A controlled (classified) area is an enclosed environment or room with a flawless control over particulate contamination. More specifically, the areas have a controlled contamination level, which is specified in terms of the number of particles for every cubic meter, for a specified particle size. The restricted areas are constructed with impeccable humidity, temperature and pressure controls in order to minimize the generation, introduction and retention of particulate matter inside the rooms.
Used for pharmaceutical manufacturing, the controlled areas ensure low levels of environmental pollutants, such as airborne microbes, dust, aerosol particles and chemical vapors. Laminar Air Flow The classified rooms help the pharmaceutical industry to manufacture products that are absolutely free from particulate and microbial contamination. Indeed, many pharmaceutical controlled rooms are clean rooms that are fitted with HEPA and ULPA filters, and dehumidifier systems in order to allow for the manipulation of preparations in moisture-free and contamination-free environments. Today, controlled area (classified area) and its use in sterile manufacturing has grown in leaps and bounds.
Objectives of Using Controlled Areas
In the pharmaceutical industry, the core objective of using controlled rooms is preventing contamination and ensuring that preparations are completely sterile. The rooms help to eliminate contamination with chemicals, bacteria, electrostatic charges, particles and fibers. Since, pharmaceutical products should not introduce undesirable particles, chemicals, and bacteria into the patients, the controlled area (classified area) and its use in sterile manufacturing has become a critical quality assurance step for every drug company. Similarly, because most surfaces of controlled rooms are made of poor conductors, they can easily develop and retain undesirable electrostatic charges. Hence, the surfaces are cleaned and controlled in such a fashion that the charges can be conducted away as soon as they are formed.
Sections and Classification of Controlled Areas
A pharmaceutical controlled area is principally divided into two sections: the general area and the critical area. The General Area is the section of the room where the existence of contaminants will not directly influence the sterility of products. The general area should, however, be properly cleaned and controlled in order to avoid the transfer of contaminants into the critical area. The Critical Area is the section around the production point, where any contaminants may gain direct access to the preparations. The critical area is usually protected using localized Laminar-Flow workstations and clean benches.
Classified areas fall into four classes (1, 2, 3 and 4) depending on the degree of air cleanliness (number of particles for every cubic foot of air) that is required. The classes are:
1. Class 1 (Class 100,000) has a designated particle count that is less or equal to 100,000 particles per cubic foot for a particle size 0.5 micron and larger, or 700 particles for each cubic foot for size 5.0 micron and larger.
2. Class 2 (Class 10,000) has a designated particle count of less or equal to 10,000 particles per cubic foot for a particle size 0.5 micron and larger, or 70 particles for each cubic foot for a particle size 5.0 micron and larger.
3. Class 3 (Class 1,000) has a designated particle count of less or equal to 1000 particles for every cubic foot for a particle size 0.5 micron and larger, or 10 particles for each cubic foot for a particle size 5.0 micron and larger.
4. Class 4 (Class 100) has a particle count of not more than 100 particles for every cubic foot for a particle size 0.5 micron and larger.
Today, the ISO standard for classified areas is used by most pharmaceutical companies.
Ensuring Complete Sterilization
In order to manufacture completely sterile products, various stages of product processing such as component preparation, filling and product preparation should be performed in separate sections of the controlled area. Hence, manufacturing operations should be divided into stage-wise sterilization (for every stage) and terminal sterilization (for the completed preparations). To achieve thorough stage-wise sterilization, the controlled room should allow for AT-REST and IN-OPERATION states. AT-REST state means the production equipment in the classified room operate without the presence of personnel. On the contrary, IN-OPERATION state means the manufacturing processes are run by a specified and limited number of personnel.
Therefore, the pharmaceutical company should grade its controlled production into four levels: A.B, C and D. Grade A should be the zone for high-risk operations such as the filling zone and the zone for making aseptic connections, open vials and ampoules. The zone should have laminar airflow systems with homogenous air speeds. Grade B should be the background environment for grade A, allowing for aseptic preparation and filling. Grade C and D should be classified areas that handle the less critical stages of sterile manufacturing.