USP Guidelines On Isolator Systems
What are isolators?
Isolators are self-contained devices that perform automated functions and provide controlled environments with little to no microorganism exposure. These isolators remove the need for human contact and are made of surfaces that can be easily decontaminated, like plastics, glass, and stainless steel. Most sterility testing that follows United States Pharmacopeia (USP) guidelines utilizes isolators. HEPA air filtration is used in isolator systems. Air filtration systems are quickly decontaminated using sterilization-in-place decontamination processes. Sterilization-in-place processes decontaminate other isolator surfaces with steam and chemical treatments to prevent microbial growth. Isolator systems are either “open” or “closed.” Closed isolators do not have a direct opening to the external environment. Instead, closed isolators use rapid-transfer ports to move materials in and out of the closed system. In contrast, open isolators allow materials to enter the isolator chamber through a defined opening protected with air overpressure. Regardless of the isolator type (i.e., open or closed), materials entering or leaving isolators are transported aseptically. As isolators eliminate direct contact between human operators and products, any aseptic manipulations within the isolator are made with half-suits. Half-suits are glove and sleeves systems that allow the operator to manipulate items within the isolator. ISO cleanroom standards, ISO cleanroom requirements, isolator system design, and sterility testing isolator systems will be covered in this article.
How are isolator systems designed?
Isolator systems are custom-made. The most important components for isolator design are air handling systems, material transfer areas, microbial monitoring systems, and microbial decontamination processes. While the design of the isolator is imperative to its function, so is the implementation of an appropriate training program for those that operate, monitor, and control isolator systems so that ISO cleanroom standards and requirements are met.
Air Handling Systems
Isolators for sterility testing contain microbial retentive filters (i.e., HEPA filters or better). Isolators are ISO Class 5 areas. Thus, isolators must meet ISO Class 5 particulate air-quality requirements unless used for manufacturing operations that generate particulates. Isolator air systems must be capable of containing sporicidal vapors and decontamination gases within the system. Further, air systems must maintain a positive pressure gradient relative to the outside environment to prevent microbial ingress during operation or the transfer of materials into or out of the isolator system. Standard overpressure levels for ISO cleanroom standards and requirements are twenty Pascals or more. Airflow within the isolators is either unidirectional or turbulent.
Material Transfer Areas (Ports & Doors)
Many isolators have attached decontamination systems that allow sterile media and other supplies to be transferred into the isolator system. Alternatively, rapid transfer ports (RTPs) are used to connect two isolators (the workstation and material transfer isolator). The nonsterile surfaces of the RTPs are attached using locking rings or flanges, and a compressed gasket system prevents microbial contamination through an airtight seal. RTPs quickly allow supplies to be aseptically transported through linking flanges and forming an airtight passage. A narrow band of the RTP’s gasket system provides the primary risk for microbial contamination. Thus, the exposed gasket areas are disinfected before airtight connections are made and materials transferred through the RTP. To further reduce contamination risk, gasket assemblies are regularly lubricated. RTP gaskets are changed periodically to prevent any cut or torn gaskets from being used, thus ensuring ISO cleanroom standards and requirements are met.
Microbial Monitoring & Decontamination Systems
Microbial monitoring and decontamination systems assure that aseptic conditions are consistently maintained within isolator systems. Microbiological monitoring programs detect any issues with isolator system operation and contaminants within the isolator. Microbiological monitoring is a form of environmental monitoring where the internal isolator environment (e.g., surfaces, air, etc.) are regularly sampled. Traditionally, samples are taken following decontamination on the first day of an operation and on the last day of operation. Settling plates and contact plates may be used for sample collection. However, low-level contaminants will not be detected with these methods. Continuous nonviable particulate monitoring within the isolator’s enclosure is ideal for maintaining ISO Class 5 particulate levels.
The greatest contamination risks for isolator systems are adding supplies and samples into the enclosure and using half-suit assembly equipment. Decontamination protocols for added materials, periodic inspections of RTP gaskets, glove selection, and glove leak monitoring are all ways to prevent microbial contamination went adding materials into an isolator. Gloves made with hypalon materials are the best for isolator systems. These gloves are resistant to punctures and the chemical sporicides used in isolator decontamination. Small glove leaks can be detected by submersing the gloves in 0.1% peptone water, filtering the solution, and plating the filtrate on growth media.
Training Programs
Isolators and clean rooms require the use of appropriate aseptic techniques to maintain product sterility and testing accuracy. Thus, aseptic technique training is needed for all isolator operators. Additionally, all training sessions and personnel evaluations related to isolator use must be documented. Regular maintenance and upkeep for ISO Class 5 certification are required for all isolator systems in service.
Where should isolators be located?
Though ISO Class 5 certified, isolators do not need to be installed in a classified cleanroom. Nor is environmental monitoring of microbes within the external environment surrounding the isolated needed. However, temperature and humidity control of the external environment is necessary for temperature-sensitive decontamination processes, such as steam sterilization. Isolators should be placed in areas with adequate space to transfer products and materials in and out of the sterile environment. Further, isolators should be installed in areas with low foot traffic and minimal access to untrained, nonessential staff.
Summary
Overall, isolators are self-contained devices that perform automated functions and provide controlled environments with little to no microorganism exposure. Most sterility testing that follows United States Pharmacopeia (USP) guidelines utilizes isolators. The most important components for isolator design are air handling systems, material transfer areas, microbial monitoring systems, and microbial decontamination processes. While the design of the isolator is imperative to its function, so is the implementation of an appropriate training program for those that operate, monitor, and control isolator systems. When outsourcing regulatory testing, ensure you choose a contract testing organization that can support you with appropriate equipment for the sterility testing of your unique medical devices or products.
Ethide Labs is a contract testing organization specializing in Sterilization Validations and Sterility Testing. Ethide Labs also offers Microbiology Testing, Bioburden Testing, EO Residual Testing, Bacterial Endotoxin Testing, Cytotoxicity Testing, Environmental Monitoring & Package Integrity Testing services for medical device companies and allied industries. Ethide is an ISO 13485 certified facility.
References
Michael J. Akers. Sterile Drug Products Formulation, Packaging, Manufacture, and Quality. Drugs and the Pharmaceutical Sciences. Informa Healthcare. 2010.
United States Pharmacopeial Convention. <1208> Sterility Testing—Validation Of Isolator Systems. Rockville, MD, USA. 2021. (USPC <1208>).
