Isolators are crucial for maintaining the sterility of pharmaceutical products, particularly in the production of biologics, vaccines, and injectable drugs, where contamination could compromise product quality and patient safety. Prior to using an isolator, its validation process must strictly adhere to the international regulations and guidelines to ensure stable equipment performance and a reliable sterile environment.
According to USP<1208> “STERILITY TESTING—VALIDATION OF ISOLATOR SYSTEMS,” it is emphasized that the isolator system must be validated before being used as part of the batch release procedure for sterility testing. To verify that the isolator system and all related equipment are suitable for sterility testing, the validation study is conducted in three phases: Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ).
The initial validation of an aseptic isolation system typically includes stages such as Design Qualification (DQ), Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ). The scope and extent of the validation plan should be based on a scientific risk assessment.
In DQ, the focus should be on the critical performance of the isolator, ensuring it meets general regulatory requirements and aligns with actual user needs. Firstly, based on the User Requirements Specification (URS), confirm the overall layout, workflow, and primary functions of the isolation system to ensure that all designs are convenient and efficient in practical use. Secondly, evaluate the compatibility of material and structural design with sterilization processes to effectively prevent incomplete sterilization and corrosion by sterilizing agents. Finally, confirm that alarm functions operate normally and that software features are reliable and consistent, ensuring the system operates safely and stably.
The model simulation test of the isolation system is also an important part of DQ, requiring joint participation from both the production and quality departments. This test must clearly define the design of the production process, materials used in the process, consumables, etc., while simulating the entire production operation to ensure that all design details of the isolation system meet the user’s overall process requirements.
Before starting the aseptic isolation validation, it is necessary to confirm the installation situation on site with the customer, such as whether the air conditioning system and exhaust system are independent, public medium confirmation, inoculation environment confirmation, and confirmation of various testing instruments. At the same time, confirm that the equipment and its supporting components are consistent with the contract to eliminate risks.
The operational qualification mainly includes the following contents:
Access and Permission Management: Through practical operation, it is verified that only authorized operators can log in to the system and run the equipment through user name and password. At the same time, the permission setting of different levels of users is checked to ensure that the three-level access permission requirements are met.
Audit Trail and Data Recording : confirm that the system can completely and accurately record the operations of operators and form log records to ensure that the operation process is traceable.
Parameter Test: Test the set parameters of the isolator to observe whether the isolator can respond normally and make accurate adjustment.
Interlock and Alarm Function: By manually operating to simultaneously open the transfer chamber door and the transfer chamber passageway door, as well as the operation chamber door and the operation chamber passageway door, check whether the interlock mechanism between doors is effective; by changing parameters such as the isolator’s pressure, wind speed, and VHP concentration, observe whether it can promptly and accurately trigger an alarm signal, ensuring that the system can timely detect abnormal conditions.
HEPA Filter Testing: The PAO test is used to test the integrity of high efficiency filter, and the leakage rate should be less than 0.01% when the upstream concentration is between 10 ug/L to 80 ug/L.
Isolator Tightness Test: Activate the isolator pressure decay test program and record the initial and final temperatures, as well as the initial pressure (it is recommended that the initial test pressure be no less than twice the normal operating pressure) and the final pressure. Calculate the hourly volume leakage rate (Q/V), which must be less than 0.5%. Additionally, the ambient temperature fluctuation during each test should not exceed ±0.5°C.
Glove Integrity Test: Use the glove integrity tester to test the integrity of each glove.
Particle Count Test: Using a particle counter, perform sampling inside the isolator under normal airflow conditions. The sampling volume per point should be 1000L, typically at 2 sampling points. The acceptance criteria are: particles ≥ 0.5 μm: ≤ 3520 particles/m³; Particles ≤ 5 μm: ≤ 20 particles/m³. These limits are used to assess the cleanliness level within the chamber.
Airflow Pattern Test: Using a pure water atomizer, perform the test under both static and dynamic conditions to verify the internal airflow pattern of the isolator system. This test is primarily applicable to laminar airflow isolators.
Pressure Differential Verification: It is necessary to verify the isolator’s ability to maintain a positive pressure differential under both static and dynamic conditions.
Temperature, Humidity, Pressure and Other Parameters: Start automatic operation, observe whether the temperature, humidity, pressure and other parameters in each stage are normal.
Dehumidification Performance Validation: Ensure that the internal humidity in the isolator is within the set range, and see whether the humidity can be kept below 40%.
Sterilization Performance Validation: Place chemical and biological indicators at designated test points inside the isolator. Initiate the sterilization program under full load conditions. Observe the color changes of the chemical indicators to assess the uniform distribution of vaporized hydrogen peroxide. Confirm that the colors of all chemical indicators are basically consistent after they change. After completing the sterilization program, collect the biological indicators and inoculate them into the medium in a biosafety cabinet. Cultivate them in a biochemical incubator at 55-60℃, observe the color changes, and confirm their sterilization performance.
Residual Effect after Sterilization Validation: After the ventilation procedure is completed, a low -concentration hydrogen peroxide tester is used to test the concentration in the isolator to confirm that the concentration is below 1ppm and within the safe exposure limit.
Through the above rigorous and compliant validation procedures, the aseptic isolator system ensures stability and reliability during aseptic pharmaceutical testing. The Isolator validation plays a vital role in the safe production and quality control of pharmaceuticals, driving the development of the aseptic drug industry and safeguarding public medication safety.
Tailin: Over 30 years experience in aseptic manufacturing
