Purification Made Simple
Why Continuous Manufacturing Can Deliver an Order-of-Magnitude Increase in Effective Manufacturing Capacity?
At the same process scale, continuous manufacturing can potentially provide an order-of-magnitude increase in productive manufacturing capacity.
CONTINUOUS MANUFACTURING (CM)REGULATORY CONSIDERATION
9/9/20266 min read
Continuous Manufacturing (CM) is often discussed in terms of sophisticated technologies: continuous chromatography, PAT, residence-time-distribution modeling, advanced process control, real-time monitoring, and increasingly complex automation.
But perhaps we have made the fundamental argument for continuous manufacturing unnecessarily complicated.
Before considering facility footprint, capital cost, labor, buffer consumption, time-to-market, or even regulatory advantages, there is a much simpler reason why continuous manufacturing can be dramatically more powerful than traditional batch manufacturing:
Time.
At the same process scale, continuous manufacturing can potentially provide an order-of-magnitude increase in productive manufacturing capacity simply because the equipment is allowed to spend much more of its available time actually processing product.
Start With a Very Simple Question
Consider a traditional downstream batch process.
Suppose a chromatography step requires approximately six hours from beginning to end.
Those six hours may include:
preparation;
equilibration;
loading;
washing;
elution;
regeneration;
cleaning;
intermediate material handling; and
preparation for the next operation.
But perhaps only two hours of that six-hour period represent the critical productive processing window.
More importantly, because the operation belongs to a larger batch manufacturing sequence, completing the step does not necessarily mean that another batch immediately begins.
Material must move through the manufacturing train. Operators, equipment, buffers, holding vessels, cleaning activities, sampling, and schedules must all be coordinated.
In practical batch manufacturing, a six-hour unit operation can therefore occupy a manufacturing slot that effectively limits the process to approximately one batch per day.
Now consider the same process function redesigned as part of a continuous manufacturing architecture.
Instead of asking:
"How many batches can we schedule?"
we ask:
"How many hours can the process continuously manufacture product?"
That seemingly simple change fundamentally alters the capacity equation.
From Hours per Batch to Productive Hours per Day
Suppose a continuous process can operate productively for 20-24 hours per day, allowing a few hours for other operational activities, interventions, or scheduled downtime.
Compare that with a conventional process effectively executing one two-hour productive processing window per day.
The comparison becomes:
Traditional batch: approximately 2 productive hours/day
versus
Continuous manufacturing: approximately 20 productive hours/day
That is a 10X difference in available productive processing time.
This is not primarily a consequence of faster pumps, larger columns, or more aggressive process conditions.
It comes from process architecture.
The continuous process is more powerful because it makes fundamentally better use of time.
The Same Scale Does Not Mean the Same Capacity
This leads to an important distinction.
When comparing batch and continuous manufacturing equipment, we frequently compare equipment size.
A 30-cm column is compared with another 30-cm column.
A 10-m^2 membrane system is compared with another 10-m^2 membrane system.
A process skid is compared with a similarly sized process skid.
But physical scale alone tells us very little about manufacturing capacity.
The more meaningful relationship is:
Manufacturing Capacity = Processing Rate × Productive Operating Time
If two systems have approximately the same instantaneous processing capability but one can productively operate ten times longer, their effective manufacturing capacities are obviously not equivalent.
A relatively small continuous system can therefore potentially provide manufacturing capacity that would require much larger equipment in a conventional batch architecture.
This is one of the fundamental economic consequences of continuous manufacturing.
Why Doesn't Batch Manufacturing Simply Run 24 Hours?
This is an important question.
Individual batch equipment certainly can operate around the clock. Pharmaceutical plants already do so.
But continuously operating equipment is not the same as operating a continuous process.
Traditional downstream processes consist of multiple time-dependent unit operations connected through intermediate material storage.
One operation finishes.
Material waits.
Another begins.
Material waits again.
Equipment changes state. Buffers change. Operators intervene. Samples are collected. Holding vessels fill and empty. Upstream and downstream schedules must be coordinated.
The problem is therefore not simply equipment utilization.
The problem is the architecture of the manufacturing process.
Continuous manufacturing attacks this problem at the architectural level.
This Is Why PI Should Be Viewed as Process Design
This brings us back to a central principle of Lisure's PI Process Design Framework (PDF):
Process Intensification is fundamentally a process design problem, not simply a process development problem.
Process Development determines how the molecule should be processed:
Which resin?
What loading?
What pH?
What conductivity?
What membrane?
What operating window?
Process Design asks a different question:
How should these established process functions be architected so that material can move through manufacturing with minimum interruption, minimum inventory, and maximum utilization of productive time?
The chemistry does not necessarily have to change.
The manufacturing architecture does.
Integration Comes Before Continuity
Continuous manufacturing should therefore not begin with the question:
"Which continuous equipment should we purchase?"
A better starting point is:
"How should this process be designed?"
That leads naturally through several levels of process intensification.
First, Process Integration asks whether multiple process functions can be combined.
Next, Connected Processing asks whether intermediate holding steps can be eliminated and material transferred directly between unit operations.
Finally, Continuous Manufacturing asks whether the process architecture can maintain continuous product-containing feed into the process and continuous product-containing output from it.
These are progressively more powerful applications of process design.
The ultimate objective is not to make every individual unit operation intrinsically continuous.
The objective is to make the manufacturing process continuous.
That distinction is critical.
10X Capacity Is Only the Beginning
The productivity argument alone can make continuous manufacturing compelling.
But the 10X example above considers essentially only one variable:
productive operating time.
It does not yet account for many other potential benefits of a well-designed intensified process.
Smaller Equipment
If equipment can be used much more productively, equivalent annual manufacturing capacity may be achievable using substantially smaller systems.
Lower Capital Requirements
Smaller equipment can lead to smaller process areas, smaller utilities, reduced buffer infrastructure, fewer intermediate vessels, and potentially smaller facilities.
Lower Operating Cost
Process integration and connected processing can reduce material handling, cleaning operations, buffer storage, operator intervention, and intermediate inventory.
Faster Manufacturing
Removing waiting periods and intermediate storage can dramatically reduce total process cycle time.
Faster Deployment and Technology Transfer
A standardized process architecture demonstrated at pilot scale may provide a more direct pathway toward manufacturing-scale implementation.
Greater Flexibility
Instead of increasing batch size by continually increasing equipment scale, capacity can potentially be increased through operating time, parallelization, or standardized manufacturing units.
The result is a fundamentally different way of thinking about scale.
And Then There Is Time-to-Market
For biopharmaceutical manufacturing, capacity is not merely an operational issue.
It is a business issue.
A smaller manufacturing platform that can be deployed faster and generate substantially greater capacity per unit of installed equipment may influence:
facility construction strategy;
clinical manufacturing;
commercial launch planning;
capacity expansion;
technology transfer; and
investment risk.
For a successful biologic, several months of earlier market entry can potentially be more economically significant than the cost of the manufacturing equipment itself.
This means that the economic argument for continuous manufacturing extends far beyond cost per gram.
What About Regulatory Complexity?
This is where the discussion becomes more nuanced.
Continuous manufacturing introduces regulatory and technical questions that conventional batch manufacturing does not always encounter in the same form.
Among them are:
material traceability and lot genealogy;
residence-time distribution;
process dynamics;
disturbance handling;
material diversion;
startup and shutdown;
sampling strategy;
process monitoring; and
definition of appropriate control strategies.
FDA's ICH Q13 framework appropriately brings many of these issues into focus.
But these should be understood as engineering problems to be solved during process design, rather than reasons why continuous manufacturing is inherently impractical.
Once the process architecture can systematically address these concerns, the regulatory discussion can become much simpler because the behavior of the manufacturing system itself becomes well defined.
The challenge, therefore, is not simply to make individual unit operations continuous.
It is to design a continuous manufacturing architecture in which material flow, process states, disturbances, residence time, traceability, and control are understandable by design.
That is precisely where a Process Design Framework (PDF) becomes necessary.
The Question May Eventually Reverse
For many years, the industry has asked:
"Why should we use continuous manufacturing?"
Perhaps the more interesting question is eventually going to become:
"If the same process can be manufactured at dramatically greater effective capacity using smaller equipment and a more integrated architecture, why would we continue designing every new facility around the limitations of traditional batch processing?"
There will certainly remain applications where batch manufacturing makes sense.
But the burden of comparison should be technical and economic—not historical.
A manufacturing architecture should be selected because it is the best way to manufacture the product, not simply because it is the way the industry has always manufactured it.
10X Is Not Really About Equipment
This may be the most important point.
When we say that a continuous manufacturing process can be 10X more powerful, we are not necessarily saying that the underlying purification process operates ten times faster.
We are saying something more fundamental.
Continuous manufacturing can use time differently.
Instead of repeatedly starting, stopping, waiting, transferring, storing, and restarting, the manufacturing system is designed around continuous material movement and sustained productive operation.
The scientific process may remain substantially the same.
The process architecture changes.
And when architecture changes, the economics of manufacturing can change with it.
That is why Lisure believes the next generation of Process Intensification and Continuous Manufacturing will not be defined primarily by individual pieces of continuous processing equipment.
It will be defined by process design.
This is the foundation of the Lisure PI Process Design Framework.