8 Particle size (µm) Airborne particle concentration (particles/m3) 100 0.1 0.2 0.3 0.5 1.0 5.0 109 108 107 106 105 104 103 102 101 ISO Class 9 ISO Class 8 ISO Class 7 ISO Class 6 ISO Class 5 ISO Class 4 ISO Class 3 ISO Class 2 ISO Class 1 Classifying Cleanrooms The production of sterile pharmaceuticals is subject to special requirements in order to minimize risks of particulate and microbial contamination. Manufacturing is carried out in clean areas within which the concentration of airborne particles needs to be controlled. The classification and monitoring of such clean areas follow the ISO 14644 standard and the EU GMP Directive 2003/94/EC. Classification Standards Pharmaceutical cleanrooms and clean air devices are classified according to ISO 14644-1. The level of airborne particulate cleanliness, applicable to a clean area, is expressed as an ISO class. The lower the classification number, the higher the level of cleanliness. The ISO class represents maximum allowable concentrations for considered particle sizes, ranging from 0.1 μm up to 5.0 μm. Figure 2 shows a graphic illustration of the nine ISO cleanroom classes with the concentration limits for the given particle sizes. Different room classes are typically necessary for the various pharmaceutical clean areas and production steps taking place. For the operational environmental monitoring of the production of sterile preparations, EU GMP distinguishes four alpha grades. Each grade is assigned maximum permitted airborne particle concentrations for sizes ≥ 0.5 μm and ≥ 5.0 μm ‘at-rest’ and ‘in operation’ state. Particles of 0.5 μm and larger can be considered as the most critical particle sizes that need to be effectively filtered out by HEPA filtration for obtaining the required aseptic process conditions. GMP grade A is the most stringent classification and equals ISO 5 according to ISO 14644-1. This type of area is expected to be almost completely free from particle sizes ≥ 5.0 μm, both ‘at-rest’ and ‘in operation’ condition. Figure 2: ISO 14644-1 Cleanroom Class Particulate Concentration Limits The graph shows the minimum and maximum particle size limits acceptable for each of the ISO classes shown. The classification lines do not represent actual particle size distributions found in cleanrooms and clean zones. Table 4: Typical Cleanroom Activities for Terminal Sterilization and Aseptic Preparation GMP Grade Examples of Typical Activities Terminal Sterilization Aseptic Preparation A Filling of products for sterilization (unusual risk profile) Handling of sterile starting materials and components Preparation of materials and products (non-sterile filtering) Handling and filling of aseptically prepared products B – Background area for grade A zones C Filling of products for sterilization (usual risk profile) Preparation of components (unusual risk profile) Preparation of materials and products (sterile filtering) D Preparation of components (usual risk profile) Handling of components after washing Sterile Manufacturing Activities The pharmaceutical industry is expected to take proactive steps in ensuring that products are safe and effective. EU GMP regulations require building a quality approach into the manufacturing process, to minimize or eliminate risk of cross-contamination and errors (Table 4).
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