In pharmaceutical industries , the working environment plays an important role in the quality of the manufactured products and that’s why cleanroom is important in pharma industries like in other industries viz. electronics, biomedical and industries that need critical manufacturing environments.
Now, what is a cleanroom? According to the US Federal Standard 209E, a cleanroom is defined as, `A room in which the concentration of airborne particles is controlled and which contains one or more clean zones.' According to ISO 14644-1, it is defined as, `A room in which the concentration of airborne particles is controlled, and which is constructed and used in a manner to minimize the introduction, generation, and retention of particles inside the room and in which other relevant parameters, e.g. temperature, humidity and pressure are controlled as necessary'.
A cleanroom is built in a contained space and controls strict environmental parameters such as humidity, pressure and temperature. The key component is the High Efficiency Particulate Air (HEPA) filter that is used to trap particles that are as small as 0.3 micron in size. HEPA filters are essential in providing contamination control.
Design and standards
The most commonly used standard related to the design of a cleanroom is the Federal Standard 209E. The standard classified the cleanliness of air for airborne particulate levels in cleanrooms and clean zones. Strict rules and procedures are followed to prevent contamination of the product. The European Community has a "Guide to Good Manufacturing Practice for Medicinal Products” and in the United Kingdom it is BS 5295. The World Health Organization (WHO) version of GMP is used by pharmaceutical regulators and the pharmaceutical industry in over 100 countries worldwide, primarily in the developing world. In some countries, the GMP follows largely the country of the principal technology provider.
Many countries follow their own standards for the design of clean room and as result a large number of cleanroom standards are developed. For example in UK followed British Standard 5295. Therefore it was felt necessary to have a worldwide standard for cleanroom classifications and design. The International Standards Organization thus developed, ISO 14644 an international standard for the design and classification of cleanroom. Other different cleanroom standards are also noted below.
The cleanrooms are designed with either positive or negative pressure based on the requirement. Normally, a positive pressure is maintained the cleanroom for pharmaceutical industries primarily to ensure that the medicines and or drugs are not contaminated by contamination coming from the outside. However, negative pressure inside the cleanroom is maintained for the special requirements. For example, the cleanroom in which penicillin is handled that must be maintained with negative pressures; as the penicillin must be kept in containment. Production and R&D of nuclear medicine must be carried out in a cleanroom in which negative pressure is maintained to prevent the release of radioactivity. A pressure differential of 5 Pa is normally maintained for both positive and negative pressure cleanroom as per regulations and standards; however there may be a little deviation depending on the process requirements.
Cleanrooms and other controlled environments are designed for a fixed volume (the room or enclosure). It may be noted that it is not a closed system. It is not possible to design a room or enclosure without any tiny chinks or leakages, in reality it is not possible to design absolutely leak proof room or enclosure. However, a permissible controlled leakage rate must be considered in the design of cleanroom. The permissible controlled leakage is important for two essential purposes viz., (i) opening and closing of the doors, and (2) regulation of pressure differentials as per standard. Proper design of clean air distribution system including downstream air returns is must. Cleanrooms are designed to achieve and maintain airflow in such a way, that the entire body of air inside the clean room moves in uniform velocity along parallel flow lines, i.e, in laminar flow.
Classification of cleanrooms
Cleanrooms are classified based on the degree of cleanliness of the air in the controlled environment. The method most easily understood and universally applied is the one suggested in versions of U.S. Federal Standard 209 up to edition `D' in which the number of particles equal to and greater than 0.5 wm is measured in one cubic foot of air and this count is used to classify the room. Federal Standard 209E has been published in 1992 in metric version and the corresponding International Standard Organisation's (ISO) standard is ISO-14644-1.
The new ISO classification is based on the following equation: where, D represents the maximum permitted concentration (in particles/m3 of air) of airborne particles that are equal to or larger than the considered particle size ; C 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 need to be specified, with 0.1 as the smallest permitted increment of and is the considered particle size in pm and 0.1 is a constant with a dimension of µm.
The above equation was chosen so that the class limits set by the Federal Standard at its standard reference point of 0.5 wm coincide closely with those found in the ISO standard.
Cleanroom classes
Different ISO Classes of cleanroom are shown in Table 1.
What is contamination?
Contamination is a process or act that causes materials, surfaces or environment to be soiled or adulterated with contaminating substances. There are two broad categories of surface contaminants: film type and particulates. These contaminants can produce a “killer defect” in a miniature circuit. Film contaminants of only 10 nm (nanometers) can drastically reduce coating adhesion on a wafer or chip. It is widely accepted that particles of 0.5 microns or larger are the target. However, some industries are now targeting smaller particles.
The following ISO clean room standards with the provisional titles are followed in many countries.
- WG1: Cleanliness classification by airborne particulate cleanliness
- WG2: Biocontamination
- WG3: Metrology and testing methods
- WG4: Design, construction and start up
- WG5: Cleanroom operation
- WG6: Terms, definitions and units
- WG7: Enhanced clean devices
- WG8: Molecular contamination
Design criteria
The design criterion for a standard cleanroom is the supply of unidirectional flow of clean air with face velocity of up 0.46 - 0.1 m/s. Air changes per unit of time should not be used with a unidirectional flow room as they are related to the volume of the room, which generally has no effect on the performance of the system. The GMP guides specify the building design, building material, care of personnel, etc and they may also give figures for the cleanliness classes of clean-rooms: particles, microorganisms, as well as the type of air filters and number of air changes per hour.
At present, cleanrooms are designed as per the standards. There are a number of cleanroom design standards available which should be considered. These are listed in Table 2.
(The author is a practicing chemical engineer based in Mumbai)