Classification of Cleanrooms
Classification of Cleanrooms
Cleanrooms are classified by the cleanliness of their air. This is now done according to ISO 14644-1. This is an international standard, and was adopted by the European Union in 1999, and the USA in 2001. However, the most easily understood classification of cleanrooms is the obsolete Federal Standard 209 of the USA; it is still widely used.
1 Federal Standard 209
The first Federal Standard 209 was published in 1963 in the USA, and titled "Cleanroom and Work Station Requirements, Controlled Environments". It was revised in 1966 (209A), 1973 (B), 1987 (C), 1988 (D) and 1992 (E), and withdrawn in 2001. The cleanroom class limits, given in the earlier 209 A to D versions, are shown in table 1. The class of a cleanroom is found by measuring the number of particles 0.5 m in one cubic foot of room air, and determining which class limit is not exceeded; this is the cleanroom classification.
Table 1 Federal Standard 209 class limits
Class
Particles / ft 0.1 mm 0.2 mm 0.3 mm 0.5 mm 5.0 mm 1 35 7.5 3 1 NA 10 350 75 30 10 NA 100 NA 750 300 100 NA 1,000 NA NA NA 1,000 7 10,000 NA NA NA 10,000 70 100,000 NA NA NA 100,000 700 In the last edition of Federal Standard 209 (E) the airborne concentrations in the room was also given in metric units, i.e. per m. This nomenclature never became established, and was only used in the occasional published article. The earlier version's nomenclature shown in table 1 continues to be used and is likely to be used for many years.
2 ISO Standards
A range of cleanroom standards is being produced by the International Organization for Standardization (ISO). Various committees of experts, nominated by countries throughout the world, are writing these standards. The standards that have been published, or being written at the time of publication of this manual, are as follows:
2.1 ISO 14644
This consists of the following parts, under the general title Cleanrooms and Associated Controlled Environments : Part 1: Classification of air cleanliness This gives the airborne particle limits for different standards of cleanrooms. It also gives the methods that should be used to measure the airborne particles when testing a cleanroom to determine its class. Part 2 :Specifications for testing and monitoring to prove continued compliance with ISO 14644-1
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This gives information, including time intervals, for testing a cleanroom to show that it still complies with the ISO 14644-1 standard. Part 3: Metrology and test methods This gives a description of the test methods that should be used to test the cleanroom to show that it is working correctly. Part 4: Design, construction, and startup This gives general guidance as to how a cleanroom should be designed, constructed and made ready for handing over to the user. Part 5: Operation This gives general advice on how to run a cleanroom. Part 6: Terms and definitions This is a collection of all the definitions of terms used in the ISO cleanroom standards. Part 7: Separative enclosures (clean air hoods, gloveboxes, isolator, mini environments)
This gives information on clean air devices such as isolators and minienvironments.
Part 8: Molecular contamination This gives information on gaseous contamination in cleanrooms.
2.2 ISO 14698
This consists of the following parts under the general title Cleanrooms and Associated Controlled Environments Biocontamination Control : Part 1: General principles and methods This gives information on how to establish methods for measuring micro-organisms in the cleanroom. Part 2: Evaluation and interpretation of biocontamination data This gives information on how to deal with the results obtained from measuring micro-organisms in a cleanroom. Both of these standards are necessary for those involved with the monitoring of micro-organisms in cleanrooms.
2.3 ISO 14644-1
ISO 14644-1 gives a method to classify cleanrooms The classification is based on the following equation:
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where: Cn is the maximum permitted concentration (in particles/m of air) of airborne particles that are equal to, or larger, than the considered particle size. Cn is rounded to the nearest whole number, using no more than three significant figures. N is the ISO classification number, which shall not exceed the value of 9. Intermediate ISO classification numbers may be specified, with 0.1 the smallest permitted increment of N. D is the considered particle size in mm. 0.1 is a constant with a dimension of mm. From the equation, the maximum permitted airborne concentration of particles, i.e. the class limit can be calculated for any given particle size. Shown in table 2 are the classes selected by ISO 14644-1 to illustrate class limits.
Table 2 Selected ISO 14644-1 airborne particulate cleanliness classes for cleanrooms and clean zones
ISO Classification number ISO Class 1 ISO Class 2 ISO Class 3 ISO Class 4 ISO Class 5 ISO Class 6 ISO Class 7 ISO Class 8 ISO Class 9
Maximum concentration limits (particles/m of air) for particles equal to and larger than the considered sizes shown below 0.1mm 10 100 1 000 10 000 100 000 1 000 000 0.2mm 2 24 237 2 370 23 700 237 000 0.3mm 10 102 1 020 10 200 102 000 0.5mm 4 35 352 3 520 35 200 352 000 3 520 000 35 200 000 1mm 5.0mm
8 83 832 8 320 83 200 832 000 8 320 000
29 293 2 930 29 300 293 000
It should be noted that there is a crossover to the Federal Standard 209 classes. If the particle concentration/m in the ISO standard is divided by 35.2 the count is converted to counts/ft . The equivalent Federal Standard 209 classification is then found at the 0.5 mm size, e.g. an ISO Class 5 is equivalent to Federal Standard 209 Class 100. A comparison in given in table 3.
Table 3 Comparison between selected equivalent classes of FS 209 and ISO 14644-1
ISO 14644-1 Class 3 Class 4 Class 5 Class 6 Class 7 Class 8 Classes FS 209 Classes
Class Class Class Class Class Class 6 1 10 100 1000 10 000 100 000
It should be appreciated that the airborne particle concentration of a given cleanroom is dependent on the particle generating activities going on in the room. If a room is empty, a very low particle concentration can be achieved, this closely reflecting the quality of air supplied. If the room has production equipment in it that is operating, there should be a greater particle concentration, but the greatest concentration occurs when the room is in full production. The classification of the room may
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therefore be carried out in these different occupancy states. The occupancy states defined in ISO 14644-1 are as follows: As built: the condition where the installation is complete with all services connected and functioning, but with no production equipment, materials or personnel present. At-rest: The condition where the installation is complete with equipment installed and operating in a manner agreed between the customer and supplier, but with no personnel present. Operational: The condition where the installation is functioning in the specified manner, with the specified number of personnel present and working in the manner agreed upon. The ISO 14644-1 standard also gives a method by which the standard of a cleanroom may be ascertained. The method is for determining the number of sampling locations, the sampling volume and counting the number of airborne particles.
3 Pharmaceutical Cleanroom Classification and Testing
Cleanrooms used for pharmaceutical manufacturing have their own standards. The two most widely used are those published by the European Union and the USA.
3.1 European Union Guide to Good Manufacturing Practice
The most recent pharmaceutical standard used in Europe came into operation on January 1997. This is called The rules governing medicinal products in the European Union. Volume 4. Good manufacturing practices - Medicinal products for human and veterinary use . It is often called the European Union Guide to Good Manufacturing Products (EU GGMP) and is called that in this book. Table 5 Airborne classification in the EU GGMP Maximum permitted number of particles/m equal to or above Grade at rest (b) in operation 0.5 mm 5 mm 0.5 mm 5 mm A 3 500 0 3 500 0 B(a) 3 500 0 350 000 2 000 C(a) 350 000 2 000 3 500 000 20 000 D(a) 3 500 000 20 000 not defined (c) not defined (c) Notes (a) In order to reach the B, C and D air grades, the number of air changes should be related to the size of the room and the equipment and personnel present in the room. The air system should be provided with appropriate filters such as HEPA for grades A, B and C. (b) The guidance given for the maximum permitted number of particles in the at rest condition corresponds approximately to the US Federal Standard 209 E and the ISO classifications as follows: grades A and B correspond with class 100, M 3.5, ISO 5; grade C with class 10 000, M 5.5, ISO 7 and grade D with class 100 000, M 6.5, ISO 8. (c) The requirement and limit for this area will depend on the nature of the operations carried out. The particulate conditions given table 5 for the at rest state should be achieved after a short clean up period of 15 20 minutes (guidance value), after the completion of operations.
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Examples of operations to be carried out in the various grades are given in the table 6. The particulate conditions for a grade A zone that is in operation should be maintained in the zone immediately surrounding the product whenever the product or open container is exposed to the environment. It is accepted that it may not always be possible to demonstrate conformity with particulate standards at the point of fill when filling is in progress, due to the generation of particles or droplets from the product itself.
Table 6 Examples of cleanroom conditions required for different operations
Grade Examples of Operations for Terminally Sterilised Products A Filling of products, when unusually at risk C Preparation of solutions, when unusually at risk. Filling of products D Preparation of solutions and components for subsequent filling Grade Examples of Operations for Aseptic Preparations A Aseptic preparation and filling C Preparation of solutions to be filtered D Handling of components after washing. Microbiological monitoring is also required to demonstrate the microbiological cleanliness of the cleanroom during production. The recommended limits are given in table 7.
Table 7 Recommended limits for microbial contamination (a)
Grade Air Sample Settle Plates cfu/m
Contact Plates Glove Print
(diam. 90 mm), (diam. 55 mm), 5 fingers cfu/4 hours (b) <1 5 50 100 cfu/plate <1 5 25 50 cfu/glove <1 5 -
A B C D Notes
<1 10 100 200
(a) These are average values. (b) Individual settle plates may be exposed for less than 4 hours. Appropriate alert and action limits should be set for the results of particulate and microbiological monitoring. If these limits are exceeded, operating procedures should prescribe corrective action. The air classification required for a cleanroom that contains an isolator depends on the design of the isolator, and its application. The room that it is in should be controlled, and for aseptic processing be at least grade D. Blow/fill/seal equipment used for aseptic production, which is fitted with an effective grade A air shower, may be installed in at least a grade C environment, provided that grade A/B clothing is used. The environment should comply with the viable and non-viable limits at rest , and the viable limit only when in operation . Blow/fill/seal equipment used for the production of products for terminal sterilisation should be installed in at least a grade D environment.
3.2 Guideline on Sterile Drug Products Produced by Aseptic
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Processing
This document is produced by the Food and Drug Administration (FDA) in the USA and published in 1987. Many pharmaceutical companies export their products to the USA. To be allowed to do so they are inspected and approved by the FDA. They must comply with the 'Guideline on Sterile Drug Products Produced by Aseptic Processing'. The FDA defines two areas in aseptic processing that are of particular importance to drug product quality. These are the critical area and the controlled area . A critical area is described in the FDA document as: one in which the sterilized dosage form, containers, and closures are exposed to the environment. Activities that are conducted in this area include manipulations of these sterilized materials/product prior to and during filling/closing operations . The controlled area is described as: an area in which it is important to control the environment, is the area where unsterilized product, in-process materials, and container/closures are prepared. This includes areas where components are compounded, and where components, in-process materials, drug products and drug product contact surfaces of equipment, containers, and closures, after final rinse of such surfaces, are exposed to the plant environment . The environmental requirements for these two areas given in the Guide are as follows: 3.2.1 Critical areas The FDA guidelines give the following information: Air in the immediate proximity of exposed sterilized containers/closures and filling/closing operations is of acceptable particulate quality when it has a per-cubic-foot particle count of no more than 100 in a size range of 0.5 micron and larger (Class 100) when measured not more than one foot away from the work site, and upstream of the air flow, during filling/closing operations. The agency recognizes that some powder filling operations may generate high levels of powder particles which, by their nature, do not pose a risk of product contamination. It may not, in these cases, be feasible to measure air quality within the one foot distance and still differentiate "background noise" levels of powder particles from air contaminants which can impeach product quality. In these instances, it is nonetheless important to sample the air in a manner, which to the extent possible characterises the true level of extrinsic particulate contamination to which the product is exposed. Air in critical areas should be supplied at the point of use as HEPA filtered laminar flow air, having a velocity sufficient to sweep particulate matter away from the filling/closing area. Normally, a velocity of 90 feet per minute, plus or minus 20%, is adequate, although higher velocities may be needed where the operations generate high levels of particles or where equipment configuration disrupts laminar flow. Air should also be of a high microbial quality. An incidence of no more than one colony forming unit per 10 cubic feet is considered as attainable and desirable. Critical areas should have a positive pressure differential relative to adjacent less clean areas; a pressure differential of 0.05 inch of water is acceptable . 3.2.2 Controlled areas
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The FDA Guidelines give the following information: Air in controlled areas is generally of acceptable particulate quality if it has a per-cubic-foot particle count of not more than 100,000 in a size range of 0.5 micron and larger (Class 100,000) when measured in the vicinity of the exposed articles during periods of activity. With regard to microbial quality, an incidence of no more than 25 colony forming units per 10 cubic feet is acceptable. In order to maintain air quality in controlled areas, it is important to achieve a sufficient air flow and a positive pressure differential relative to adjacent uncontrolled areas. In this regard, an air flow sufficient to achieve at least 20 air changes per hour and, in general, a pressure differential of at least 0.05 inch of water (with all doors closed), are acceptable. When doors are open, outward airflow should be sufficient to minimize ingress of contamination .
Bill Whyte has extracted the above information from his book 'Cleanroom Technology'.
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