The production of sterile products has special requirements particularly in case of medicines. These products must be produced in conditions that ensure purity. The products must also be free from viable organisms and should have limited or permissible particulate/contaminants.
It is thus, important to use the tested procedures meant to manufacture the sterile products. Owing to their special manufacturing requirements, sterile medicinal products are prepared in special facilities known as clean rooms. These rooms are designated to reduce the risk of microbial and particulate contamination at all the stages of the manufacturing process.
The clean area used to produce sterile products is commonly designated as a suite of clean rooms. With this system, the operators enter the clean rooms by way of a changing room. Within this area the operators put on clean room clothing before entering into the clean rooms. The changing room has a lower standard of environmental quality. A clean room is for the preparation of sterile medicines in the form of oral, liquid, eye drops and respells, etc.
Production of sterile products should be carried out in a clean environmental with a limit for the environmental quality of particulate and microbial contamination. This limit for contamination is necessary to reduce the risk of product contamination.
In addition, the temperature, humidity and air pressure of the environmental should be regulated to suit the clean room processes and the comfort of the operators.
For the manufacture of sterile pharmaceutical preparations, the clean areas are classified into the following four grades and shown in Table 19.1:
(i) Grade A:
It is a zone for high risk operations such as filling and making aseptic connections. Normally, such conditions are provided by a laminar airflow work station. Laminar airflow systems provide a homogeneous air having a speed of approximately 0.45m/second.
(ii) Grade B:
In aseptic preparation and filling, it is the background environment for the grade A zone.
(iii) Grades C and D:
These are the clean areas for carrying out less critical stages in the manufacture of sterile products. Levels (limits) of detection of microbiological contamination should be established for ‘alert and action’ purposes, and for monitoring the trends in air quality.
The alert level of microbial limits is specified in the standard operating procedures (SOP). If it crosses the microbial limits, investigation is carried out to ensure the process under control. Alert levels can be established during environmental monitoring programme.
If microbiological levels in the controlled environment exceed than the specified in the standard operating procedures it is called ‘action level’. The colony forming units (CFU) in action levels are always higher than the alert levels. Limits are expressed as CFU for the microbiological monitoring of clean areas in operation.
Values are average of three replicates. Individual settle plates may be exposed for less than 4 hours. These grades are categorized for a particulate quality in the environmental air, when the clean area is operating in both a ‘manned’ and ‘unmanned’ state. In addition, these are graded by the microbial monitoring of the air and operators during functioning.
The standards are shown m Table 19.2: