With an increasing diversity of therapies and drug product ranges, facility designs also require diversification. Inevitably, the facility designs of the future will not be a legacy of the known, but a utilization of different tools from the toolbox of facility layouts. The therapeutic drug manufacturing industry has realized that change is needed; flexibility in clinical material and full-scale production is necessary to become more efficient and agile. The topic of flexible facilities has become a hot button issue and has received attention from industry experts and conference organizers alike. Flexibility, though, is often used in combination with modular, which does not necessarily mean what the industry expects. This article will review different facility layouts and flexible design opportunities.
The need for flexibility
Facility flexibility has become a frequent discussion point over the last few years1,2,3 and the question arises: “Why the focus on flexibility?” The answer for this demand lies within a multitude of factors, one certainly being the need to increase capacity utilization to reduce the cost of goods sold (COGS). Other reasons are to ramp capacity up and down in accordance to demand or to utilize the process environment for patient-by-patient basis treatments. More biopharmaceutical drug product manufacturers are looking into entering specific global regions with smaller production facilities instead of utilizing a central large-scale site and shipping the product under cold chain scrutiny to different global regions. Others want to secure raw material supplies, like excipients or active ingredients, and therefore build sites instead of relying on sub-suppliers. Or think about mobile sites, which could be deployed from location to location, depending on the demand base. All of these needs would be easier fulfilled when the facility shows flexibility in purpose, design, deployment, and implementation. Flexibility does not necessarily mean one looks solely at the cost per cleanroom area, but the total cost of a facility, time-to-run, repurposing, and product life cycles. In addition, the typical one drug product classification industry is switching to other drug treatment possibilities and looks into the future – for example, cell therapies. The spread of facility designs is widening to fulfill the different application requirements. The end-users requested new choices in facility layouts and vendors developed such choices, from classical large scale brick and mortar facilities to small-scale isolator solutions. However, when looking for flexibility in a facility layout, one should consider the different options to fully understand whether it meets the requirements or not. Flexibility needs to be defined by the end-user and only then appropriate choices can be made, including total cost and purpose.
The multitude of facility designs
Brick and mortar environments are nowadays called “traditional facilities” and often represent large-scale, one product facilities. These facilities are dedicated to a single product or product line, even to the point that the facility has only one product lifespan. Sometimes it is said that such-and-such product financed the site,—i.e., the site is commonly built when the product is close to approval. It can then take up to four years to have the facility up and running. There are alternative facility architectures available—for example, modular container and modular stick-built. These facility systems have the advantage to have a time-to-run of half the time of a traditional facility. The container solutions are planned and equipped off-site and assembled at the future facility location. Once assembled, these production site systems convert very much into a traditional site. Similarly, modular stick-built facilities, which are built by framing and wall-paneling a specific area, resemble a traditional production site format. The stick-built cleanroom area can be erected in an inexpensive shell space, which allows fast track implementation. For this approach, the time consuming activity becomes the validation of the area and the HVAC superstructure. Other, newly introduced cleanroom options are isolator based or autonomous unit based systems. When one describes flexible cleanroom designs, these two options are easily scalable with the potential for multi-product use.
All of these designs have their purpose, benefits, and disadvantages. Most of these designs do not represent a single, optimal solution, but are utilized in a hybrid mode. In some of the applications, focus is on containment to protect the environment and personnel. In these instances, a hybrid of isolators within an autonomous unit or modular environment would be most suited. In other instances, process stream and space utilization optimization is required, which can be done by segregation forms and interconnections between the individual spaces. Once again, any of these facility designs are a tool in the toolbox of choices for the planning sites of the drug manufacturers or the engineering firm. The very specific choices, which need to be made, are requirement based. A decision matrix and risk assessment can determine which of the cleanroom facility layouts should be utilized for parts or the entire process.
The flexible facility
Recently, some described a flexible facility to be a ballroom design at a lower cleanroom classification utilizing single-use processing equipment and relying on the single-use components to be the primary barrier. The reason for a ballroom design at a lower classification is the reduction of operating costs and, respectively, the reduction of the cost of goods sold. The question in this scenario would be, how reliable is the primary containment and do we really want to compromise an entire area to a potential contamination for a reduction of COGS? Ultimately, it is the end-user’s decision but the reliance on a single-use technology as primary barrier, under the assumption of no flaws in that barrier or any human failure, sound fairly haphazard—at least for costly biologics.4 Ballroom designs were adopted in the semiconductor industry, but these industry requirements cannot be simply mirrored to the biopharmaceutical industry. Ballroom areas being segregated via isolator based or autonomous unit designs make more sense, as a large area can rapidly be outfitted with cleanroom modules, creating speed, flexibility, and vital containment.
Modular facility constructions are excellent in time-to-run when compared to traditional facility types, but can resolve into traditional facility designs once interconnected. Modular facility designs are two-fold: off-site container build, which are interconnected to a building with its internal segregation; or modular stick/panel build, which represents a cleanroom cluster within a shell building. These designs convey flexibility, especially in the planning phase, but can lose the flexibility once assembled. A recent paper stated the fact very well: “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.”5
A flexible factory means that the flexibility is available during the planning and build phase, but moreover during utilization. Flexibility of facilities is often related to two major factors—multi-product processing and scalability.6 Multi-product use in a facility means the surrounding environment needs to be easily cleanable and sanitizable. This includes the HVAC system which can only be achieved when the cleanroom space has separate air handling and HVAC units. Scalability means meeting capacity demands. The facility may need 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 but duplicable. Other factors are mobility and achievable product-lifecycles. In some instances, one may want to move a purification process dedicated cleanroom system into a different position in the process or to a decontamination area. In others, the entire facility may be moved to a different area or region, and the cleanroom areas are repurposed. Mobility of the cleanroom system is required in both scenarios, which cannot be done with a fixed build cleanroom area. Isolator based or autonomous systems run independently (Figure 1) and not necessarily from a centralized air handling system. An autonomous system is a cleanroom “box” that has typical cleanroom design, finish, supplies, etc., but has its own redundant air handling system and quick connects for the supplies.
Figure 1: Cleanroom autonomous unit layout.
This does not mean that these systems are an obvious choice—the best option always depends on the application, the purpose, and the scope of the facility. A proper evaluation of all options available to the end-user needs to be done, which probably often ends in a hybrid solution, but hopefully an optimal solution.
The future of facilities
Facilities as we know them from the past will still exist in future — however, not with the prevalence as seen before. Current drug manufacturers and engineering firms alike will have the ability to make choices from the increasing portfolio of facility components and designs. As with every aspect in manufacturing processes, there is no “one-size-fits-all” system, neither in an equipment piece nor unit operation, entire process, or production site. The future processes and facilities will be driven by the product to be produced within the site by the economic as well as regional parameters, but the key will be flexibility. Hopefully, regulators will support such optimization and the potential for facility redundancy by using the cookie cutter principle and being able to ramp capacity up and down as needed. Ultimately, quality will not be compromised, especially with cleanroom segregation, increasingly compact air handling systems, containment using single-use technology, but most of all creating an environment minimizing any human failures or effects.
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. 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. P. Thomas (2013) On Simplicity, Single-use and Shire, Pharmaceutical Manufacturing, pp. 12-14.
5. A. Pralong (2013) Single-use technologies and facility layout – a paradigm shift, Biopharma Asia Magazine, Vol 2, Issue 1.
6. R.B. Holtz, D. Powers (2012) Integration of a Single-Use Platform Process within an Innovative Facility Design, BiopharmInternational.com
Maik W. Jornitz is Chief Operating Officer for G-CON Manufacturing LLC, manufacturer of G-CON PODS. www.gconbio.com