Clean room standards

Since metered-dose aerosols are not claimed to be sterile products, filling of the product does not require rated clean room standards as described in U.S. federal standard 209C. Frequently, however, high-efficiency particulate air (class 100,000) is employed above any open tanks and filling lines. This practice is used to reduce the likelihood of particulate and microbial contamination in the product. 

Extreme care has to be exercised to avoid contaminating the tape-cast sheets with dust which would seriously reduce yield and impair reliability, and a high level of cleanliness, including clean room standards, are required for processing the thinner layers. 

Clean Room Standards and Room Classification Clean room technology is the most typical feature of aseptic manufacture. The major regulatory sources of guidance to appropriate technology and air standards for aseptic filling [2,3,4]... 

The two Clean Room Standards FS 209 and BS 5295 are referenced in the regulatory documents governing aseptic filling. Table 1 compares the air classifications recommended or required for aseptic filling clean rooms in these pharmaceutical regulatory documents and references the particular Standards cited in support. Strictly speaking, the only options for room classification are the 1976 revision of BS 5295 and the 1973 and 1988 revisions of FS 209. 

Pharmaceutical guidance document Designation of class for aseptic manufacture Referenced clean room standard class Referenced clean room standard... 

Table 2 Comparison of Particle Count Requirements in Clean Room Standards Applicable to Aseptic Filling (FS 209 Class 100 [M 3.S j. BS 5295.1976 Class I, BS 5295.1989 Classes E and F)...

Classification and monitoring to the Clean Room Standards requires that particular numbers of samples of air be taken per unit floor area, that samples be taken in specified locations, and that samples be taken at appropriate frequencies. Table 2 summarizes these requirements. It is evident that the evolution of the US standard from FS 209B to FS 2WE. both for validation and for routine monitoring, is toward the as otherwise specific" condition, which bounces the onus for decision-making back to the user and his customer. This is not the case for the British Standard. To validate a clean room, the British Standard BS 5295.1989 asks for more locations and more replicate testing at each location than BS 5295.1976 or either revision of the U.S. standard.. 

Fig. 13 Sampling locations for compliance with Clean Room Standards BS S29S.1989 andFS209D.

Clearly there are issues here that the pharmaceutical industry needs to address. Particles of the smaller sizes specilied for measurement in the Clean Room Standards are not of direct concern to particulate contamination issues facing manufacturers of sterile pharmaceuticals. Furthermore, it is the quality of clean room technology that is the factor of greatest importance to the pharmaceutical industry, of which the attainment of clean room classification is merely an indirect index. In these circumstances a major increase in the amount of testing required to claim compliance with a particular classification offers no benefit to the industry, and may indeed unnecessarily increase testing costs, downtime, etc. 

Table 3 compares the minimum filter efficiencies cited in the guidance documents on aseptic manufacturing and in the Clean Room Standards. It is curious that the specification for filter efficiency in the Orange Guide" is tighter than the specifications given in the two Clean Room Standards it refer-... 

Table 3 Comparison of Minimum Filter Efficiencies Referenced in Guides to Aseptic Pharmaceutical Manufacture and Clean Room Standards...

Overall, the standards being adopted worldwide for classification of aseptic pharmaceutical filling rooms are those of FS 209. This is because of the practical flexibility of this standard. The British Standard has diverged from strict equivalence with its introduction of levels of testing activity that may be more appropriate to the electronics industry. The availability of Clean Room Standards has been important to the development and responsible control of... 

In some instances the terminology of room classification may be used where it is neither specifically necessary nor specifically correct. The FDA Guideline (2) refers to a "per-cubic-foot particle count of no more than 1(X) in a size range of 0.5 fim and larger (Class 1(X)) when measured not more than one foot away from the worksite and upstream of the air flow. The sampling requirements of the Clean Room Standards may be omitted when superfluous to the purposes of aseptic manufacture. 

The following example illustrates some of these features. In a clean room with automated transporting and processing facilities, there are two quality classes of air. The space close to the small items under processing and the treating facilities should be exposed only to air of class A quality (very low contaminant level) and the rest of the room air is class B quality (normal standard). Figures 11.2 and 11.3 (see color insert) represent two out of a large number of parameter studies. 

Bioclean classes The various standards of contaminant control to which clean rooms are held. 

Classes for clean rooms Many national standards are in use for the classification of clean rooms. It is recommended that the standard of the country in which they are to be installed be referred to. 

Clean room A room in which the environmental conditions of air purity, temperature, moisture content and air movement are maintained to High and accurate standards. 

Clean zone Any area, such as a clean room, in which set standards of air purity and other environmental conditions are maintained. 

For Clean Rooms (rooms of a very high standard) dust count per unit volume will be specified, but other specifications for room cleanliness are usually in terms of filtration performance against a standard test dust. Other important features are resistance to air flow and dustholding capacity, leading to the fan energy required and filter life. 

Clean Room and Work Station Requirements, Controlled Environment, Sec. 1-5 Federal Standard 209, Office of Technical Services, U.S. Department of Commerce, Washington, DC, Dec. 16, 1963. 

The average air flow velocity, or the average or total air flow volume, for the clean room or clean zone should be within 5% of the value specified for the clean room or clean zone, or within other standardized tolerance limits. 

All finished products are tested for sterility in a controlled-access clean room environment in a laminar flow hood, which provides no greater level of a microbial challenge than that encountered in the fill environment. The testing environment consists of a gowning room and sterility test suite that meets the same air quality standards as the hlling suite. 

Commercial standard solutions for flame atomic absorption are not necessarily suitable for plasma and furnace analyses. The latter methods require purer grades of water and acids for standard solutions and, especially, for dilutions. For the most sensitive analyses, solutions are prepared in a dust-free environment (a clean room with a filtered air supply) to reduce background contamination that will be detected by your instruments. 

Pollution also affects the manufacture of certain materials and products. This is evidenced by the need for clean rooms in metrology standards laboratories and in the production of certain electronics materials and of component assembly operations, In addition to elaborate filtering systems, such rooms are held at a slightly positive pressure (above outside atmospheric pressure) to prevent the entry of raw air from the outside. 

A controlled environment such as a clean zone or clean room is defined by certification according to a relevant clean room operational standard. Parameters that are evaluated include... 

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