Clean Room Classification and Pharmaceutical Cleanroom Classification

Clean Room Classification and Pharmaceutical Cleanroom Classification



Clean rooms are classified by the cleanliness of their air. The method most easily understood and most universally applied is the one suggested in the earlier versions (A to D) of Federal Standard 209 of the USA. In this old standard the number of particles equal to and greater than 0.5 m m is measured in one cubic foot of air and this count used to classify the room. The most recent 209E version has also accepted a metric nomenclature. In the UK the British Standard 5295, published in 1989, is also used to classify clean rooms. This standard is about to be superseded by BS EN ISO 14644-1.

Federal Standard 209


This standard was first published in 1963 in the US and titled "Clean Room and Work Station Requirements, Controlled Environments". It was revised in 1966 (209A), 1973 (209B), 1987 (C), 1988 (D) and 1992 (E). It is available from:


Institute of Environmental Sciences and Technology

940 East Northwest Highway
Mount Prospect, Illinois, 60056 USA
Tel: 0101 708 255 1561
Fax: 0101 708 255 1699
e-mail: iest@iest.org:


The clean room classifications given in the earlier A to D versions are shown in Table 1.

Table 1: Federal Standard 209D Class Limits



In the new 209E published in 1992 the airborne concentrations in the room are given inmetric units, (i.e. per m3), and the classifications of the room defined as the logarithm of theairborne concentration of particles ³ 0.5 m m e.g. a Class M3 room has a particle limit forparticles ³ 0.5 m m of 1000/m3. This is shown in Table 2.


Table 2: Federal Standard 209E Airborne Particulate Cleanliness Classes




British Standard 5295:1989

This standard is available from:
B S I Standards
389 Chiswick High Road
London W44 AL
Tel 0181 996 9000
Fax 0181 996 7400
e-mail: info@bsi.org.uk



Because of the imminent publication of EN ISO 14644-1 parts of this British Standard have a limited life. Parts will be superseded by the ISO standards as they appear as an EN standard.


The British Standard is in five parts. These are:

Part 0 - General introduction and terms and definitions for clean rooms and clean air devices. (4 pages)

Part 1 - Specification for clean rooms and clean air devices. (14 pages)

Part 2 - Method for specifying the design, construction and commissioning of clean room and clean air devices. (14 pages)

Part 3 - Guide to operational procedures and disciplines applicable to clean rooms and clean air devices. (6 pages)

Part 4 - Specification for monitoring clean rooms and clean air devices to prove continued compliance with BS 5295. (10 pages)


Part 1 of the standard contains ten classes of environmental cleanliness. Shown in Table 3 are the classes given in the standard. All classes have particle counts specified for at least two particle size ranges to provide adequate confidence over the range of particle size relevant to each class.

Table 3 BR 525 Environmental Cleanliness Classes



BS EN ISO Standard

Because of the large number of clean room standards produced by individual countries it is very desirable that one worldwide standard of clean room classification is produced. The first ISO standard on clean rooms has been published (June 1999) as 14644-1 ‘Classification of Air Cleanliness’. It is about to be adopted as a European standard and hence a standard for all countries in the EU. This standard is available from standard organizations throughout the world and in the UK is available from the BSI. Shown in Table 4 is the classification that has been adopted. Table 4. Selected ISO 209 airborne particulate cleanliness classes for clean rooms and clean zones.



The table is derived from the following formula:




where:
  • Cn represents the maximum permitted concentration ( in particles/m3 of air ) of airborne particles that are equal to or larger than the considered particle size.
  • Cn is rounded to the nearest whole number.
  • 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 m m. 0.1 is a constant with a dimension of m m. Table 4 shows a crossover to the old FS 209 classes e.g.

ISO 5 is equivalent to the old FS 209 Class 100.

The occupancy state is defined in this standard 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 standard also gives a method by which the performance of a clean room may be verified i.e. sampling locations, sample volume etc. These are similar to FS 209. It also includes a method for specifying a room using particles outside the size range given in the table 4. Smaller particles (ultrafine) will be of particular use to the semiconductor industry and the large (³ 5m m macro particles) will be of use in industries such as parts of the medical device industry, where small particles are of no practical importance. Fibers can also be used.


The method employed with macro particles is to use the format:

‘M(a; b);c’

where

  • a is the maximum permitted concentration/m3
  • b is the equivalent diameter.
  • c is the specified measurement method.
An example would be:

‘M(1 000; 10m m to 20m m); cascade impactor followed by microscopic sizing and counting’.


Pharmaceutical Clean Room Classification


EU GGMP


The most recent set of standards for use in Europe came into operation on the 1st of January 1997. This is contained in a ‘Revision of the Annex to the EU Guide to Good Manufacturing Practice-Manufacture of Sterile Medicinal Products’. The following is an extract of the information in the standard that is relevant to the design of clean rooms:

For the manufacture of sterile medicinal products four grades are given. The airborne particulate classification for these grades is given in the following table.



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 209E 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 in the table for the "at rest" state should be achieved in the unmanned state after a short "clean up" period of 15-20 minutes (guidance value), after completion of operations. The particulate conditions for grade A in operation given in the table 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. 

Examples of operations to be carried out in the various grades are given in the table below. (see also par. 11 and 12).



Additional microbiological monitoring is also required outside production operations, e.g. after validation of systems, cleaning and sanitization.


Notes:
(a) These are average values.(b) Individual settle plates may be exposed for less than 4 hours.(c) 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.

Isolator and Blow Fill Technology (extract only)

The air classification required for the background environment depends on the design of the isolator and its application. It 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 sterilization should be installed in at least a grade D environment.

Guideline on Sterile Drug Products Produced by Aseptic Processing

This document is produced by the FDA in the USA and published in 1987. Two areas are defined. The ‘critical area’ is where the sterilized dosage form, containers, and closures are exposed to the environment. The ‘controlled area’ is where unsterilized product, in-process materials, and container/closures are prepared.

The environmental requirements for these two areas given in the Guide are as follows:

Critical areas ‘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 particulates, 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 characterizes 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 particulates or where equipment configuration disrupts laminar flow.

Air should also be of a high microbial quality. An incidence of no more than one colonyforming 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’.


Controlled areas ‘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 airflow and a positive pressure differential relative to adjacent uncontrolled areas. In this regard, airflow 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’.






This information was compiled from various sources including the listed agencies and the handbook ‘Clean Room Technology’ as written by Bill Whyte.

Cleanroom Classifications

Cleanrooms are classified by how clean the air is. In Federal Standard 209 (A to D) of the USA, the number of particles equal to and greater than 0.5mm is measured in one cubic foot of air, and this count is used to classify the cleanroom. This metric nomenclature is also accepted in the most recent 209E version of the Standard. Federal Standard 209E is used domestically. The newer standard is TC 209 from the International Standards Organization. Both standards classify a cleanroom by the number of particles found in the laboratory's air. The cleanroom classification standards FS 209E and ISO 14644-1 require specific particle count measurements and calculations to classify the cleanliness level of a cleanroom or clean area. In the UK, British Standard 5295 is used to classify cleanrooms. This standard is about to be superseded by BS EN ISO 14644-1.




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 mm or larger permitted per cubic foot of air. The standard also allows interpolation, so it is possible to describe e.g. "class 2000."




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 cubic metre of air. So, for example, an ISO class 5 cleanroom has at most 105 = 100,000 particles per m³.




Both FS 209E and ISO 14644-1 assume log-log relationships between particle size and particle concentration. For that reason, there is no such thing as zero particle concentration. Ordinary room air is approximately class 1,000,000 or ISO 9.


ISO 14644-1 Cleanroom Standards

Classmaximum particles/m3FED STD 209E
equivalent
>=0.1 µm>=0.2 µm>=0.3 µm>=0.5 µm>=1 µm>=5 µm
ISO 1102
ISO 210024104
ISO 31,000237102358Class 1
ISO 410,0002,3701,02035283Class 10
ISO 5100,00023,70010,2003,52083229Class 100
ISO 61,000,000237,000102,00035,2008,320293Class 1,000
ISO 7352,00083,2002,930Class 10,000
ISO 83,520,000832,00029,300Class 100,000
ISO 935,200,0008,320,000293,000Room Air


BS 5295 Cleanroom Standards

maximum particles/m3
Class>=0.5 µm>=1 µm>=5 µm>=10 µm>=25 µm
Class 13,000000
Class 2300,0002,00030
Class 31,000,00020,0004,000300
Class 420,00040,0004,000