Segregation, cleanability, and automation/process closure are proven ways to protect viral containment through a pandemic and beyond.
The COVID-19 pandemic has shone a spotlight on a challenge that has already been at the center of biotech facility design for years: viral containment. In order to keep both operators and end-user patients safe, biotech facility architects regularly employ the strategies of segregation, cleanability, and automation/process closure for the sake of safety. Due to the effects of COVID-19 pandemic, there is potential for safety solutions that are commonplace in biotech ATMP projects to transfer into unrelated commercial design projects.
Owing to the nature of viral vector materials biotech facilities handle, they are held to strict regulatory scrutiny and must adhere to regulations such as the Federal Code of Regulations Title 21 (CFR-21), EudraLex Annex 1 “Manufacture of Sterile Medicinal Products” and Eudralex Volume 4 “Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products”. The recommendations below stem from these and other related regulations.
Within the Eudralex guidelines, the phrase “appropriate mitigation measures are taken to avoid cross-contamination or mix-ups” is stated multiple times. In practice, this translates into physically separated areas and dedicated paths of travel for personnel, materials (such as viral products), and equipment.
One of the main ways that biotech facilities achieve segregation is through unidirectional flow. The idea is to have a dedicated entry which is separate from the exit. As an analogy, think of the ubiquitous American city block. The supply corridor is like the well-controlled and maintained front-facing street where people and materials enter. The return corridor may be considered analogous to the alley, where waste is removed.
In a facility setting, a true unidirectional flow means that a person enters the manufacturing space through a dedicated supply corridor and exits the space through a return corridor on the backside of the manufacturing suite. This is very different from traditional double-loaded corridors seen in most commercial buildings, with rooms on both sides and all entry and exit points through a single corridor. While the use of double-loaded corridors is space efficient, it increases the risk of a clean object crossing paths with a dirty object. At times, biotech facilities will still use double-loaded corridors, but will compensate by ensuring that the manufacturing process is adequately closed or contained and that each room has a controlled flow within itself. In such cases, objects enter on one side of the room, move in a U-shape around the outside edge of the room, and then return to the same corridor through a dedicated exit.
Another way that spatial segregation is achieved in biotech facilities is through careful consideration of facility layout. First, we assess what areas are needed for the facility to operate: warehousing space, administration offices, manufacturing areas, staff locker rooms, etc. Then we look at the adjacency of each of these areas to each other. An obvious example is that the warehouse needs to be close to where raw materials would enter into the production core—there should be no “people-dominated” spaces in between. In addition, that incoming raw material should not cross paths with waste exiting the facility. The trick is to understand what needs to be connected and then block out the facility to minimize the amount of times that dissimilar flows are crossing. As a biotech facility is planned, maps of the building are made and labeled with flow arrows showing which way people, products, materials, equipment, and waste are intended to flow through the facility.
This idea of minimizing or eliminating crossing flow-paths can be extended into other commercial spaces through the use of floor arrows directing staff throughout the building in a unidirectional flow. It may be possible to implement unidirectional flow within staff lockers rooms, washrooms, or the facility’s cafeteria. Or facilities may designate a set of staff entry doors and a set of exit doors to prevent personnel from crossing paths during shift change.
Temporal segregation simply means segregation by time. It involves sequencing the movement of clean and dirty materials, personnel, or equipment through the same space—but at different times. This concept is used when it is inevitable that there will be a person crossing with a waste flow, or a clean product crossing paths with a dirty one.
This approach allows some amount of time in between when a possible contaminant crosses the same location as something that needs protected from contamination. Temporal segregation may even mean adding a cleaning procedure before another person or clean object is able to move through that location.
This approach may be implemented in some facilities through staggered workflows. For example, upstream operators may work Mondays, Tuesdays and alternating Fridays, while downstream operators work Wednesdays, Thursdays, and alternating Fridays. Separating employee activity chronologically is one way to achieve greater segregation within a facility.
Segregation by environmental control
An important part of segregating clean and dirty processes is through environmental controls such as the heating, ventilation, and air conditioning systems. These can be powerful stop guards against the spread of viral vectors within a biotech facility. Read more about how to achieve contamination control by use of these systems.
Of course, applying these ideas may involve a lot of retrofitting because most commercial buildings were never built with segregation principles in mind. With some creative and critical thinking, however, it may still be possible to employ greater segregation to promote containment of contagions in almost any commercial space.
There are varying levels of cleanliness that need to be taken into account depending on the use of each space within a biotech facility. While cleanrooms face the most scrutiny, all areas of a biotech facility should encourage cleanliness, including the staff washrooms, the administration areas, the warehouse space, etc. The design principles used to achieve cleanliness in a biotech facility can be lifted and applied to other commercial settings.
Some of a facility’s cleanability is driven by how the space is designed. Here is some of the regulatory guidance an architect must take into account:
Per Eudralex: “To reduce accumulation of dust and to facilitate cleaning there should be no uncleanable recesses and a minimum of projecting ledges, shelves, cupboards and equipment.”
Per CFR-21: “All rooms and work areas where products are manufactured or stored shall be kept orderly, clean, and free of dirt, dust, vermin and objects not required for manufacturing.”
Adhering to these regulations translates into crack and crevice-free construction. It requires elimination of any areas promoting stagnation or particle build-up. Any surfaces that will attract or collect particles need to be kept to an absolute minimum or gotten rid of entirely. On a practical level, this means minimizing the amount of surfaces available to touch in a cleanroom. All surfaces need to be easily cleanable and therefore free of ledges where debris can collect—including window sills. All walls are constructed to be flush surfaces up-and-down with no sills or ledges.
There is no room for dust bunnies within a biotech facility. This is why they are designed with very squared off rooms with no extra nooks or crannies whatsoever. In high classification rooms, this is taken to the next level by replacing 90 degree corners with rounded inserts, therefore widening the radius of the crevice so that it can be cleaned more easily.
Additionally, airflow returns are placed at floor level instead of at the ceiling. This downward airflow pattern drives particulates and contaminants down to the floor, reducing the amount of air-borne or suspended contaminants. The airflow then sweeps particulates across the floor towards one of these floor level low wall returns. Sometimes these low wall returns even feature filters to prevent contaminants from re-circulating in the HVAC system.
Other commercial spaces can apply these principles by minimizing places where dust and dirt can build up. While only new designs can implement permanent features like flushed wall construction, all commercial facilities can encourage an elimination of clutter and superfluous furniture, including extra fabric seating, wall shelves or decorations. Office staff should be encouraged to keep personal items to a minimum so that desks and other surfaces can be cleaned easily.
Biotech facilities are again challenged to meet specific regulatory guidance regarding what kinds of materials can be used within their facilities, especially within designated clean areas.
Per Eudralex: “In clean areas, all exposed surfaces should be smooth, impervious, and unbroken in order to minimize the shedding or accumulation of particles or micro-organisms and to permit the repeated application of cleaning agents, and disinfectants where used.”
As stated in the above regulatory guidance, one of main reasons that construction materials must be hard-wearing is to withstand cleaning from rigorous daily cleaning regimes. Corrosive cleaning agents such as Spor-Klenz and bleach are often used in the surface wipe-down process. Viral-containing facilities are often decontaminated by fogging, which means introducing and circulating a cloud of vaporized hydrogen peroxide (VHP) which kills viruses, bacteria, and pretty much all living things on contact. Materials must be specifically selected to withstand repeated contact with VHP.
Materials that are suitable for use in biotech manufacturing facilities include epoxy floors, epoxy-painted walls, glass and stainless steel. No carpeting can be used due to possible dust particles and no wood is allowed, as it carries potential for bio-burden.
Other commercial facilities can take a cue from biotech facilities by selecting hard-wearing materials that can stand up to increased cleaning procedures and are resistant to chipping, flaking, oxidizing, or other deterioration that could foster a dusty environment. Where possible, woven textiles should be replaced with wipeable vinyls and window coverings should be washable.
The installation of touchless sensors is a great way to reduce cleaning workload and cross-contamination. Some biotech facilities leverage technology like touchless sensors on toilets, urinals, and sinks, as well as motion-activated motorized doors to reduce touch. Many of these are already common in non-cGMP facilities, but we suspect that we will see a push for even more integration of touchless sensors within all types of commercial design projects.
The main takeaways from an examination of cleanability within a biotech facility are the need for clean design, good material selection, and the implementation of touchless sensors in common areas. Of course, there is an ongoing balance between public safety and cost. There is only so much money available to build any facility. Even within a biotech facility, not all surfaces outside of the manufacturing core are wipe-down friendly. Other commercial facilities can similarly look at which areas are the most high-risk and concentrate their efforts on increasing ease of cleanability in those areas.
Process Closure and Automation
An especially exciting part of biotech facility design is process closure and automation. Because these have already been a main focus of modern biotech facility design, many of these facilities are less impacted by return-to-work protocols than other manufacturing counterparts. With many facilities coping with reduced headcounts due to social distancing recommendations, biotech facilities that have already embraced automation and process closure are well-positioned to maintain throughputs.
In a biotech facility, we are constantly looking for new ways to close off the process from the cleanroom environment itself. By adding a layer of protection between the product and the environment, it essentially allows for one less layer of protection between the operator and that same environment. This better protects the product from the environment at large and could even mean less stringent environmental controls or one less burdensome layer for the operator to wear.
This pandemic has brought to light the real risks of having an infected operator on the line in any industry. We already know that operators are the dirtiest presence within clean areas, so it follows that a reduction of workers equals a reduction of risk. An increased level of automation reduces the amount of workers required in any facility.
Automation also decreases errors. Automating standard operating procedures to protect products and personnel reduces the impact of human error, which means greater product and personnel safety. Just as telecommuting and other remote workflows have become common across the business world, the biotech manufacturing industry will likely see a trend towards greater automation of equipment.
The principles of process closure and automation can be applied to other facilities by examining what tasks can be closed off from others or done by machine. The COVID-19 era of work is a great time to scrutinize common practices to see if there are safer, more efficient ways to carry out common tasks within a facility. This will look very different from industry to industry, but we are confident that there are improvements possible to make any commercial facility better able to meet the challenges of this pandemic.
In conclusion, the broad ramifications of COVID-19 will affect commercial design from this point forward. Look to tried-and-true biotech design principles to bring greater segregation, cleanability, and automation to any commercial manufacturing facility.