Patient safety often requires that drug products be filled and packaged in sterile conditions. Sterile cleanrooms and isolators prevent contamination during the filling process. The use of cleanrooms is well established, and isolators are gaining increased acceptance. Each method, however, has its drawbacks such as making process interventions more difficult. In certain applications, restricted-access barrier systems (RABS), which can provide a level of aseptic quality near that of isolators, offer an efficient alternative and more process flexibility.
The aseptic processing of parenteral drugs and other sterile products such as opthalmic medicines and inhalers requires sterile handling to prevent the product from coming into contact with particulate and microbial impurities. For this reason, processing usually is performed in sterile rooms (see Figure 1).
Figure 1: Equipment in a cleanroom. Curtains mounted to the sterile air manifold or a safety partition separate the aseptic area from the cleanroom. The machine often will have its own filtration.
Production equipment such as filling machines must have a hygienic design and must be sanitized regularly. In addition, operators cannot enter the sterile room until they change their clothing and are disinfected. Despite the precautions, experience with this methodology has shown that the major contamination source for the product continues to be the operators themselves. Incomplete disinfections, inappropriate operator actions, and problematic machinery that requires frequent manual interventions can cause viable contamination. Any biological contamination of a processing line and its associated drugs may pose a risk to patients receiving the product.
To prevent such risk, the production areas, production machinery, and processes must be validated for aseptic quality. For example, operators must work according to precise, certified standard operating procedures (SOPs), which require special training programs. In addition, the production technology must function reliably to minimize operator interventions. The sanitation procedures must ensure the maximum removal of microbial impurities. Complete sterilization (the removal of all divisible organisms) of the entire machine and the entire area is hard to achieve with open-cleanroom methodology (1).
The pros and cons of isolator technology.
Products with higher standards and greater security requirements necessitate the use of isolator technology, which completely encloses the aseptic working area (see Figure 2).
Figure 2: Equipment in an isolator. Air is prepared and recirculated in the isolator through double-window systems or return-air ducts.
The high air-purity cleanroom (ISO class 5) inside an isolator is limited to the space above the machine's baseplate (2). The surrounding external area can have a lower air quality (a minimum of class 8) as long as the physical separation is maintained (3–5). This separation can be achieved using:
- a separation wall between the aseptic area and the surrounding area (e.g., a plastic curtain [soft wall] or a metal partition with glass windows [hard wall]);
- gloveports in the separation wall for manual interventions such as materials handling for microbiological monitoring or for responding to process disruptions;
- sterile-transfer mechanisms for moving production components, tools, and monitoring material (double-door transfer systems are common);
- mouseholes with format-specific parts to minimize the space around incoming and outgoing containers;
- positive interior pressure relative to the surrounding room.