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Pharmaceutical Clean Room Classification


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.
Medicinal Cleanroom Classific...
(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).
Cleanroom Uses by Class
Additional microbiological monitoring is also required outside production operations, e.g. after validation of systems, cleaning and sanitization.
Microbial Contamination Limits
(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’.
Comparison of CR Standards
This information was compiled from various sources including the listed agencies and the handbook ‘Clean Room Technology’ as written by Bill Whyte.