Aseptic processes are designed to minimize exposure of sterile articles to the potential contamination hazards of the manufacturing operation. Limiting the duration of exposure of sterile product elements, providing the highest possible environmental control, optimizing process flow, and designing equipment to prevent entrainment of lower quality air into the Class 100 (ISO 5) clean area are essential to achieving high assurance of sterility .
Both personnel and material flow should be optimized to prevent unnecessary activities that could increase the potential for introducing contaminants to exposed product, container-closures, or the surrounding environment. The layout of equipment should provide for ergonomics that optimize comfort and movement of operators. The number of personnel in an aseptic processing room should be minimized. The flow of personnel should be designed to limit the frequency with which entries and exits are made to and from an aseptic processing room and, most significant, its critical area. Regarding the latter, the number of transfers into the critical area of a traditional cleanroom, or an isolator, should be minimized. To prevent changes in air currents that introduce lower quality air, movement adjacent to the critical area should be appropriately restricted.
Any intervention or stoppage during an aseptic process can increase the risk of contamination. The design of equipment used in aseptic processing should limit the number and complexity of aseptic interventions by personnel. For example, personnel intervention can be reduced by integrating an on-line weight check device, thus eliminating a repeated manual activity within the critical area. Rather than performing an aseptic connection, sterilizing the preassembled connection using sterilize-in-place (SIP) technology also can eliminate a significant aseptic manipulation. Automation of other process steps, including the use of technologies such as robotics, can further reduce risk to the product.
Products should be transferred under appropriate cleanroom conditions. For example, lyophilization processes include transfer of aseptically filled product in partially sealed containers. To prevent contamination, a partially closed sterile product should be transferred only in critical areas.(Appropriately designed transfer equipment provides these conditions and can be qualified for this purpose)
Facility design should ensure that the area between a filling line and the lyophilizer provide for Class 100 (ISO 5) protection. Transport and loading procedures should afford the same protection.
The sterile drug product and its container-closures should be protected by equipment of suitable design. Carefully designed curtains and rigid plastic shields are among the barriers that can be used in appropriate locations to achieve segregation of the aseptic processing line. Use of an isolator system further enhances product protection.
Due to the interdependence of the various rooms that make up an aseptic processing facility, it is essential to carefully define and control the dynamic interactions permitted between cleanrooms. Use of a double-door or integrated sterilizer helps ensure direct product flow, often from a lower to a higher classified area. Airlocks and interlocking doors will facilitate better control of air balance throughout the aseptic processing facility. Airlocks should be installed between the aseptic manufacturing area entrance and the adjoining unclassified area. Other interfaces such as personnel transitions or material staging areas are appropriate locations for air locks. It is critical to adequately control material (e.g., in-process supplies, equipment, utensils) as it transfers from lesser to higher classified clean areas to prevent the influx of contaminants. For example, written procedures should address how materials are to be introduced into the aseptic processing room to ensure that room conditions remain uncompromised. In this regard, materials should be disinfected according to appropriate procedures or, when used in critical areas, rendered sterile by a suitable method.
If stoppered vials exit an aseptic processing zone or room prior to capping, appropriate assurances should be in place to safeguard the product, such as local protection until completion of the crimping step. Use of devices for on-line detection of improperly seated stoppers can provide additional assurance.
Cleanrooms are normally designed as functional units with specific purposes. The materials of construction of cleanrooms ensure ease of cleaning and sanitizing. Examples of adequate design features include seamless and rounded floor to wall junctions as well as readily accessible corners. Floors, walls, and ceilings should be constructed of smooth, hard surfaces that can be easily cleaned. Ceilings and associated HEPA filter banks should be designed to protect sterile materials from contamination. Cleanrooms also should not contain unnecessary equipment, fixtures, or materials.
Processing equipment and systems should be equipped with sanitary fittings and valves. With rare exceptions, drains are considered inappropriate for classified areas of the aseptic processing facility other than Class 100,000 (ISO 8) areas. It is essential that any drain installed in an aseptic processing facility be of suitable design.
Equipment should be appropriately designed (CFR 211.63) to facilitate ease of sterilization. It is also important to ensure ease of installation to facilitate aseptic setup. The effect of equipment design on the cleanroom environment should be addressed. Horizontal surfaces or ledges that accumulate particles should be avoided. Equipment should not obstruct airflow and, in critical areas, its design should not disturb unidirectional airflow.
Deviation or change control systems should address atypical conditions posed by shutdown of air handling systems or other utilities, and the impact of construction activities on facility control. Written procedures should address returning a facility to operating conditions following a shutdown.
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