Currently the need of a paradigm shift in the facility design of pharmaceutical and biopharmaceutical production sites has been stated in multiple papers and conferences (1, 2, 3). The reasons for such facility layout changes are manifold and, for example, can be newly evolving drug developments, changes in process technologies, transformation of the treatment or patient base or purely economical reasons, which focus on capacity utilization and process flexibilities. Ultimately, there is a change process happening, a shift from large area, product dedicated brick and mortar facilities to more versatile but multiple facilities in different regions.

With that new demand by the industry comes the promise of the delivery of the expected, in the form of “flexible facilities”, “modular facilities” or ”manufacturing on demand”. This article will review “the tools in the toolbox” of facility designs, especially ones labeled modular or flexible or both. A serious review of the promises and statements made might be of value.

 

What’s out there?

Besides the traditional brick and mortar facilities, there are alternative facility designs available, for example, modular container, modular stick-built, isolator or containment based and autonomous cleanroom POD designs (Table 1). All of these designs have their purpose, benefits and disadvantages (Table 2). Often these designs are utilized in a hybrid mode and not necessarily totally independent. Once again any of these facility designs are a tool in the toolbox of choices for the drug manufacturer or the engineering firms supporting such. The very specific choices, which need to be made, are requirement based. What is the purpose of the facility, what are the requirements to fulfill the purpose? Ultimately it boils down to the particular need of the application and end-user.

 

Facility Design	Description
Bricks & Mortar	The traditional type facility, build often for one product and large scale. Lifespan of the facility is commonly one product lifecycle. Very dedicated and purpose-build facility design. HVAC systems in the mezzanine level supply large areas.
Modular Container	Off-site build container systems, which are interconnected at the final location to a complete facility. The container modules can be outfitted and designed to purpose. Centralized HVAC system.
Stick-built Modular	The facility is framed out and finished with modular wall panels. The wall panels can be of different surface finish or designs to accommodate for example room-to-room pass through or windows. HVAC systems in the mezzanine level supplying multiple rooms.
Isolator or Controlled Environment Module	Build off-site and most commonly introduced into either a cleanroom or at least CNC area. Depending on the system, it creates an excellent containment option and can be repurposed and effortlessly sanitized. Some systems are connected to a centralized HVAC system, others might have their own.
Autonomous POD	Off-site build autonomous cleanroom module. Available in various standard dimension, but can be modified into project designs. Effortlessly sanitized and decontaminated. The PODs are mobile and contain their own HVAC system.

Table 1: Description of the different facility designs available.

A decision matrix will determine, which one of the tools shall be utilized for the project and/or for a section of the project. As mentioned, a facility may not necessarily be designed with one of the facility options, but often resolves into a hybrid solution of two or three of the options listed. For example, cell therapeutic or antibody conjugate processing happens often in production isolators or other containment options, which are surrounded by a class B environment, which can be any type of cleanroom. Autonomous cleanroom POD solutions are most commonly connected to a stick-built corridor system. It is not that there is a one-fits-all approach, which makes a modern facility more viable, it is the approach to pick and chose the right design solutions for an optimal fulfillment of the specified purposes. This approach has been utilized for many years in the design of the production processes. End-users moved away from the legacy models to evaluation of the best process equipment choice for a particular unit operation, even if it means multiple vendor use.

 

Facility Design	Strength	Weakness
Bricks & Mortar	·   Extensive experience level with such facilities ·   Dedicated product segregation ·   Large areas ·   Time-to-run 24-48 months	·   Difficult to repurpose ·   One product lifecycle ·   High CAPEX ·   Up to 4 years time-to-run ·   Inflexible ·   Large HVAC superstructure ·   Difficult to decontaminate if necessary
Modular Container	·   CAPEX 70-90%of traditional built ·   Time-to-run 18-24 months ·   Off-site build-up	·   Interconnected to one large facility losing its flexibility at that point ·   Large HVAC superstructure ·   Shipping costs ·   Not scalable
Stick-built Modular	·   CAPEX 50% lower than traditional built ·   Time-to-run 6-24 months ·   Build into a shell building ·   Potentially scalable	·   Interconnected to one large facility losing its flexibility at that point ·   Large HVAC superstructure ·   On-site build-up
Isolator or Controlled Environment Module	·   CAPEX 50% lower than traditional built ·   Time-to-run 12-18 months ·   Modules are repurposable ·   Possible to decontaminate ·   Scalable	·   Size limitations make the use of larger equipment difficult ·   BSL containment limitations ·   Centralized HVAC
Autonomous POD	·   CAPEX 40-50%of traditional built ·   Time-to-run 6-18 months ·   Moved into a shell building ·   PODs are repurposable ·   Easy to decontaminate ·   Redundant HVAC system in each POD ·   Scalable	·   Shipping costs ·   Equipment size excursions require project POD

Table 2 – Strength and weakness analysis of the different facility designs available.

What does flexible mean ?

First of all one probably should distinguish between modular and flexible, both terms are used interrelated, but are most often totally unrelated. Modular facility designs are excellent concepts, which, as described above, can be deployed faster than traditional facility layouts. However, most modular facilities, when interconnected become inflexible and very much like traditional facilities. For example modular container systems, which are built off-site and ultimately interconnected to a total facility at the final location, are nothing new and have been built for many years. These facilities were beneficially compared to traditional sites, except the advantages listed were the faster time-to-run. Now these facilities are not just labeled modular, but also flexible, which could be argued to be the case. What is so flexible, when modular containers are interconnected to one facility? Even the modules lose the modularity during interconnection. Similarly, modular stick-built facilities are just called modular, because one can add framing and “modular” wall panels. Truly modular or flexible? Probably not and very well observed by Alain Pralong in a recent paper (4), who states “Until now, modular facilities have reproduced traditional architecture with regard to embedding utilities piping and HVAC ducts in the interspace between the physical module limits and the suspended ceiling making refurbishment, if required, extremely complicated.” These modular facilities are as flexible as traditional facility designs and therefore modular and flexible should not be used in the same context.

Then what does flexible facility really mean? Flexibility of facilities is often related to two major factors; multi-product processing and scalability. Other factors are mobility and achievable product-lifecycles. Processing flexibility is often used in conjunction with single-use equipment technologies. These unit operations have a multitude of technology and economical benefits. One benefit, the single-use systems represent the first containment barrier, which created flexibility and the potential of multi-product process opportunities. However, the reliance here is on the robustness of the single-use processes. If there would be any breach incident, the containment responsibility shifts to the surrounding environment. This means if one wants to maintain the flexibility of the production, the surrounding environment needs to be easily cleanable and sanitizable. This includes the HVAC system, which requires being compact to achieve a validated sanitization process, which can only be achieved when the cleanroom space has separate HVAC units. The other part of facility flexibility, scalability, means that processes and facility parts are required to “pulse” with the capacity demands needed. The facility needs to be able to ramp-up fast, if the drug demand is increasing and as easily ramp-down, if the demands are reduced. That does not mean that the production processes are out of control, they are just processing different demands of drug product at the same quality. Therefore the process and surrounding environment requires being robust, and able to be duplicated. A cookie cutter principle of the production process in its environment would be ideal to scale and to copy the facility into other regions of the world.

Conclusion

Flexibility and modularity are often used interchangeably, however one should review such offerings carefully and realize that most modular facility designs turn into a traditional facility layout, losing the flexibility in that instance. Flexibility though, meaning multi-product processes and being easily scalable, might be achieved in any such building with single-use technology processes, however the reliance of containment is very much focused on the robustness of the single-use equipment.

True flexibility comes with autonomy of the critical cleanroom space; as such autonomous, compact cleanroom system can be painlessly decontaminated and sanitized, controlled and re-used. The cleaning and repurposing of autonomous cleanroom spaces make them ideal for multi-product processing, Furthermore, these systems can be deployed fast track and, if needed, moved.

Ultimately, the vision of flexible facilities has to be “mini-sites”, which can be utilized anywhere, and built and run within months to fulfill local health requirements. Single-use process equipment created the first step to such sites, which now is completed by autonomous cleanroom modules.

References

(1) H. L. Levine, J. E. Lilja, R. Stock, H. Hummel, S. D. Jones (2012) Efficient, Flexible Facilities for the 21st Century, BioProcess International 10(11)

(2) Hodge G. Hodge (2009) The Economic and Strategic Value of Flexible Manufacturing Capacity. ISPE Strasbourg Conference, 28–29 September 2009, Strasbourg, France.

(3) A. Shanley, P. Thomas (2009) Flexible Pharma: Puzzling Out the Plant of the Future, PharmaManufacturing.com

(4) A. Pralong (2013) Single-use technologies and facility layout – a paradigm shift,Biopharma Asia Magazine, Vol 2, Issue 1