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I. Glossary
Isolator
A contained, decontaminated environment meeting Grade A/ISO 5 conditions used for aseptic process manufacturing that provides an uncompromised, continuous isolation of its interior from the external environment. Once decontaminated by a validated cycle, an isolator prevents the microbiological contamination of sterile products and product contact surfaces of the interior by enclosures and the supply of continuous, controlled overpressure of HEPA-filtered air.
Closed Isolator Systems
Excludes external contamination from the isolator's interior by transfer material via aseptic connection to auxiliary equipment, rather than using openings to the surrounding environment. Closed systems remain sealed throughout operations.
Open Isolator Systems
Designed to allow for the continuous or semicontinuous ingress and/or egress of materials during operations through one or more openings. Openings are engineered (e.g., using continuous overpressure) to exclude the entry of external contamination into the isolator.
Restricted Access Barrier System
An area that includes one or more critical work areas that is fully or partially enclosed with ridged or semi-rigid walls, which restricts the access of aseptic processing personnel, via fixed gloves, to the critical work area during aseptic operations.
II. Key Considerations for Aseptic Production
Q1. What should be the pressure difference between the interior of the isolator and the surrounding area?
When designing an isolator for aseptic processing, during critical operations, the pressure difference between the internal environment of the isolator and the external environment must be positive pressure to prevent reverse airflow. The set value of the pressure difference between the internal environment of the isolator and the background environment should typically be greater than 10 Pa, and this positive pressure should be maintained and monitored throughout the operation.
In a sterile facility where components are transferred in the isolator using a conveyor belt, material transfer ports (such as mouse holes) are usually required between different environments. The mouse holes must be subject to positive pressure from a space with higher cleanliness. The direction of the positive pressure airflow must be proven through visual studies.
Both the internal and external pressures of the isolator should be continuously monitored and appropriate warning limits set to provide indications of deviations from the acceptable pressure difference.
Q2. What are the key considerations for the design of isolation glove?
Risk assessment should be adopted to identify, evaluate and mitigate the risks associated with the installation and use of isolation gloves during aseptic operations. When determining the location and composition of isolation gloves, factors that may pose risks to the aseptic process performance and product sterility should be taken into account, such as:
01. Ergonomics for addressing personnel fatigue and safety
02. Diversity of personnel height and reach range
03. Direction and location of planned and anticipated activities, operations, and interventions
04. Proximity of key working surfaces, transfer ports, and exposed sterile items, components, containers, and products
05. Excessive turbulence caused by HEPA airflow obstruction in key working areas
06. Airflow obstruction limits the adequate distribution of decontamination chemicals, steam, or gases
07. Crowding of materials and glove openings
08. Weight and orientation of materials and items handled by personnel wearing gloves
09. Decontamination and ventilation capabilities of gloves
10. Positioning of glove decontamination, ventilation, and when not in use
11. Proximity of sharp objects or surfaces that can puncture gloves or glove openings
12. Convenience of glove placement and wearing
13. Locations of environmental monitors, instruments, and sampling points
14. Work that requires flexibility, such as turning handles or accessories
15. Thickness of glove material to prevent puncturing, cracking, or excessive wear
16. Ability to fully seal gloves and glove openings
17. Ability to confirm or detect glove integrity
18. Validity period of gloves
19. Exposure to direct sunlight may cause degradation of gloves or glove sealing materials
20. Personnel with sharp nails or jewelry that may puncture gloves during operation
21. Safe storage location of gloves in the isolator after or during operation
Q3. How should the isolator be designed to minimize the risks associated with the intervention measures?
The design of intervention measures within the isolator should aim to minimize the intervention factors that may lead to microbial contamination, such as:
1. The duration, complexity, and proximity of the intervention to the exposed sterile products, components, and surfaces.
2. The design of the isolator and the process should allow for intervention and operation in an class A / ISO 5-level space to comply with appropriate aseptic techniques.
3. The number and location of glove ports should be designed based on the needs of the intervention and the ease of operation.
4. Activities that do not require protection under Class A/ISO 5 standards should be conducted outside the isolator or in areas where there is no exposure of sterile products, materials, and surfaces.
5. Consider using robotic technology, automated process steps, and technologies that reduce intervention to minimize the intervention during installation, operation, and sampling processes.
6. Materials and equipment within the isolator should be placed in locations that avoid congestion and where there is no excessive exposure to sterile products, materials, and surfaces that require contact.
Q4. What level should the rooms surrounding the isolator be?
The current FDA recommendations suggest that the background environment for operation should not be lower than ISO Class 8; the current EU GMP Appendix 1 suggests a static ISO Class 8 (Class D).
