When the process changes faster than the plant

The article published in MakingPharma&Future described how the evolution of New Chemical Entities (NCEs), rising containment requirements and growing pressure on time to market are changing the role of pilot plants. The next step concerns the design model itself: increasingly dynamic processes and continuous development activities now require a degree of adaptability that was difficult to anticipate when many of today’s operating facilities were designed.

This does not mean that traditional plants were designed incorrectly. On the contrary, they were the engineering response to a context characterised by relatively stable processes, long production campaigns and limited need for reconfiguration.

The problem arises when a design model developed for a stable environment is applied to a scenario in which the process is continuously evolving.

Plants were designed for a different context

For many years, pilot plant design was driven by a clear objective: to create reliable facilities optimised for a specific manufacturing process.

The sequence of unit operations, layout, utilities, containment systems and automation were defined around a process expected to remain substantially unchanged for much of the facility’s operating life.

This approach made it possible to achieve high levels of operational efficiency, reliability and regulatory compliance, effectively meeting the needs of the pharmaceutical industry at the time.

Today, however, the same facility may be required, within just a few months, to handle NCEs with different physicochemical properties, containment requirements and operating sequences. The industrial context has changed, while the underlying design model has remained largely the same.

When rigidity becomes a limitation

Any significant change to the manufacturing process inevitably has an impact on the facility.
Introducing new equipment, changing the sequence of unit operations or adapting containment systems may require modifications to the layout, utilities, automation and qualification documentation.

In an environment shaped by continuous development work, these interventions are no longer exceptional events but recurring conditions.

The rigidity of the plant architecture therefore translates into downtime, higher modification costs, additional qualification activities and greater complexity in lifecycle management.

The limitation does not lie in the performance of individual pieces of equipment, but in the ability of the system as a whole to adapt rapidly to change.

Containment can no longer be added later

The growing number of highly potent NCEs has also changed the role of containment.
In traditional design models, containment systems are often developed after the layout and spatial organisation have already been defined. This approach may be adequate when the process is established and containment requirements are well understood.

During NCE development, however, the toxicological profile evolves progressively and containment requirements may change as knowledge increases.

As a result, containment, process, layout, building and utilities can no longer be addressed as separate disciplines. They need to be developed in an integrated way from the earliest stages of design.

The process evolves faster than the plant

NCE development is a dynamic path characterised by continuous optimisation.
Across the different stages of development, new unit operations may be introduced, unnecessary steps may be removed and different technologies may be adopted in response to experimental results.

The plant, by contrast, is traditionally designed as a relatively stable configuration intended to retain the same architecture for many years.

This creates a progressive mismatch between the speed at which the process evolves and the plant’s ability to evolve with it.

The more frequently changes occur, the wider the gap becomes between the needs of pharmaceutical development and the characteristics of the production infrastructure.

Flexibility alone is not enough

In the pharmaceutical industry, the term flexibility is frequently used to describe facilities capable of manufacturing different molecules.

However, the ability to handle different products does not necessarily imply the ability to adapt the plant architecture rapidly to continuously evolving processes.

The real challenge is not simply to make equipment more flexible, but to design infrastructures capable of evolving with the manufacturing process, integrating new technologies, different containment strategies and future operating needs without requiring extensive structural modifications.

The change required therefore concerns not individual technologies, but the design model on which the plant is conceived. Only an approach focused on process evolution can respond effectively to the needs of future NCEs.

The evolution of NCEs has highlighted a limitation that goes beyond the performance of individual technologies or equipment used in GMP pilot plants. The critical issue lies in the way the project is developed and, above all, in the order in which the main design decisions are made.

For many years, this approach provided an effective response to the needs of the pharmaceutical industry. Today, however, the increasing dynamism of processes makes it necessary to rethink not only technical solutions, but also the design methodology on which those solutions are built.

A facility’s ability to adapt to future change depends on decisions made at the very earliest stages of the project.

The order of design decisions needs to change

Pharmaceutical facility design traditionally follows an established sequence. The project starts with the definition of the building, continues with the development of the overall layout and only later addresses the manufacturing process, containment systems, utilities, automation and qualification activities.

For many years, this approach delivered reliable results, particularly when the manufacturing process was already established and expected to remain largely unchanged over the operating life of the facility.

NCE development changes this scenario. During research and development, the process evolves continuously and may require new unit operations, different technologies or containment requirements that could not have been anticipated in the early stages of the project.

When the building and layout are defined before the process has reached an adequate level of maturity, every subsequent evolution tends to propagate through the entire infrastructure. Available space, logistical flows, utilities and plant installations then become constraints that limit the facility’s ability to adapt.

The issue therefore does not lie in the quality of the design, but in the sequence in which design decisions are made.

The process must drive design decisions

In facilities intended for NCE development, the process is the element with the highest degree of uncertainty and the greatest likelihood of change.

For this reason, it cannot be treated simply as an input to be adapted to an infrastructure that has already been defined. Instead, it should become the reference point around which all other design disciplines are progressively developed.

Building, layout, containment, utilities and automation should be developed as a consequence of process needs, rather than becoming constraints to which the process itself must adapt.

Only by reversing this logic is it possible to preserve the facility’s ability to evolve over time.

Containment must be developed together with the process

During the development of an NCE, the toxicological profile evolves progressively and containment requirements may evolve with it.

Treating containment as a separate discipline, developed only after the layout or building has been defined, increases the risk that future modifications will affect a growing number of plant systems.

A design model oriented towards evolution should instead treat containment and process as closely interdependent elements to be developed simultaneously from the earliest project stages.

In this way, decisions concerning spaces, flows, utilities and auxiliary systems can also evolve while preserving the coherence of the overall architecture.

The architecture must be designed to evolve

Traditionally, a facility is designed to achieve the configuration considered optimal at the time it is built.

In GMP pilot plants, this approach increasingly shows its limitations. The introduction of new unit operations, adoption of different technologies, evolution of automation systems or updates to regulatory requirements are not exceptional events, but normal conditions in pharmaceutical development.

The plant architecture should therefore be conceived so that these evolutions can be managed without compromising the overall structure of the system and without requiring extensive interventions on the infrastructure.
The objective is not to eliminate change, but to make it an integral part of the design.

Towards a new design model

The evolution of NCEs makes clear that a facility’s ability to adapt over time depends not only on the technologies installed, but also on the criteria used to conceive the project as a whole.

The design of GMP pilot plants therefore requires an approach in which the process drives design decisions, containment is developed in an integrated way and the architecture is designed to evolve with manufacturing needs.

These premises provide the basis for a new design model capable of turning process evolution from an operational constraint into a core principle of plant architecture.

THE SERIES

This article continues the series launched in MakingPharma&Future with “Pilot plants for the new era of New Chemical Entities”, which focused on the new requirements created by NCE development and on the need to rethink pilot plant architecture. The following articles develop the Isolator Atoll Concept, examining its methodological principles and their operational translation into the design of modular and reconfigurable GMP facilities.