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Q1. What precautions should be taken for the cleaning method of the interior of the isolator (non-product contact surfaces) before decontamination?
The development of cleaning methods should be based on process and product requirements, the design of the isolator's interior, and the surfaces that need to be cleaned. Aspects that may need to be considered include:
1. Dedicated or multi-product isolators
2. The location of the surfaces to be cleaned within the isolator
3. The complexity and variability of the cleaning method
4. The activities carried out at designated locations within the isolator
5. The exposure of the product to potentially contaminated environments or surfaces
6. The toxicity and potency of the previous product
7. The sensitivity of the next product to the previous product
8. The difficulty of removing product residues and foreign matter from the isolator surfaces
9. The ability to visually or analytically detect the presence of product residues or foreign matter
10. The diversity of products handled or filled within the isolator
11. The impact of cleaning agent residues on the product or the interior of the isolator
12. The quality and cleanability of the material surfaces
13. The impact of product or foreign matter residues (including cleaning agent residues) on the decontamination process
14. Other controls implemented for the risk of residues and foreign matter contamination from the previous product.
The design of the isolation unit should be suitable for cleaning and disinfection procedures. Considerations in the design may include the following factors:
1. The construction materials inside the isolation unit should be cleanable and resistant to cleaning and disinfectant chemicals, as well as handling and processing.
2. The surfaces should be smooth and free of holes.
3. The surfaces should have proper drainage and should not accumulate water.
4. There should be no excessive or deep seams near the exposed products or product contact surfaces, as these may hide product residues or foreign substances.
5. Key spaces (areas, surfaces, or environments that may cause contamination risks to the product or product contact surfaces if contaminated by microorganisms or chemicals) should be able to undergo cleaning procedures.
6. The areas within the isolation unit where products are exposed or where foreign substances are generated or hidden should be restricted.
Q2. What is the decontamination method inside the isolator?
The decontamination agents are usually dispersed in two basic states: gas and vapor. The vapor state of VHP can be used for decontamination of pharmaceutical isolators. VHP disinfection is a very effective and complex process because of its dual nature (usually presenting a liquid phase and vapor (gas) phase in the chamber). The biphasic equilibrium is extremely sensitive to minor differences in temperature, VHP, and water concentration, so it is almost impossible to know the exact physical parameters of the process at any given time and location. Therefore, there are no industry standards specifying the process parameters required for the mechanical design of the vapor generation or distribution system. As a result, the commercial systems used in the entire industry are diverse, with different designs and process descriptions.
Regardless of which system is used, the basic principle of this process is the same. VHP is distributed in the decontamination chamber until there is sufficient VHP deposition (i.e., adsorption/condensation) on the decontamination surface to achieve the desired decontamination effect. The generally accepted understanding is that increasing the saturation of the VHP environment can improve efficiency because there is a large amount of liquid VHP deposited on the surface. However, excessive VHP deposition may lead to prolonged aeration and increase the issues of material compatibility and VHP intrusion. Depending on the concentration of VHP and water, pressure and temperature, systems can be used that are either below or above saturation (i.e., indicating that the temperature is lower or higher than the dew point of the VHP-water mixture). Two main methods used industrially to generate VHP vapor are the hot plate evaporation method and the atomization method.
Q3. During the development and verification process of the decontamination cycle, what situations and configurations should be taken into account?
The conditions and configurations that should be considered during the development and validation of the decontamination cycle may include:
1. Environmental conditions (temperature, humidity range and variations)
2. Air velocity of fans and blowers (fixed value or variable) or isolators without fans
3. Concentration of decontaminants, dosage levels and usage rates
4. Minimum and maximum loading
5. Loading position and direction
6. Characteristics of the loading material
7. Compatibility of materials with decontaminants or the process
8. Substances or materials on the surface that may have a negative impact on the decontamination process or result
9. Exposure of the material and loading surface
10. Stacking or placement of materials
11. Wrapping or folding packaging materials to prevent surface decontamination
The purpose of developing and validating the decontamination cycle is to ensure that the decontamination process is stable and can provide the required log reduction of spores under the conditions that pose the greatest challenge to the inactivation or decontamination distribution of biological indicators (BI), while maintaining within the planned operating conditions. The isolator environment and loading characteristics play a crucial role in the effectiveness of the decontamination cycle.
Q4. How does the oil-based integrity test reagent for the HEPA filter affect the decontamination cycle of the isolator?
If an oil-based material is used for the filter test, it is necessary to ensure that there is no residue of any material on the filter, as it may interact with the VHP in the system and have a negative impact on the effectiveness of the decontamination process. The risk assessment of the tested system should include this consideration, and the time for the high-efficiency filter test is preferably carried out before the reconfirmation cycle.
Q5. During the confirmation process of the decontamination cycle, does each type of loading need to be confirmed?
The most conservative approach is to confirm each production cycle or loading as a separate activity. Conducting tests on each loading mode can provide data to prove that each method is controlled and the products are produced as expected. The reconfirmation process should be consistent with the original verification strategy. If this method includes confirming each loading within the isolator, the reconfirmation should imitate this method. An alternative revalidation strategy can be selected, such as alternating loading, so that all loading can be confirmed within a certain period of time. This method requires data collection and support based on risk principles. Only by ensuring the control of the process through data and strong monitoring procedures can it be achieved. In appropriate assessment situations, a grouping strategy (such as minimum and maximum loading) can also be adopted.
Q6. For cyclic development and cyclic verification, which type of biological indicator should be used?
1. The biological indicator should be a qualified organism (for example, Thermophilus Facultative Spore-forming Bacillus), with a spore count/carrier of no less than 10^6.
2. The microbial count recovery rate of the incoming biological indicator control should be within the range of 50% to 300%.
3. The biological indicator should be treated and stored according to the temperature and humidity conditions specified by the supplier before use.
4. The carrier should be made of a material commonly used in isolators, usually stainless steel. Based on risk assessment, if the material of these carriers significantly differs from stainless steel and may affect the decontamination cycle, additional research may be required. The spores of the biological indicator should be directly inoculated onto these samples made of different materials.
5. The biological indicator should be packaged in a material that is permeable to H2O2 and easy to handle in the laboratory.
6. The D value of the biological indicator should be known and should be comparable between one verification and the next, so as to make the verification comparable and to observe any changes in the VHP decontamination effect.
7. There should be different methods to determine the D value. Firstly, the D value should be tested in the established isolator system, not just for a certain batch of the biological indicator. The test results may depend on the system used for the test and the testing method. The D value can be defined as the time required to kill 90% of the bacterial count and decrease by 1 log value. In an unoccupied position, a fractional method can be used for a preliminary check.
8. The D value is usually determined at the regular position of the isolator, rather than on inaccessible surfaces. The placement layout of the biological indicator should enable the air to reach all sides to achieve the best absorption effect. In larger isolator systems, due to the significant potential differences in surfaces and air flow, the determination of the D value is more difficult.
9. Using the D value of the biological indicator batch provided by the supplier instead of confirming it in one's own isolator system before use poses a significant risk. The D value depends on the saturation of hydrogen peroxide in the air and the consistency of the cycle over time. If the hydrogen peroxide level does not change and there is no saturated VHP in the air, the calculated D value will have a significant difference.
Q7. During the development and validation process of the VHP decontamination cycle, how should multiple biological indicators be used and evaluated?
The investigation should take into account situations that may have adverse effects on the decontamination cycle, such as:
1. Confirmation of microbial growth of the indicator
2. Batch-to-batch variability of the biological indicator
3. D value, bacterial count and antibacterial property of the biological indicator
4. Preparation and handling of the biological indicator
5. Spore clumping or blockage (poor spores) of the biological indicator
6. Review of the processing, cultivation and recovery methods
7. Placement layout and position of the biological indicator
8. Insufficient exposure of the decontaminant
9. Parameters and concentrations of the decontamination cycle
10. Changes in temperature or humidity
11. Conditions, biological load and cleanliness inside the isolator
12. Effectiveness of the decontaminant storage
13. Monitoring results of chemical indicators
