Verification of pharmaceutical aseptic isolation systems

Verification of the isolator system must be completed prior to aseptic operation with a sterile isolator. In order to verify that the isolator and its ancillary equipment can be used for aseptic operation, the verification of the isolator system can be divided into three parts: installation verification, performance verification, and operational verification. The following points should be considered during the validation of the sterile isolator system. At certain stages of the verification process (eg IQ, OQ, PQ), the tasks of the various phases of testing are not determined, and the functions of the isolator should be verified and documented before the isolator is used for the determined detection.

1 , installation confirmation IQ

The IQ phase includes a detailed appearance description of the isolator system, such as isolator size, internal structure, and materials used. With regard to the contact surface and the transfer system, it is necessary to draw a picture clearly and dimension it. Whether the designed isolator meets the specifications for use needs to be verified, such as air replenishment, vacuum, external exhaust, temperature and humidity control, etc. Other equipment used with the isolator system is also described in detail; any design specification revisions should be described in detail. Equipment guides and copies should be catalogued and saved and available to the operator when needed. Once the design specification compliance is verified, all drawings, methods, and equipment drawings are cataloged, saved, and retrievable.

All documents should be reviewed again, easy to verify that reflects the key attributes of installing the system requirements. This establishes a common benchmark that meets the isolator system design specifications and installation requirements. When performing analysis in failure mode or high-risk situations, potential process control issues and equipment problems that may cause the test to fail may be discovered and should be identified and documented in the documentation. If necessary, the system can be modified to reduce the risk of failure to a low point and the control method for the key points is established. The results of the installation confirmation are summarized as an installation confirmation report, and the recommendations include the following documents:

  • Equipment: Equipment should meet design specifications and be listed. IQ report should verify: compliance

The metered equipment is received and installed according to the manufacturer's requirements.

  • Structural material: The structural material of the key parts of the isolator system is tested to meet the design requirements.

The compatibility of the sterilization method for the separator material should be verified.

  • Instrumentation: The instrument is verified to meet its accuracy requirements and is listed.
  • Functional specifications: All operating functions, such as specified in the operating manual, process, instrument chart

The functionality should be verified to be enforceable and meet specifications. All connections to the isolator system and other systems should be reviewed and their function verified to meet design requirements.

  • Filter certification: testing and certification of HEPA filters and microbial retention filters; test knots

A copy of the certificate and certificate should be included in the IQ report. Check the purchase contract and verify that the air filtration system meets the specifications.

  • Computer software: All computer software related to the isolator system lists names, specifications,

Document number. The computer system disk is checked for stickers and stored safely.

2 , operation verification OQ

The OQ phase verifies that the operation of the isolator system is in accordance with the functions of the specification.

  • Operational Performance Check: This test verifies that all alarms and alarms function in accordance with the instructions.

All set points and adjustable parameters of the system should be verified to meet the specified requirements.

  • Isolator integrity testing: Isolators should maintain integrity under normal operating conditions. In the interval

A leak test can prove that the isolator complies with the manufacturer's instructions and is safe before it is sterilized with a chemical sterilant. In order to avoid external pollution, the isolator is usually operated at a positive pressure of 20-80 Pa. If the isolator system requires a constant positive pressure, it must be verified during the verification that the pressure setting during operation can be maintained and controlled.

  • Sterilization cycle validation: Perform a sterile cycle to verify that the actual value of the operation is consistent with the individual steps of the sterility period and the set values. Several different sterilization methods can be used to remove microorganisms from the isolator and auxiliary system. Chemical reagents that can be used for isolator sterilization include peracetic acid, chlorine dioxide, ozone, and hydrogen peroxide. Different reagents have different exposure conditions and process control. The selected sterilization method should meet the manufacturer's operational requirements, and it is critical to describe these methods in the practical procedures. Control of temperature and humidity in the isolator room is critical when using hydrogen peroxide vapor sterilization. The temperature inside the isolator is also important, especially in the use of hydrogen peroxide vapor sterilization. The key is to maintain the concentration of hydrogen peroxide and avoid condensation points below hydrogen peroxide. Some chemical reagents, such as chlorine dioxide and ozone, require an increase in the humidity of the isolator prior to sterilization. In OQ, the ability to control humidity must be verified if a sterilization method with high humidity requirements is used.

The concentration and concentration profile of the sterilant is also important. When the sterilant is present in a gaseous or vapor state, its concentration can be detected by chemical indicators, spectroscopic methods or electrodes. The distribution of sterilant can also be measured using chemical indicators (note: chemical indicators can only provide qualitative rather than quantitative information).

When sterilizing with a sterilizing agent in a gaseous or steam state, it is required to use a fan inside the isolator to evenly distribute the sterilizing agent. The position and orientation of the fan can be adjusted to ensure proper airflow distribution. Since the shelf, equipment, gloves, sleeves and skirts can affect the airflow distribution mode, the airflow distribution under the full load state of the isolator must be detected, and the placement of the articles is described in detail and recorded as a file. Smaller transfer isolators are sometimes used as portable surface sterilization units that chemically sterilize the items and utensils in the portable surface isolator prior to entering the isolator through the transfer chamber. In the OQ process, the placement of items and utensils in the portable surface sterilizer should be developed, and the placement map should be reviewed and recorded on the OQ. (Note: Chemical sterilants act on the surface of the equipment, so some covered equipment surfaces can leave microorganisms and survive). After the bactericidal action time is reached, the sterilizing agent can be removed from the separator using fresh air or other fresh air treated by the sterilization device. The gas is vented to the atmosphere through an venting opening through an open channel; or through a closed passage, a sterilizing device is used in the channel to remove and eliminate the sterilant. If an open exhaust duct is used, the airflow and safety of the exhaust system should be checked.

  • Study of the sterilization cycle: After the completion of OQ, conduct a study of the sterilization cycle to establish the day

The parameters necessary for the sterilization process are often sterilized. Some methods commonly used in the industry for aseptic process validation are feasible, such as bioburden and overkill. The sterilization process performs a biological indicator challenge test. The number of spores and heat resistance of biological indicators are known. In any case, the true D value of the biological indicator should be obtained; (see Biological Indicators - Heat Resistance Test "55"); obtaining D values ​​from biological indicator suppliers is acceptable. If it is not possible to obtain an accurate D value and it is not possible to prove the effectiveness of the sterilant concentration, the entire cycle (cycle) can be confirmed using a half cycle (cycle) method.

3 , performance verification PQ

PQ is to verify that the function of the isolator system is in accordance with the operator's requirements. After the PQ process is complete, sterilization cycles are suitable, outlet sterilizing agent is suitable to be detected, the data of all the PQ process should be statistics, analysis and archiving.

  • Cleaning confirmation: Under normal circumstances, cleaning is not critical for some aseptic operations.

However, the residual product may have an impact on the inspection. The residue of the bactericidal product has a particularly significant effect on the test results. When detecting low levels of contamination, these residual substances will have an impact on the test. Since the powder is easily diffused, the influence of the residue of the sterilizing powder product on the test result is important. For sterility test isolator systems and operator requirements, this level of cleaning is not as visible as visible contamination. The materials used in cleaning methods, cycles, equipment, and cleaning isolators are recorded in documents.

  • Aseptic verification: the inner surface of the isolator, the equipment inside the isolator, and the various materials that are fed into the isolator

Microorganisms should be removed. Sterilization of the isolator surface, sterility testing equipment, sterilization of the test article, and product contact sites or contact points of the product drug components are different. Isolator sterilization can be evaluated using an over-sterilized log reduction. If the sterilization cycle is exceeded, the sterility assurance level is no longer determined. After the isolator sterilization operation is completed, through the maintenance of the air filtration system, the adoption of good article transfer technology, and more importantly, the integrity of the aseptic isolator gloves is maintained, and the sterility of the isolator is ensured.

It can be confirmed by the negative fraction method or the overkill method that the sterilization method for the isolator, test article, and sterilizing inspection equipment can reduce the number of microorganisms of a suitable, highly resistant biological indicator by 6 logs. drop. (Look at the biological indicator "1035" for sterilization). The overkill assay is applicable to biological indicators of 104 spores per unit, while the negative fraction method is applicable to biological indicators with a number of spores greater than or equal to 105 per unit . Testing with a sufficient number of biological indicators can statistically prove that the sterilization effect is reproducible and that the distribution of the sterilizing agent is suitable. When the equipment and items in the isolator are fully loaded, more indicators are required for testing. Therefore, when there is no one or more sufficient amount of sensors to measure the concentration of the biocide, it is conceivable to increase the placement of the bioindicator. In three consecutive sterilization tests, the bactericidal power of six log drops proved to be sterilizable. The operator establishes a cycle in which the isolator is resterilized. This cycle can be a few days or a few weeks, based on the ability to maintain aseptic (see the internal environment of the isolator aseptically maintained)

  • Sterile maintenance of the internal environment of the isolator: the isolator system remains within a sterile cycle

The ability of the environment to be sterile must be verified. Microorganisms in the event of a malfunction of the isolator system or accidental contamination inside the isolator must be detected. Microbiological testing typically includes a routine sampling procedure that can include, for example, the first day after sterilization and the day after the sterile maintenance period. The medium placed in the isolator was shown to be sterile. The inside of the isolator can be monitored using a flat contact double disc or a cotton swab. However, since the residual medium causes the isolator to be contaminated, it is good to test after the test is completed. If the medium remains in the test, carefully clean it from the inside of the isolator. Air sampling and media detection dual discs can be used, but they are not very sensitive when detecting very low levels of contamination inside the isolator. The path that zui may contaminate is the process of testing the utensils and samples into the isolator. It is critical to verify that all items entering the interior of the isolator are sterile, and the gasket should be inspected regularly to ensure its integrity and to prevent microbial entry. Gloves and jumpsuits are another source of possible contamination. Because the operator wears gloves to treat the sterility test items, the gloves should be specially concerned. It is difficult to check the tiny damage on the gloves. When the gloves are used, the slight damage on the gloves can be reflected when the clothes are used. Note: The method of detecting finger colonies by medium contact method is insufficient in detecting low level of contamination. Soak the glove with 0.1% peptone solution, filter the solution, and then place the filter on the growth medium plate. This method can detect leaks that are not detected by other methods.)

Continuous dust particle detection inside the isolator is ideal for rapid detection of filter leaks. The second option is to use a portable dust particle detector for cycle detection. Dust particle detection sampling does not pose a risk to the aseptic environment inside the isolator.

  • Interpretation of sterility test results: If the person does not have direct contact with the work area, the verified transmission pass

The road is not broken, the microbes inside the isolator are removed and there is a high level of sterility assurance, then false positives in the sterility test are difficult to occur. However, the isolator is a mechanical device and good aseptic technique is still necessary. Only when the "sterility test and investigation "71" is fully complied with can the conclusion that the positive result be invalidated.

  • Training and safety: because the sterility inspection operation is carried out in the clean room, the operator specializes in the isolator

The program is trained. All training records and assessments of operator operations should have a separate record and be documented. It is essential to perform the necessary safety training for all personnel who operate or maintain the isolator. The safety of personnel using fungicides must be evaluated. Safety data for raw materials using direct biocides or a similar safety data file is necessary. Precautions for storage and safety should be in accordance with regulations. The isolator and all connected channel safety checks should be performed before the isolator is used.

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