow-control performance affects composition accuracy. Composition and mixing affect pH performance. Hydraulic transition behavior affects stabilization time. And stabilization time directly affects buffer consumption and waste.

This is particularly important when inline dilution is integrated directly into process chromatography.

Lisure's Inline Dilution Process Chromatography (ICPC) system was developed around this systems-engineering perspective. Rather than treating inline dilution as an auxiliary buffer-preparation function added to a chromatography skid, ICPC integrates buffer dilution, fluid delivery, monitoring, and chromatography operation as a single process system.

The result is a system capable of achieving performance including:

Lisure ICPC achieves buffer dilution ratio Up to 1:300 while the representative benchmark is below 2:100. Lisure ICPC controls pH within ±0.1 while the average performance in the industry is ~±0.15. Lisure ICPC has a buffer mixing stabilization time~0.5 min while the standard performance is ~2 min.

These performance differences are not the result of any single component. They are consequences of the overall system architecture.

That relationship is worth examining.

The First Challenge: Inline Dilution Is a Dynamic-Range Problem

At first glance, inline dilution seems straightforward.

A concentrated buffer stream and a dilution stream are delivered at controlled flow rates, mixed inline, and monitored for the required final composition.

At modest dilution ratios, this is relatively easy.

At very high dilution ratios, however, the engineering problem changes.

Consider the difference between operating near a 2:100 ratio and approaching 1:300. The concentrate stream can become extremely small relative to the total process flow.

The system is therefore being asked to control simultaneously:

a relatively large process flow and a very small concentrate flow.

This creates a fluid-delivery dynamic-range problem.

A pump has an operating range within which it can deliver fluid with acceptable accuracy, repeatability and control stability. Asking the same pump to cover an excessively wide range means that, eventually, the required flow approaches the lower end of its useful controllable range.

This is why simply specifying a larger maximum-flow pump does not necessarily produce a better inline-dilution system.

In fact, increasing the maximum capacity of a pump while requiring the same pump to accurately deliver extremely small flows can make the control challenge more difficult.

Lisure's approach: expand the system range rather than force the pump range

Lisure ICPC uses eight pumps covering a much broader range of fluid-delivery conditions.

The objective is not simply to provide more pumps.

The objective is to avoid asking one fluid-delivery device to perform accurately across an unnecessarily extreme operating range.

The system can instead operate different fluid streams within more appropriate hydraulic ranges.

ICPC also provides multiple concentrate inlets that can accommodate different concentrate strengths for the same buffer stream.

This introduces another degree of freedom.

Instead of solving every process requirement entirely through increasingly extreme flow ratios, both concentrate strength and delivered flow can be considered when selecting an appropriate operating condition.

The resulting design space is much larger.

This is an important systems-engineering principle:

When the required process range exceeds the practical controllable range of an individual component, redesign the architecture rather than simply demanding more from the component.

That principle is one of the reasons ICPC can achieve dilution ratios as high as 1:300.

Why High Dilution Ratio Matters

A higher achievable dilution ratio is not simply an impressive equipment specification.

It can fundamentally change buffer-management strategy.

If a final process buffer can be produced from a substantially more concentrated solution, less concentrate volume needs to be prepared, stored and transferred.

This can potentially reduce requirements associated with:

• buffer preparation volume;

• concentrate storage;

• vessel size;

• transfer operations;

• facility footprint; and

• buffer-management infrastructure.

The value becomes increasingly important as manufacturing scale increases or as a process requires many different buffer compositions.

Inline dilution therefore should not be viewed only as a mixing technology.

It can become part of the facility and process architecture.

pH Performance Is Also a System Property

The same reasoning applies to pH.

It is tempting to view pH accuracy primarily as an instrumentation problem:

Install a sufficiently accurate pH sensor and the system should achieve accurate pH control.

But the sensor can only measure the fluid that the system has created.

Actual inline pH performance depends on the entire chain:

Fluid Delivery → Dosing Resolution → Mixing → Measurement → Control Response

If the concentrate flow is unstable, the resulting composition will be unstable.

If the ratio between streams cannot be controlled accurately, the resulting pH can vary.

If mixing is incomplete, the pH sensor may observe a condition that does not adequately represent the final homogeneous stream.

And if the hydraulic response is slow, the control system may spend unnecessary time chasing a moving process condition.

This relationship becomes more demanding at high dilution ratios.

When one stream represents only a very small fraction of total flow, relatively small deviations in that stream can become important to final composition.

The ability of Lisure ICPC to maintain pH performance of approximately ±0.1 should therefore be understood as an integrated result of fluid-delivery range, dosing capability, mixing, instrumentation and control—not as an isolated pH-probe specification.

The Hidden Cost of Stabilization Time

Another chromatography-system specification receives considerably less attention:

How long does the system take to establish a usable buffer condition after a transition?

For a conventional system, approximately two minutes may appear insignificant.

But in a production chromatography process, stabilization time is not just time.

It is flow multiplied by time.

If buffer cannot be directed to the process while the system is establishing the required composition, that buffer may be discharged to waste.

Conceptually:

Buffer loss during stabilization ≈ Flow Rate × Stabilization Time

This simple relationship has major implications at manufacturing scale.

Consider a hypothetical system operating at 5,000 L/h.

A two-minute stabilization period corresponds to approximately:

166 L buffer.

A 0.5-minute stabilization period corresponds to approximately:

40 L buffer.

The difference is approximately:

120 L for a single transition.

That is a 75% reduction in stabilization-associated flow volume.

Now multiply that by the number of buffer transitions in a chromatography cycle.

Then multiply it again by the number of chromatography cycles in a campaign.

And then consider multiple chromatography systems operating over the life of a facility.

A seemingly small improvement measured in minutes can become a significant amount of buffer.

Why ICPC Can Stabilize Faster

Lisure ICPC approaches this problem at the hydraulic-system level.

Two design concepts are particularly important:

a recirculation-loop-based flow pre-establishment mechanism and a specialized dilution-valve design.

The underlying principle is straightforward even without discussing the proprietary implementation details.

In a conventional transition, the system may need to establish the required flow rates, hydraulic conditions, mixing ratio and resulting composition after the transition begins.

During that transient period, the resulting solution may not yet satisfy the process requirement.

ICPC is designed so that important hydraulic conditions can be pre-established before the newly prepared buffer is committed to the chromatography process.

In simplified terms:

Conventional approach

Transition → Establish Flow → Establish Ratio → Stabilize Mixing → Confirm Condition → Process

versus:

ICPC approach

Pre-establish Hydraulic Condition → Transition → Rapid Stabilization → Process

This architectural difference allows the buffer mixing stabilization period to be reduced from a representative value of approximately 2 minutes to approximately 0.5 minute.

The important innovation is not merely “faster switching.”

It is the recognition that the hydraulic state of the system can be prepared before the process needs it.

Faster Stabilization Becomes More Valuable at Larger Scale

This relationship is especially important because stabilization loss scales approximately with flow.

At small scale, saving 90 seconds may have limited economic significance.

At commercial scale, the same 90 seconds occurs at a much larger volumetric flow rate.

The economic value of faster stabilization increases with manufacturing scale.

The same design feature that appears to save only 1.5 minutes can prevent hundreds of liters from being unnecessarily diverted during a single transition in a sufficiently large-flow system.

Look Beyond Maximum Flow Rate

This example also illustrates why chromatography systems should not be evaluated primarily by maximum flow rate.

Maximum flow is important, but it describes only one end of the operating envelope.

For an integrated inline-dilution chromatography system, equally important questions include:

How low can each required stream be accurately controlled?

How wide is the usable dynamic range?

How quickly can the system establish a new hydraulic condition?

How accurately can composition and pH be maintained across that range?

How much buffer is consumed during transitions?

How effectively can concentrate strength and flow ratio be combined to expand the operating window?

Two systems with the same nominal maximum flow rate can therefore have very different practical process capabilities.

The distinction lies in the architecture between the specification numbers.

Inline Dilution and Chromatography Together

There is another reason Lisure refers to the technology as Inline Dilution Process Chromatography, rather than simply an inline buffer-dilution system.

The dilution system and chromatography system ultimately serve the same process.

Treating them as separate equipment functions can lead to duplicated fluid delivery, additional transition volume, more complicated flow paths, longer stabilization requirements and additional automation interfaces.

Integrating them allows the system to be designed around the actual chromatography sequence.

The question becomes:

How do we deliver the correct process fluid to the chromatography operation, at the correct flow, composition and time, with the minimum unnecessary transition?

A Practical Technology

New process technologies are often demonstrated under carefully controlled development conditions but have limited manufacturing experience. ICPC has moved beyond that stage.

Lisure ICPC systems have been implemented at more than 20 customer sites, providing practical experience with different processes, operating conditions and customer requirements.

That experience is important because high-performance fluid processing is rarely determined by a single theoretical design parameter.

Real systems must operate across different recipes, buffer conditions, process flow rates, chromatography operations and manufacturing environments.

Repeated implementation provides the feedback necessary to refine not only components but the architecture of the system itself.

Performance Is the Result of Architecture

The ICPC example points to a broader lesson in bioprocess equipment design.

A specification such as: 1:300 dilution cannot be separated from pump range and concentrate strategy.

A specification such as: ±0.1 pH cannot be separated from fluid delivery, mixing, instrumentation and control.

A specification such as: 0.5-minute stabilization cannot be separated from hydraulic architecture and transition strategy.

And stabilization time cannot be separated from: buffer consumption and waste.

These are not isolated specifications. They form a chain of engineering relationships:

Fluid-Delivery Architecture

Extended Dynamic Range

Higher Dilution Capability

Accurate Composition and pH

Faster Hydraulic and Mixing Stabilization

Reduced Buffer Waste

More Efficient Chromatography Operation

Chromatography system performance is not created by the specification sheet. The specification sheet is the result of the system architecture.

And ICPC is one example of what becomes possible when that architecture is designed around the process from the beginning.

©2025

Lisure Technology Co.

2559 US-130

Cranbury, NJ 08512