Process Integration, Connected Processing and Continuous Manufacturing: Three Different Design Problems

Process Intensification (PI) has become an increasingly broad term in biopharmaceutical manufacturing.

Process integration, connected processing, continuous chromatography, inline conditioning, continuous filtration, automated material transfer, and Continuous Manufacturing (CM) are frequently discussed under the same PI umbrella.

They are related—but they are not the same thing.

More importantly, they do not solve the same engineering problem.

This distinction matters because Process Intensification should not begin by asking which PI technology should be installed. It should begin by identifying what process design problem we are trying to solve.

From the perspective of the Lisure PI Process Design Framework (PDF), three fundamental design problems can be distinguished:

Process Integration — How can process functions be combined?

Connected Processing — How can independent process steps work together?

Continuous Manufacturing — How can the manufacturing process itself operate continuously?

Understanding the difference between these three questions provides a much clearer foundation for designing an intensified biopharmaceutical process.

1. Process Integration: Can We Do More With Fewer Operations?

The first design problem is Process Integration.

Traditional downstream manufacturing is generally constructed as a sequence of discrete unit operations.

Clarification.

Capture chromatography.

Virus inactivation.

Polishing chromatography.

Virus filtration.

UF/DF.

Each operation exists because a particular process function needs to be performed.

Over time, however, the physical separation of these functions can become accepted as an inherent property of the process.

But is it?

Process Integration challenges that assumption.

The fundamental question is:

Can multiple process functions be combined, overlapped, or otherwise integrated so that the overall process becomes simpler?

Consider several conceptual examples.

Could clarification and capture become part of a more integrated operation?

Could buffer exchange occur as part of material transfer rather than as a separate processing step?

Could concentration and buffer exchange be integrated differently?

Could certain filtration and chromatography functions be arranged so that an intermediate operation is reduced or eliminated?

These questions are fundamentally different from asking how to optimize the individual unit operation.

We are changing the relationship between process functions.

The potential benefits are straightforward:

• fewer processing steps;

• less equipment;

• shorter total processing time;

• fewer material transfers;

• smaller facility footprint;

• reduced intermediate inventory; and

• potentially lower capital and operating costs.

Process Integration therefore addresses the first PI design problem:

How can we simplify the manufacturing process itself?

Integration Does Not Necessarily Mean Continuous

This distinction is important.

Two or more process functions can be highly integrated while the resulting operation remains time-dependent.

Process Integration therefore should not automatically be equated with Continuous Manufacturing.

A highly integrated process may still start, process a defined quantity of material, stop, and wait for the next operation.

It may nevertheless represent significant Process Intensification.

This is why PI should not be reduced to a simple choice between "batch" and "continuous."

There are multiple dimensions through which a manufacturing process can be intensified.

Process Integration is one of them.

2. Connected Processing: Can Independent Operations Work Together?

The second design problem begins after individual process functions and unit operations have been defined.

The question now becomes:

How should these operations interact with each other?

In traditional batch manufacturing, this problem is largely solved by intermediate storage.

One operation finishes processing.

Its product is transferred into a holding vessel.

The next operation can begin later.

This is an extremely effective architecture because the holding vessel decouples the two operations.

Upstream can finish without downstream being ready.

Downstream can start without upstream still operating.

Each operation can largely maintain its own schedule.

Connected Processing changes this relationship.

Instead of allowing each process step to operate independently, we ask:

Can material move directly from one operation into the next?

Once that question is asked, an entirely different set of engineering considerations emerges.

The output of one operation becomes the input of another.

Processing rates must become compatible.

Material-transfer conditions become important.

Equipment states can no longer be considered entirely independently.

Process dynamics begin to propagate across equipment boundaries.

Automation and control become increasingly important.

The engineering problem has changed.

Process Integration asks how functions can be combined.

Connected Processing asks how separate functions can interact.

Connection Is More Than Piping

This is another distinction worth emphasizing.

Physically connecting two pieces of equipment with tubing or piping does not necessarily create a connected process.

A true process connection requires the two operations to interact in a coordinated way.

Material quantity matters.

Flow matters.

Timing matters.

Process conditions matter.

Equipment availability matters.

Quality requirements matter.

Control matters.

The connection therefore exists not merely at the mechanical level, but at the process and operational levels.

This is why Connected Processing should be considered a process design discipline rather than simply a piping configuration.

The objective is not merely:

Connect Equipment A to Equipment B.

The objective is:

Design Process A and Process B so that material can reliably move between them as part of an integrated manufacturing operation.

That is a considerably more demanding engineering problem.

Connected Does Not Necessarily Mean Continuous

Here again, terminology matters.

A process can be connected without being fully continuous.

Two unit operations may directly transfer material without a conventional intermediate batch hold, yet the overall manufacturing process may still contain time-dependent operations elsewhere.

Connected Processing therefore represents another important level of Process Intensification without necessarily satisfying the conditions of Continuous Manufacturing.

This distinction gives process designers much more flexibility.

The choice does not have to be:

Traditional batch process or fully Continuous Manufacturing.

There is a broad design space between those two extremes.

Significant benefits may be achieved through Process Integration and Connected Processing even when full continuity is neither necessary nor economically justified.

3. Continuous Manufacturing: Can the Process Itself Become Continuous?

Continuous Manufacturing introduces the third and most comprehensive design problem.

Here the question is no longer limited to combining process functions or connecting neighboring equipment.

The question becomes:

Can the overall manufacturing process operate continuously?

This requires us to move the system boundary outward.

Instead of evaluating whether an individual chromatography system, filtration system, or other unit operation is continuous, we evaluate the manufacturing process as a whole.

What enters the process?

How does material move through it?

What leaves the process?

How does the manufacturing system behave over time?

This leads to an important principle within the PI Process Design Framework:

Continuous Manufacturing should be defined at the process boundary, not merely by the operating mode of individual equipment.

A process containing continuous chromatography is not necessarily a continuous manufacturing process.

A process containing continuous filtration is not necessarily a continuous manufacturing process.

Even several continuous technologies connected together do not automatically establish continuity at the overall manufacturing level.

Continuous technologies are enabling technologies.

Continuous Manufacturing is a property of the process architecture.

Three Problems, Three Different Questions

The distinction can therefore be summarized very simply.

Process Integration

What process functions can be combined?

The primary design objective is simplification.

Connected Processing

How can separate process operations work together?

The primary design objective is coordination and direct material handover.

Continuous Manufacturing

How can the overall manufacturing process operate continuously?

The primary design objective is continuity at the process level.

These three questions are related, but they are not interchangeable.

And importantly, one does not necessarily require the next.

A manufacturer may pursue Process Integration without Connected Processing.

A process may use Connected Processing without becoming fully continuous.

And a Continuous Manufacturing strategy will generally require careful consideration of both integration and connectivity—but its design objective extends beyond either one individually.

This Creates a Design Spectrum

Rather than thinking of Process Intensification as a binary transition from batch to continuous, it may be more useful to think about a design spectrum.

At one end is a traditional process consisting of independent unit operations.

Process Integration begins reducing unnecessary functional separation.

Connected Processing begins reducing unnecessary operational separation.

Continuous Manufacturing addresses continuity across the overall manufacturing process.

As we move along this spectrum, the nature of the engineering problem changes.

The process becomes less dependent on isolated equipment and increasingly dependent on the behavior of the overall system.

That has implications for equipment design.

It has implications for automation.

It has implications for process control.

It has implications for facility design.

It has implications for technology transfer.

And ultimately, it changes how we should think about the relationship between Process Development and Process Design.

Process Development Still Defines the Science

None of this diminishes the importance of Process Development.

Process Development determines the scientific foundation of the manufacturing process.

Which resin should be used?

What loading condition is appropriate?

What pH and conductivity are required?

What membrane should be selected?

What impurity clearance must be achieved?

What operating ranges maintain product quality?

Those are essential questions.

But once those scientific requirements are established, another set of questions begins.

Can process functions be integrated?

Can process boundaries be removed?

Can operations interact directly?

Can manufacturing operate more productively?

Can the same underlying process be executed using a fundamentally better manufacturing architecture?

Those are Process Design questions.

This is precisely why Process Intensification should not simply be viewed as an extension of Process Development.

Start With the Design Problem

This perspective also changes how organizations might approach PI projects.

Instead of starting with:

"We want to implement continuous chromatography."

Start with:

"What are we trying to improve about this manufacturing process?"

If the objective is reducing equipment and processing steps, Process Integration may be the appropriate starting point.

If the objective is eliminating intermediate storage and reducing total process time, Connected Processing may become more important.

If the objective is maximizing productive manufacturing time and establishing continuous material flow across the process, Continuous Manufacturing becomes the larger architectural problem.

The technology selection should follow the process design objective—not define it.

Process Intensification Is a Hierarchy of Design Decisions

This brings us back to the broader principle behind Lisure's PI Process Design Framework.

Process Intensification should not be understood simply as a collection of advanced technologies.

It is better understood as a hierarchy of process design decisions.

First, simplify the process.

Ask what can be integrated.

Then, examine the boundaries.

Ask what can be connected.

Finally, examine the manufacturing architecture.

Ask what continuity should mean for the process as a whole.

The appropriate answer will not necessarily be the same for every molecule, every facility, or every manufacturing strategy.

Nor should it be.

The objective of Process Intensification is not to make every process look the same.

The objective is to determine how a given process can be manufactured in the most effective way.

The Technology Comes After the Architecture

The biopharmaceutical industry now has an extraordinary range of technologies available for Process Intensification and Continuous Manufacturing.

That is good news.

But the availability of technology makes process design more important, not less.

The critical question is no longer simply:

"What can this equipment do?"

It is:

"What should the manufacturing process do—and what architecture will allow it to do it?"

Once that question has been answered, equipment, automation, PAT, control systems, and digital technologies can be selected and engineered accordingly.

That is the difference between assembling PI technologies and designing an intensified process.

And it is why we believe Process Integration, Connected Processing, and Continuous Manufacturing should be understood as three related—but fundamentally different—process design problems.

Process Intensification begins with technology possibilities. But successful Process Intensification begins with Process Design.

That is the foundation of the Lisure PI Process Design Framework (PDF).

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Lisure Technology Co.

2559 US-130

Cranbury, NJ 08512