In March 2016, the University of Delaware opened a brand new Nanofabrication Facility (UDNF), dubbed the ‘machine shop of the 21st century’. The $30-million facility’s laboratory will be used to make devices as small as 10nm across. This will have implications for numerous disciplines, from soil science to biomedical research.

The lab is, on one hand, notable for the work it will facilitate. Open to internal and external users, it has been designed to accommodate research on the nanoscale for the next quarter of a century, during which time we are likely to see unprecedented developments in this field.

"As people start to use the facility, it is not easy to gauge the type of research that will take place at UDNF," explains Iulian Codreanu, director of operations at the centre. "But we have had interest from industries and other local universities, as well as a diverse collection of university departments.

It is, however, also attracting attention from certain circles for quite another reason; specifically, the lab has spent several million dollars on air-handling systems that will ensure its 8,500ft² workspace benefits from the best in clean-room technology. Within an ordinary room, you would expect to find around 100,000 or more particles measuring 500nm across or larger, within every cubic foot of air. This comprises dust, airborne microbes and chemical vapours. The UDNF lab, however, is rated for two layers of clean: ISO 5, corresponding to no more than 100 particles of this size within a cubic foot of air, and ISO 6, corresponding to no more than 1,000. This ensures the air will be almost entirely free from contaminants.

"Cleanliness and environmental conditions such as temperature and humidity are critical to the research that takes place in UDNF," explains Codreanu. "The nanofabrication process consists of a number of steps where the ‘work piece’ moves from one end of the facility to another; the transport is done by hand, and the work piece is exposed to the air. A dust particle is hundreds of times larger than the smallest features researchers can fabricate in our facility, and it would destroy the circuits on the work piece."

Clean air for cleaner studies

While the air-handling systems do not eliminate the dust particles altogether, they do drastically reduce their numbers, reducing the chance of a collision with the work piece. Codreanu uses the analogy of a basketball hitting an ant, which would render the ant-scale work, such as lithography and etching, impossible.

It goes without saying that anyone who enters the clean room must be fully prepared. They must first visit the ‘gowning room’, where they receive full face and body coverage, including a hairnet, face mask and jumpsuit. They must also be fully trained and take care to conform to protocols.

The lab’s humidity and temperature control systems are similarly critical. Some of the chemicals used within
the fabrication process are moisture-sensitive, meaning that if humidity is not tightly controlled, they may cease to function.

Likewise, changes in temperature could cause the work piece to expand or contract. As it moves from one end of the facility to the other, the work piece is processed by various different bits of equipment and, if it changes size, it will no longer fit the alignment steps it visits along the way.

The facility therefore uses two types of air-handling system: the ‘global’ system, which maintains the state of the clean room relative to the rest of the building and controls humidity; and the ‘local’ system, which controls temperature and air cleanliness. Air is being perpetually sucked up through vents, passed through two levels of filtration, and then pushed back inside.

"The global system consists of two make-up air units [MAUs] and two exhaust systems with four exhaust fans each," says Codreanu. "Each MAU and exhaust system provides half of the maximum airflow capacity, and they all operate independently of each other. This type of redundancy is essential to maintaining space pressurisation during preventive maintenance.

"A dust particle is hundreds of times larger than the smallest features researchers can fabricate in our facility, and it would destroy the circuits on the work piece." 

"The local system consists of fifteen recirculating air units [RAUs] that constantly circulate the air through high-efficiency particulate air [HEPA] filters. It is capable of performing 300 air changes an hour."

Sterile safety

The facility also has a computer system that monitors the particle count in real time, ensuring the airflow through the RAUs can be adjusted based on how many particles are coming through. While, in the past, it was assumed that greater airflow invariably led to greater cleanliness, we now know this not the case. Changing the air more frequently can actually foster unwelcome turbulence, meaning today’s clean-room designers seek to optimise, rather than increase, the rate of air change.

This can be performed via a computational fluid dynamic model, which simulates the airflow patterns of a space. If the air-change rate is kept relatively low, there’s another benefit in the form of serious energy savings. As a general rule, fan power is approximately proportional to the cube of the air-change rate, so reducing the airflow by 30% therefore results in a power reduction of two thirds. This, in turn, can help the lab cut costs.

Now more than ever, clean-room designers need to bear many different factors in mind, with the precise specifics dependent on the client. Within the pharma industry, it is generally imperative that clean rooms comply with ISO 5, with the higher classes such as ISO 4 better suited to the electronics industry. This classification system, ISO 14644-1, applies around the world, although various domestic classifications, such as US Federal Standard 209E, are often used concurrently. It is based on a logarithmic scale, with fewer small particles permitted as you move up the various classes.

The standards also set limits for particles larger than 100nm. For instance, within every cubic metre of air, an ISO 5 clean room can have 29 particles larger than 5µm and an ISO 4 clean room is not allowed to let any through at all. The very highest ISO categorisation, ISO 1, permits just two particles larger than 200nm, although such clean rooms are extremely rare and broadly inapplicable to the pharma industry.

For pharmaceutical companies specifically, the real objective of a clean room is to ensure sterility. While some products are not sterilised until the end of the process, others require fully aseptic manufacturing operations. In the the latter case, it is imperative the product is not contaminated by any microbial or particulate matter, and this is where clean rooms become critical.

Because patient safety is at stake, pharma clean rooms must conform to a wide range of standards. Notably, US Food and Drug Administration (FDA) lists current Good Manufacturing Practices (GMPs) for sterile drug products produced by aseptic processing. The agency details best practice in some depth: HEPA filters, for instance, should be regularly checked to ensure they have not begun to leak; and airflow should be carefully monitored, with the room designed to prevent turbulence and stagnant air in critical areas.

There should be minimal intervention from laboratory personnel, who are advised to move slowly and deliberately, to contact sterile materials with sterile instruments only, to keep the body out of the path of unidirectional airflow and to maintain proper gown control. All components related to the clean room should also be subject to quality assessments, with a quality-control unit responsible for investigating any errors that have occurred.

As FDA guidance explains: "Clean rooms are normally designed as functional units with specific purposes. Floors, walls, and ceilings should be constructed of smooth, hard surfaces that can be easily cleaned. Ceilings and associated HEPA filter banks should be designed to protect sterile materials from contamination. Clean rooms also should not contain unnecessary equipment, fixtures, or materials. To prevent changes in air currents that introduce lower quality air, movement adjacent to the critical area should be appropriately restricted."

A bright nano future

In years to come, we can expect to see more nanotechnology applications within pharma, such as targeted drug delivery systems. As this takes place, it will necessarily bring with it a greater need for clean rooms that filter out stray particles at the nano scale.

"Our clean room at UDNF is not exclusively designed for biomedical research," explains Codreanu, "but the integration of the nano and bio worlds is a vibrant area of research, and I expect it to develop further. We have had interest from the bioengineering department."

The development makes sense: after all, it would be difficult to conduct cutting-edge research within a subpar laboratory. Whether a clean room is used for manufacturing purposes or for R&D, it seems clear that workspaces of this kind afford important opportunities to the pharmaceutical industry. For researchers at the University of Delaware, the possibilities are ready and waiting to be tapped.