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.
The modern cleanroom was invented by American physicist Willis Whitfield. An employee of the Sandia National Laboratories, Whitfield created the initial plans for the cleanroom in 1960. 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. Within a few years of its invention in the 1960s, Whitfield's modern cleanroom had generated more than $50 billion in sales worldwide. The cleanroom eventually entered the hospital industry in the United Kingdom, primarily in hospital pharmacies.
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.
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); only airborne particles are controlled. Particle levels are usually tested using a particle counter and microorganisms detected and counted through environmental monitoring methods.
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.
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.
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.
Air flow principles
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.
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 Aspergillusand Pencillin.
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.
US FED STD 209E cleanroom standards
|≥0.1 µm||≥0.2 µm||≥0.3 µm||≥0.5 µm||≥5 µm|
|This section may be confusing or unclear to readers. (March 2015)|
US FED STD 209E was officially cancelled by the General Services Administration on November 29, 2001, 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
|≥0.1 µm||≥0.2 µm||≥0.3 µm||≥0.5 µm||≥1 µm||≥5 µm|
|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||1.0×106||237,000||102,000||35,200||8,320||293||Class 1,000|
|ISO 7||1.0×107||2.37×106||1,020,000||352,000||83,200||2,930||Class 10,000|
|ISO 8||1.0×108||2.37×107||1.02×107||3,520,000||832,000||29,300||Class 100,000|
|ISO 9||1.0×109||2.37×108||1.02×108||35,200,000||8,320,000||293,000||Room air|
BS 5295 cleanroom standards
|Class||≥0.5 µm||≥1 µm||≥5 µm||≥10 µm||≥25 µm|
BS 5295 Class 1 also requires that the greatest particle present in any sample can not exceed 5 μm.
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).
|At Rest||At Rest||In Operation||In Operation|
|0.5 µm||5 µm||0.5 µm||5 µm|
- Air Quality Index
- Data recovery lab
- Secure environment
- ISO 14644
- ISO 14698
- Contamination control
- Pneumatic filter
- Air ionizer
- Semiconductor device fabrication
- Clean Room Guidelines for Pharma Industry
- 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.
- 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
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