Ensuring that sterile and contamination free environments are maintained has become even more critical for manufacturers of sterile pharmaceuticals today due to the need to control the potential for cross contamination in drug manufacturing which is particularly important when dealing with the production of sterile drug products, Biologics and High-potency compounds. One of the primary technologies used today in achieving this level of environmental control, the Isolator.
Isolators are highly effective means of providing a physically sealed barrier between the product and the surrounding environment thus greatly reducing the potential for product contamination by personnel or by the surrounding environment. Regulatory expectations on sterile product manufacture continue to tighten which has resulted in isolators being used as a preferred alternative to traditional cleanroom-based processing methods.
Regulatory agencies like the FDA and EMA strongly endorse the use of advanced contamination control technologies like isolators to enhance product safety and reliability of manufacture.
The success of isolators as a manufacturing technology requires that manufacturers are compliant with the best practices related to the design, use, cleaning and monitoring of isolators.
Isolators are used in many different types of operations including:
Design features of the isolator include:
Airflow design must ensure that the proper conditions are maintained during the use of the isolator to maintain sterility and control of the environment.
When decontaminating an isolator, the most widely used method of decontamination is with vaporized hydrogen peroxide (VHP).
VHP is a vaporized form of hydrogen peroxide that is generated and circulated throughout the isolator to kill microorganisms that are located on surfaces.
To validate the decontamination cycle, biological indicators are used to establish that the environment within the isolator is sterile prior to beginning production.
Ways to transfer materials into an isolator are:
Best Practices for glove integrity management include:
Generally speaking, the following types of activities will be included in any Environmental Monitoring Program:
- Airborne particulate monitoring
- Microbial sampling
- Surface contamination testing (Active and Passive)
- Differential Pressure Monitoring
Their purpose is to assist you in determining whether or not an isolator environment is within acceptable limits.
All regulatory agencies provide guidelines for the ongoing monitoring of the isolator environment as an element of a total contamination control program.
Personnel must be trained to understand:
- Procedures associated with their e.g. operation of the Isolator
- Principles of Aseptic Technique
- Procedures associated with the transfer of materials
- Emergency Handling Procedures
Training programs should include a mix of theory and practical (hands-on) training. Well-trained employees will contribute towards the continued reliability and success of the Isolator System.
Service of the isolator system may include:
Validation includes:
The European Union Good Manufacturing Practice (EU GMP) Annex 1 outlines how isolators can be used as a key technological innovation in the manufacture of sterile medicines using aseptic techniques.
Manufacturers must show their:
1. Robust contamination control strategies
2. Validated decontamination procedures
3. Continuous environmental monitoring
4. Appropriate documentation and employee training
Organizations that can prove their effectiveness in using isolator technology can greatly reduce the level of regulatory concerns and the likelihood of inspection failures.
Areas of development and integration will likely include:
1. Robotics filling systems
2. Automated material transfer systems
3. Real time monitoring of the manufacturing environment
4. Digital control of the manufacturing process
All of these advancements will provide increased assurance of sterility and increase manufacturing effectiveness.
Isolator technology will also become increasingly important in the manufacture of sterile pharmaceutical products such as biologicals, vaccines and advanced biologics.
As a key element of contamination prevention/sterility assurance in the production of pharmaceuticals, isolators provide a sealed barrier between the product and its surrounding environment, thereby reducing the potential for microbial contamination significantly.
Further, the appropriate implementation of isolators requires adherence to best practices regarding their design, decontamination processes, glove-maintenance procedures, environmental monitoring methods (for both the isolator and product) and operator training.
By implementing isolators correctly, pharmaceutical companies can expect increased product quality, compliance with regulations and increased patient safety, as well as produce higher-quality sterile pharmaceutical products generally.
Regulatory agencies like the FDA and EMA strongly endorse the use of advanced contamination control technologies like isolators to enhance product safety and reliability of manufacture.
The success of isolators as a manufacturing technology requires that manufacturers are compliant with the best practices related to the design, use, cleaning and monitoring of isolators.
What is Isolator Technology?
An isolator is a containment system used to protect both pharmaceutical materials and processes from external sources of contamination and prevent direct contact between the operators and the product. Isolators contain physical barriers that can include rigid walls, glove ports and sealed transfer systems.Isolators are used in many different types of operations including:
- Manufacturing of sterile drug products
- Aseptic filling processes
- Handling of potent compounds
- Sterility testing
- Cell and gene therapy production
Benefits of Isolator Technology
The use of isolator technology has clear advantages in comparison to traditional cleanroom systems.1. Improved Contamination Control
Isolators provide an optimized, contamination-free environment that eliminates microbial contamination caused by both personnel and external environment.2. Decreased Human Intervention
Personnel are typically a major source of contamination in the aseptic manufacturing process and using an isolator reduces the direct human intervention with the product that reduces the chances of contamination.3. Increased Product Safety
When isolating the manufacturing process from the outside environment, the contamination risks of the final product are greatly decreased and the assurance of sterile product increases.4. Decreased Operating Costs
Although isolators generally have a higher initial capital investment than cleanrooms, they can reduce the long-term operating costs associated with maintaining cleanroom classifications.5. Compliance with Regulatory Requirements
Isolators help companies to be in compliance with Good Manufacturing Practices and provide modern contamination control methods.Best Practices for Implementing Isolator Technology
The pharmaceutical industry can achieve maximum benefits from isolators if the proper best practices are followed when designing, operating and maintaining them as follows:1. Properly Design the Isolator
The overall performance of the isolator system will be affected by the design of the isolator.Design features of the isolator include:
- Clean and smooth surfaces
- Little or no joint/crevice
- Good airflow and air filtration systems
- Ergonomic glove port locations
- Designed for automated product filling operation
Airflow design must ensure that the proper conditions are maintained during the use of the isolator to maintain sterility and control of the environment.
2. Use of Effective Decontamination Procedures
Isolators must be thoroughly decontaminated before each production cycle to eliminate any microorganisms.When decontaminating an isolator, the most widely used method of decontamination is with vaporized hydrogen peroxide (VHP).
VHP is a vaporized form of hydrogen peroxide that is generated and circulated throughout the isolator to kill microorganisms that are located on surfaces.
To validate the decontamination cycle, biological indicators are used to establish that the environment within the isolator is sterile prior to beginning production.
3. Strict Material Transfer Procedures
Any material that is brought into an isolator must be transferred in manner that minimizes the chance of contamination.Ways to transfer materials into an isolator are:
- Rapid Transfer Port (RTP)
- Alpha-Beta Container System
- Air Lock Chamber
4. Correct Glove Integrity Management
Gloves, as an individual component of the isolator system, are one of the most critical aspects of the system as they are likely the weakest point in the isolator barrier.Best Practices for glove integrity management include:
- Glove leak testing on a routine basis
- Inspection of gloves for damage on a routine basis
- Establishing proper glove replacement schedules
5. Environmental Monitoring
While the use of isolators provides a high level of control against contamination, Environmental Monitoring is nevertheless needed to confirm the performance of your system.Generally speaking, the following types of activities will be included in any Environmental Monitoring Program:
- Airborne particulate monitoring
- Microbial sampling
- Surface contamination testing (Active and Passive)
- Differential Pressure Monitoring
Their purpose is to assist you in determining whether or not an isolator environment is within acceptable limits.
All regulatory agencies provide guidelines for the ongoing monitoring of the isolator environment as an element of a total contamination control program.
6. Operator Training and Qualification
Although isolators minimize the amount of human intervention, operators continue to be the most important factor in ensuring the integrity of the system.Personnel must be trained to understand:
- Procedures associated with their e.g. operation of the Isolator
- Principles of Aseptic Technique
- Procedures associated with the transfer of materials
- Emergency Handling Procedures
Training programs should include a mix of theory and practical (hands-on) training. Well-trained employees will contribute towards the continued reliability and success of the Isolator System.
7. Periodic Maintenance and Calibration
Periodic service is required for the isolator system to provide continued proper operation.Service of the isolator system may include:
- Inspection and Replacement of HEPA Filters
- Calibration of Monitoring Instruments
- Service of All Mechanical Components
- Validation of the Decontamination System
8. Validation of Isolator Units
Isolator systems must be validated before they may enter into use.Validation includes:
- Installation Qualification (IQ)
- Operational Qualification (OQ)
- Performance Qualification (PQ)
Regulatory Expectations of Isolator Technology
Current regulations imposed by the pharmaceutical industry place significant emphasis on contamination control and sterile processes.The European Union Good Manufacturing Practice (EU GMP) Annex 1 outlines how isolators can be used as a key technological innovation in the manufacture of sterile medicines using aseptic techniques.
Manufacturers must show their:
1. Robust contamination control strategies
2. Validated decontamination procedures
3. Continuous environmental monitoring
4. Appropriate documentation and employee training
Organizations that can prove their effectiveness in using isolator technology can greatly reduce the level of regulatory concerns and the likelihood of inspection failures.
Future Trends in Isolator Technology
Isolator technology will continue to advance and implemented into more places as pharmaceutical manufacturers evolve and modernize their manufacturing operations.Areas of development and integration will likely include:
1. Robotics filling systems
2. Automated material transfer systems
3. Real time monitoring of the manufacturing environment
4. Digital control of the manufacturing process
All of these advancements will provide increased assurance of sterility and increase manufacturing effectiveness.
Isolator technology will also become increasingly important in the manufacture of sterile pharmaceutical products such as biologicals, vaccines and advanced biologics.
As a key element of contamination prevention/sterility assurance in the production of pharmaceuticals, isolators provide a sealed barrier between the product and its surrounding environment, thereby reducing the potential for microbial contamination significantly.
Further, the appropriate implementation of isolators requires adherence to best practices regarding their design, decontamination processes, glove-maintenance procedures, environmental monitoring methods (for both the isolator and product) and operator training.
By implementing isolators correctly, pharmaceutical companies can expect increased product quality, compliance with regulations and increased patient safety, as well as produce higher-quality sterile pharmaceutical products generally.
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