In recent years, the discussion for flexible facility needs became widespread. The motivations for such flexible facility needs are manifold, for example, the requirement to rapidly deploy additional manufacturing capacities or scalability without interrupting existing processes. In addition, the transformation of the treatment or patient base to more personalized medicines necessitates the need to rethink manufacturing and process platforms. For these therapies, the processing space is not only small, but also has a strict containment requirement. Last but not least, there are purely economic reasons to reduce cost of goods. Large area, single product-dedicated brick and mortar facilities are giving way to multiple product versatile facilities.

The Variations of Facility Designs

Discussions of flexible facilities usually bring about a discussion of generic modular designs. These alternatives to traditional brick and mortar facilities range from modular container, modular stick-built, and isolator or containment-based solutions to autonomous cleanroom unit designs. Most of these modular labeled designs have advantages over the traditional built, especially regarding speed in building these facilities.

Having said this, most of the modular designs may be as inflexible as the traditional brick and mortar structures as these systems are interconnected and rigid once assembled. Utilizing similar air handling interconnection and fixed placement, these modular options are as inflexible as legacy systems.

Each facility design option has advantages and drawbacks (Table 1). As a result, these designs are often utilized in a hybrid and synergistic mode. Such a combination can result in the design of an optimal structure for the specific application. This “tool in a toolbox” approach should be employed by drug manufacturers and their supporting engineering firms.

In using this approach, questions that should be asked include: What is the purpose of the facility? What are the requirements to fulfill the purpose? What are the cost benefits (not just cost per square foot but total cost ownership)? How attainable are the budget and delivery times required? Finally, the design utilized boils down to the particular need of the application and end-user. A “one size fits all” approach will not usually result in an optimal result.

Table 1: Strengths & weaknesses of main design options

Facility Design	Strength	Weakness
Brick & Mortar	Extensive experience level with such facilities Dedicated product segregation Large areas	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 to 90 percent of traditional built Time-to-run 18 to 24 months Off-site build-up	Interconnected into one large; no flexibility Large HVAC superstructure Shipping costs Not scalable
Stick-Built Modular	CAPEX 50 percent lower than traditional built Time-to-run 6 to 24 months Built into a shell building Potentially scalable	Interconnected within the facility; no flexibility Large HVAC superstructure On-site build-up
Isolator or Controlled Environment Module	CAPEX 50 percent lower than traditional built Time-to-run 12 to 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 to 50 percent of traditional built Time-to-run 6 to 18 months Moved into a shell building PODs are repurposable Easy to decontaminate Redundant HVAC system in each POD Scalable	Shipping costs Large equipment may require custom sized POD

The Rise of Modularity

Traditional brick and mortar facilities were typically built for one product and sized for the highest projected sales prior to the therapeutic’s approval so that demand could be met by the facility. This approach resulted in overcapacity, higher costs and longer timelines. Pre-construction budgets and timelines were often inaccurate.  Also, with the advent of single use equipment, these type of facility layouts voided the flexibility of single-use processes, since these processes are often mobile and do not fit into the rigid layouts.

Additionally, excursions were hard to manage in such facilities as the epoxy coated gypsum wall damage could result in ingress of moisture into the hygroscopic material. These undesirable factors had the industry searching for new options and have resulted in a rapid adoption trend of modular/podular cleanroom infrastructures.

Single-use technology has been and will continue to be an enabler for more flexible modular/podular manufacturing areas. Process intensification and shrinkage of the manufacturing footprint have generated the ability to design cleanroom modules which can be built off-site, prequalified and moved rapidly into a shell building.

The modular/podular cleanroom infrastructure build is much faster and pre-construction delivery timelines and cost budgets meets the industry’s demand for reliability. Delivery time and cost estimates are based on repeatable schedules and bill of materials as well as minimal on site time with the rapid move in of such units. Instead of a typical on-site productivity level of 80 percent (due to logistics, lay down constraints, etc.), an off-site build can run at 100 to 140 percent productivity level utilizing overtime when required.

A more recent evolution are the predesigned, turnkey facility solutions now being established. These entire facilities can shorten the build time and reduce costs by providing standardized options. As an example, a 4 x 2,000L monoclonal antibody turnkey site can be built in 12 months versus 24 to 36 months. From a standardized, prefabricated cleanroom unit to a predesigned turnkey facility is not a quantum leap, but a mind-set change to a standardized, off-the-shelf approach. Instead of spending copious amounts of hours on new designs, essentially re-inventing the wheel, these designs utilize and employ industry best practices which results in speed and reduced costs.

Conclusions

Facility design requirements are evolving just as bioprocess technologies did in the transformation from stainless steel to flexible and agile single-use process technologies. These innovative technologies have created new facilities opportunities and modular/podular solutions are clearly part of the new facility future. A cross-road between facilities and processes emerge; processes shifted from multi-use to single-use and now facilities move from single-use (product dedicated) to multi-use (multi-product). Flexible processes lose their flexibility if they are forced into uncompromising, inflexible facility and cleanroom infrastructures. Total flexibility is achieved however, when flexible processes are placed into flexible facilities.

Some major pharmaceutical companies and A&E firms have started to embrace the revolution recognizing that the familiar “brick and mortar” and “stick built” approaches will be replaced by advances in technology. Modular/podular cleanroom infrastructure adoption is rising rapidly, revealing that technology improvements are not limited to the processes. The future may bring about turnkey facility solutions and with it speed of design and construction. Time will tell.

About the Author

Maik W. Jornitz, CEO of G-CON Manufacturing Inc., is a technical expert with over 30 years of experience in bioprocesses, especially sterilizing grade filtration and single-use technologies, including regulatory requirements, integrity testing, systems design, and optimization. Jornitz has published 10 books, 15 book chapters and over 100 scientific papers. He is Chair of the PDA Science Advisory Board, as well as working member of BPOG, ASTM, an advisory board member of the Biotechnology Industry Council, ICAV and multiple science journals. He recently has been recognized as one of the top ten global industry influencers. He received his M.Eng. in Bioengineering at the University of Applied Sciences in Hamburg, Germany and accomplished the PED program at IMD Business School in Lausanne, Switzerland.