By Dr. Tim Sandle
Regular readers of this blog will know that the main cleanroom standard: ISO 14644, is undergoing revision and that the drafts are out for public comment.
The ISO 14644 standard is made up of seven parts. The first two parts are the ones which are being revised, namely:
- ISO 14644-1 Cleanrooms and associated controlled environments: Part 1: Classification of air cleanliness by particle concentration
- ISO 14644-2 Cleanrooms and associated controlled environments: Part 2: Specifications for monitoring and periodic testing to prove continued compliance with ISO 14644-1
The most significant changes with respect to these two standards, as summarized by Tony Harrison vice-chairman of the PHSS, are:
- The Upper Confidence Limit calculation and Student ‘T' Test are removed
- The ‘square root rule' for calculating the number of sample locations for classification has been removed
- A new table has been added to determine the number of sample locations for classification according to the size of the area to be classified
- Normative reference to ISO 21501-4 is now included, making compliance with ISO 21501-4 a requirement (ISO 21501-4 provides a calibration procedure and verification method for particle counters used to classify and monitor cleanrooms)
- The Air Cleanliness Classification Table defining the maximum allowable number of particles for each ISO class has been modified. Most significantly to the pharmaceutical and healthcare industries, reference to the number of particles >5micron has been completely removed for ISO Class 5 (significant because EU GMP Annex 1 refers to particles 5micron for Grade A conditions and refers to this being equivalent to ISO Class 4.8 and, although the FDA cGMP does not refer to 5micron particles, it does refer to ISO Class 5 as being the environment for aseptic sterile manufacturing, thus implying that the area should attain the related 5micron cleanliness)
Tim Sandle, Ph.D, M.A., BSc (Hons), CBiol, MSBiol., MIScT – Dr. Sandle is the Head of Microbiology at the UK Bio Products Laboratory. Dr. Sandle is a chartered biologist and holds a first class honors degree in Applied Biology; a Masters degree in education; and obtained his doctorate from Keele University. His role involves overseeing a range of microbiological tests, batch review, microbiological investigation and policy development. In addition, he is an honorary consultant with the School of Pharmacy and Pharmaceutical Sciences, University of Manchester and is a tutor for the university's pharmaceutical microbiology M.Sc course. Dr. Sandle serves on several national and international committees relating to pharmaceutical microbiology and cleanroom contamination control (including the ISO cleanroom standards). He is currently chairman of the PharMIG LAL action group and serves on the NBS cleaning and disinfection committee. He has written over eighty book chapters, peer reviewed papers and technical articles relating to microbiology. He is currently the editor of the Pharmaceutical Microbiology Interest Group Journal and runs an on-line microbiology forum (www.pharmig.blogspot.com). Dr. Sandle is an experienced auditor and frequently acts as a consultant to the pharmaceutical and healthcare sectors.
This article is about the manufacturing or research environment. For the method used to avoid copyright infringement, see Clean room design. For the software engineering methodology, see Cleanroom software engineering. For the TV episode, see The Clean Room.
A cleanroom or clean room is an environment, typically used in manufacturing, including of pharmaceutical products or scientific research, as well as aerospace semiconductor engineering applications 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.
The modern cleanroom was invented by American physicistWillis Whitfield. As 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 USD in sales worldwide.
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. There are also modular cleanrooms.
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 is 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.
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.
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
Air flow pattern for "Turbulent 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.
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 number. Common bacterial genera include Micrococcus, Staphylococcus, Corynebacterium, and Bacillus, and fungal genera include Aspergillus and Pencillin.
Cleanroom classification and standardization
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; for example SNOLAB is maintained as a class 2000 cleanroom.
A discrete, light-scattering airborne particle counter 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. Some classes do not require testing some particle sizes, because the concentration is too low or too high to be practical to test for, but such blanks 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.
ISO 14644-1 and ISO 14698
ISO 14644-1 and ISO 14698 are non-governmental standards developed by the International Organization for Standardization (ISO). The former applies to clean rooms in general (see table below); the latter to cleanrooms where biocontamination may be an issue.
|Class||Maximum particles/m3 a||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||35b||d||e||Class 1|
|ISO 4||10,000||2,370||1,020||352||83b||e||Class 10|
|ISO 5||100,000||23,700||10,200||3,520||832||d,e,f||Class 100|
|ISO 6||1,000,000||237,000||102,000||35,200||8,320||293||Class 1,000|
|ISO 7||c||c||c||352,000||83,200||2,930||Class 10,000|
|ISO 8||c||c||c||3,520,000||832,000||29,300||Class 100,000|
|ISO 9||c||c||c||35,200,000||8,320,000||293,000||Room air|
|a All concentrations in the table are cumulative, e.g. for ISO Class 5, the 10 200 particles shown at 0,3 μm include all particles equal to and greater than this size.|
b These concentrations will lead to large air sample volumes for classification. Sequential sampling procedure may be applied; see Annex D.
US FED STD 209E
US FED-STD-209E was a United Statesfederal standard. It was officially cancelled by the General Services Administration on November 29, 2001, but is still widely used.
|≥0.1 µm||≥0.2 µm||≥0.3 µm||≥0.5 µm||≥5 µm|
EU GMP 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||In Operation|
|0.5 µm||5 µm||0.5 µm||5 µm|
|Grade D||3,520,000||29,000||Not defined||Not defined|
BS 5295 is a British Standard.
|≥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. BS 5295 has been superseded, withdrawn since the year 2007 and replaced with "BS EN ISO 14644-6:2007".
|Wikimedia Commons has media related to Cleanrooms.|
- ^ abcYardley, 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.
- ^"Willis Whitfield - Father of the Cleanroom"(PDF). Cleanroom online. September 2015. Retrieved 2016-05-18.
- ^What is a modular cleanroom?
- ^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.
- ^ abSandle, 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.
- ^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 /
- ^"ISO 14644-1:2015 - Cleanrooms and associated controlled environments -- Part 1: Classification of air cleanliness by particle concentration". ISO. Retrieved 2016-09-12.
- ^Cancellation of FED-STD-209E - Institute of Environmental Sciences and Technology
- ^"Archived copy"(PDF). Archived from the original(PDF) on 2008-05-28. Retrieved 2008-04-17. , page 148
- ^"NUFAB SAFETY & PROTOCOL"(PDF). Retrieved 24 February 2016.
- ^Understanding Cleanroom Classifications
- ^Market Venture Philippines Inc. web site (2006-04-19). "What is a Clean Room?". Archived from the original on 2012-08-28. Retrieved 2007-06-02.
- ^"BS 5295-0:1989 - Environmental cleanliness in enclosed spaces. General introduction, terms and definitions for clean rooms and clean air devices". 2016. Retrieved 2016-04-18.