Cleanroom

Cleanroom used for the production of microsystems. The yellow lighting is necessary for photolithography, to prevent unwanted exposure of photoresist to light of shorter wavelengths.

Cleanroom from outside

Entrance to a cleanroom with no air shower

Cleanroom for microelectronics manufacturing with fan filter units installed in the ceiling grid

Cleanroom cabin for precision measuring tools

Typical cleanroom head garment

A cleanroom or clean room is an environment, typically used in manufacturing or scientific research, with a low level of environmental pollutants such as dust, airborne microbes, aerosol particles, and chemical vapors. More accurately, a cleanroom has a controlled level of contamination that is specified by the number of particles per cubic meter at a specified particle size. To give perspective, the ambient air outside in a typical urban environment contains 35,000,000 particles per cubic meter in the size range 0.5 μm and larger in diameter, corresponding to an ISO 9 cleanroom, while an ISO 1 cleanroom allows no particles in that size range and only 12 particles per cubic meter of 0.3 μm and smaller. In the pharmaceutical industry, clean rooms play a crucial role in the manufacturing of pharmaceutical products which are required to be free from microbial and particulate contamination and protected from moisture. Such pharmaceutical products are manufactured and manipulated in cleanrooms, which are fitted with HEPA and, if required, ULPA filters as well as dehumidifier systems.^[1]

History

The modern cleanroom was invented by American physicist Willis Whitfield.^[2] An employee of the Sandia National Laboratories, Whitfield created the initial plans for the cleanroom in 1960.^[2] Prior to Whitfield's invention, earlier cleanrooms often had problems with particles and unpredictable airflows. Whitfield designed his cleanroom with a constant, highly filtered air flow to flush out impurities.^[2] Within a few years of its invention in the 1960s, Whitfield's modern cleanroom had generated more than $50 billion in sales worldwide.^[3] The cleanroom eventually entered the hospital industry in the United Kingdom, primarily in hospital pharmacies.^[4]

Overview

Cleanrooms can be very large. Entire manufacturing facilities can be contained within a cleanroom with factory floors covering thousands of square meters. They are used extensively in semiconductor manufacturing, biotechnology, the life sciences, and other fields that are very sensitive to environmental contamination.

The air entering a cleanroom from outside is filtered to exclude dust, and the air inside is constantly recirculated through high-efficiency particulate air (HEPA) and/or ultra-low particulate air (ULPA) filters to remove internally generated contaminants.

Staff enter and leave through airlocks (sometimes including an air shower stage), and wear protective clothing such as hoods, face masks, gloves, boots, and coveralls.

Equipment inside the cleanroom is designed to generate minimal air contamination. Only special mops and buckets are used. Cleanroom furniture is designed to produce a minimum of particles and to be easy to clean.

Common materials such as paper, pencils, and fabrics made from natural fibers are often excluded, and alternatives used. Cleanrooms are not sterile (i.e., free of uncontrolled microbes);^[5] only airborne particles are controlled. Particle levels are usually tested using a particle counter and microorganisms detected and counted through environmental monitoring methods.^[6][7]

Some cleanrooms are kept at a positive pressure so if any leaks occur, air leaks out of the chamber instead of unfiltered air coming in.

Some cleanroom HVAC systems control the humidity to low levels, such that extra equipment ("ionizers") is necessary to prevent electrostatic discharge problems.

Low-level cleanrooms may only require special shoes, with completely smooth soles that do not track in dust or dirt. However, for safety reasons, shoe soles must not create slipping hazards. Access to a cleanroom is usually restricted to those wearing a cleanroom suit.^[8]

In cleanrooms in which the standards of air contamination are less rigorous, the entrance to the cleanroom may not have an air shower. An anteroom (known as a "gray room") is used to put on clean-room clothing.

Some manufacturing facilities do not use fully classified cleanrooms, but use some cleanroom practices to maintain their contamination requirements.^[9]

Air flow principles

Air flow pattern for "Turbulent Cleanroom"

Air flow pattern for "Laminar Flow Cleanroom"

Cleanrooms maintain particulate-free air through the use of either HEPA or ULPA filters employing laminar or turbulent air flow principles. Laminar, or unidirectional, air flow systems direct filtered air downward or in horizontal direction in a constant stream towards filters located on walls near the cleanroom floor or through raised perforated floor panels to be recirculated. Laminar air flow systems are typically employed across 80% of a cleanroom ceiling to maintain constant air processing. Stainless steel or other non shedding materials are used to construct laminar air flow filters and hoods to prevent excess particles entering the air. Turbulent, or non unidirectional, air flow uses both laminar air flow hoods and nonspecific velocity filters to keep air in a cleanroom in constant motion, although not all in the same direction. The rough air seeks to trap particles that may be in the air and drive them towards the floor, where they enter filters and leave the cleanroom environment. US FDA and EU have laid down guidelines and limit for microbial contamination which is very stringent to ensure freedom from microbial contamination in pharmaceutical products.^[10][11]

Personnel contamination of cleanrooms

In the healthcare and pharmaceutical sectors, control of microorganisms is important, especially microorganisms likely to be deposited into the air stream from skin shedding. Studying cleanroom microflora is of importance for microbiologists and quality control personnel to assess changes in trends. Shifts in the types of microflora may indicate deviations from the “norm” such as resistant strains or problems with cleaning practices. In assessing cleanroom microorganisms, the typical flora are primarily those associated with human skin (Gram-positive cocci), although microorganisms from other sources such as the environment (Gram-positive rods) and water (Gram-negative rods) are also detected, although in lower numbers. Common bacterial genera include Micrococcus, Staphylococcus, Corynebacterium, and Bacillus, and fungal genera include Aspergillus and Pencillin.[7] Cleanroom classifications Cleanrooms are classified according to the number and size of particles permitted per volume of air. Large numbers like "class 100" or "class 1000" refer to FED-STD-209E, and denote the number of particles of size 0.5 µm or larger permitted per cubic foot of air. The standard also allows interpolation, so it is possible to describe, for example, "class 2000". A discrete-particle-counting, light-scattering instrument is used to determine the concentration of airborne particles, equal to and larger than the specified sizes, at designated sampling locations. Small numbers refer to ISO 14644-1 standards, which specify the decimal logarithm of the number of particles 0.1 µm or larger permitted per m3 of air. So, for example, an ISO class 5 cleanroom has at most 105 particles/m3. Both FS 209E and ISO 14644-1 assume log-log relationships between particle size and particle concentration. For that reason, zero particle concentration does not exist. The table locations without entries are nonapplicable combinations of particle sizes and cleanliness classes, and should not be read as zero. Because 1 m3 is about 35 ft3, the two standards are mostly equivalent when measuring 0.5 µm particles, although the testing standards differ. Ordinary room air is around class 1,000,000 or ISO 9.[12] US FED STD 209E cleanroom standards Class maximum particles/ft3 ISO equivalent ≥0.1 µm ≥0.2 µm ≥0.3 µm ≥0.5 µm ≥5 µm 1 35 7.5 3 1 0.007 ISO 3 10 350 75 30 10 0.07 ISO 4 100 3,500 750 300 100 0.7 ISO 5 1,000 35,000 7,500 3000 1,000 7 ISO 6 10,000 350,000 75,000 30,000 10,000 70 ISO 7 100,000 7006350000000000000♠3.5×106 750,000 300,000 100,000 700 ISO 8 US FED STD 209E was officially cancelled by the General Services Administration on November 29, 2001,[13][14] but is still widely used. It also specify classes of clean room with respect to their impact on pharmaceutical manufacturing process. 1.Critical 2) Controlled Area. Critical area is meant for manufacture or manipulate a product require to be free from microbial and particulate matter or sterile. While controlled area have certain allowable limit of microbial load, as pharmaceutical product processed in these area further passes through process of sterilisation and final filtration which takes care of freedom from microbial contamination and particulate matter. ISO 14644-1 cleanroom standards Class maximum particles/m3 FED STD 209E equivalent ≥0.1 µm ≥0.2 µm ≥0.3 µm ≥0.5 µm ≥1 µm ≥5 µm ISO 1 10 2.37 1.02 0.35 0.083 0.0029 ISO 2 100 23.7 10.2 3.5 0.83 0.029 ISO 3 1,000 237 102 35 8.3 0.29 Class 1 ISO 4 10,000 2,370 1,020 352 83 2.9 Class 10 ISO 5 100,000 23,700 10,200 3,520 832 29 Class 100 ISO 6 7006100000000000000♠1.0×106 237,000 102,000 35,200 8,320 293 Class 1,000 ISO 7 7007100000000000000♠1.0×107 7006237000000000000♠2.37×106 1,020,000 352,000 83,200 2,930 Class 10,000 ISO 8 7008100000000000000♠1.0×108 7007237000000000000♠2.37×107 7007102000000000000♠1.02×107 3,520,000 832,000 29,300 Class 100,000 ISO 9 7009100000000000000♠1.0×109 7008237000000000000♠2.37×108 7008102000000000000♠1.02×108 35,200,000 8,320,000 293,000 Room air BS 5295 cleanroom standards   maximum particles/m3 Class ≥0.5 µm ≥1 µm ≥5 µm ≥10 µm ≥25 µm Class 1 3,000   0 0 0 Class 2 300,000   2,000 30   Class 3   1,000,000 20,000 4,000 300 Class 4     200,000 40,000 4,000 BS 5295 Class 1 also requires that the greatest particle present in any sample can not exceed 5 μm.[15] GMP EU classification EU GMP guidelines are more stringent than others, requiring cleanrooms to meet particle counts at operation (during manufacturing process) and at rest (when manufacturing process is not carried out, but room AHU is on). Class maximum particles/m3[16] At Rest At Rest In Operation In Operation 0.5 µm 5 µm 0.5 µm 5 µm Grade A 3,500 0 3,500 0 Grade B 3,500 0 350,000 2,000 Grade C 350,000 2,000 3,500,000 20,000 Grade D 3,520,000 29,000 n/a n/a See also Air Quality Index Data recovery lab Secure environment ISO 14644 ISO 14698 Contamination control Pneumatic filter Air ionizer Semiconductor device fabrication References ↑ Clean Room Guidelines for Pharma Industry ↑ 2.0 2.1 2.2 Yardley, William (2012-12-04). "Willis Whitfield, Clean Room Inventor, Dies at 92". New York Times. Retrieved 2013-06-22.  ↑ "Sandia physicist, cleanroom inventor dies at 92". KWES (Associated Press). 2012-11-26. Retrieved 2012-12-03.  ↑ World at work: Hospital pharmacy clean‐rooms ↑ In NASA’s Sterile Areas, Plenty of Robust Bacteria New York Times, 9. October 2007 ↑ Sandle, T (November 2012). "Application of quality risk management to set viable environmental monitoring frequencies in biotechnology processing and support areas". PDA J Pharm Sci Technol 66 (6): 560–79. doi:10.5731/pdajpst.2012.00891.  ↑ 7.0 7.1 Sandle, T (November 2011). "A review of cleanroom microflora: types, trends, and patterns". PDA J Pharm Sci Technol 65 (4): 392–403. doi:10.5731/pdajpst.2011.00765.  ↑ Cleanroom Clothing ↑ Your Cleanroom Supplier :: Hutchins & Hutchins, Inc ↑ Limits for Microbial load for clean room as per US FDA and EU Guidelines for pharmaceutical products ↑ Cleanroom Air Flow Principles ↑ Cleanroom Classification / Particle Count / FS209E / ISO TC209 / ↑ Cancellation of FED-STD-209E - Institute of Environmental Sciences and Technology ↑ http://www.wbdg.org/ccb/FEDMIL/notices.pdf, page 148 ↑ Market Venture Philippines Inc. web site ↑ Pharmaceutical equipment and technologies External links Wikimedia Commons has media related to Cleanrooms. Cleanroom Wiki--The Global Society For Contamination Control (GSFCC) Clean Room Requirements in Pharma