Medium simulation filling test for sterility
The most useful methods for evaluating the operability of an aseptic process are process simulation tests and medium simulation filling tests. In the past, the medium simulation filling test only focused on the aseptic filling stage, and did not evaluate the aseptic operation process that may affect the quality of the aseptic final product. Therefore, the main purpose of the current medium simulation filling test is to evaluate the ability to produce aseptic products under the established aseptic production environment and process control conditions, demonstrate the feasibility of the specified aseptic process design and changes, demonstrate the feasibility of relevant operations in the aseptic process, evaluate the operation level of aseptic process personnel, identify potential microbial contamination factors in the aseptic process, and comply with current GMP requirements.
mediumFilling simulation should simulate as much as possible the contact between the surface of the product itself and the equipment, the container sealing system, key links and key process operations, depending on the type of production process of the product.
The simulated filling operation steps of the aseptic production process, because the aseptic production process of lyophilized powder injection is a relatively complete aseptic production process, the following is an example to introduce the concerns of the simulated filling test of the medium.
Media simulation filling test should mainly focus on the following but not all, the status of the production line, the frequency of the test, the type of medium, the filling duration, the number of filling, the volume of the container (vials), the speed of the production line, the filling volume, the challenge test, culture, results and ratings, clearance and cleaning, the valid period in the simulation filling, etc.
The status of the production line and the frequency of the test, during the confirmation of the new production line, at least three consecutive tests to meet the requirements are performed per shift; the continuous production line is repeated twice a year according to each shift and process; the production line is decommissioned before a aseptic filling; the following changes need to be re-verified, the production line has undergone major changes, the equipment directly in contact with the product, the container has changed, and the main production personnel involved in the production have changed.
The type of medium should be based on the dosage form of the product, the selected medium should be able to support a wider range of microorganisms, preferably in line with the internal species; the clarity should be easy to observe the turbidity, and the concentration should follow the concentration recommended by the supplier. If a filter is used in the aseptic production process, the medium should be able to filter through the same level of filter in the production process. If dilution filtration is required, the medium concentration should provide verification of microbial growth ability; at the same time, the medium liquid should be able to cover all production equipment.
Filling duration For initial verification, the medium filling experiment should be arranged at different times within a week; for re-verification, it can be selected to be carried out at the end of a week or under other worst conditions; the filling time should cover the actual production shift; The duration should be determined according to the time required for setting up the operation and intervention activities, as well as the actual aseptic operation time; when simulating filling in large quantities, some blank samples (empty or filled) can be used to maintain the dynamic environment of the simulation experiment; The duration of manual filling or sealing operation should not be shorter than the entire process of the actual production process; The continuous test should cover the lyophilization process, where the simulated unsealed container is placed in a partially vacuumed cavity, taking care to avoid the steps that cause the medium to boil, freeze or lyophilize, and ensure that the medium remains in an aerobic state To reduce the inhibition of microorganisms.
The factors affecting the quantity of filling are the actual batch, the type of intervention operation, the quantity, the time, and the type of open/isolated plant, which should be sufficient to simulate commercial production conditions and evaluate the possibility of contamination in commercial batches. Small batches should be at least equal to the number of products. The guidelines do not specify a maximum batch (≥ 5000 pieces), and generally acceptable starting points are 5,000 to 10,000 pieces.
The volume of the container (vials) should take into account the extreme size of the filling container (maximum container and minimum container). In the initial test, the second largest container can be used, and the third smallest container can be used. The largest container (usually the slowest filling speed due to the large filling volume), usually has a large opening, so the latent risk of microbial invasion in the environment is large; The smallest container (usually the fastest filling speed due to the small filling volume) reflects the greatest difficulty in operation; Small containers are prone to breakage, poor stability, and are more likely to break and clog in the equipment; Containers of other sizes should also be included in the verification plan in the daily evaluation; Amber bottles should not be used, but transparent bottles should be used so that the growth of microorganisms can be visually checked.
The production line speed should include the filling speed range of the actual production process. During the first verification of the filling line, the lowest speed can be selected for one time, and the highest speed can be selected for the other two times. The normal medium simulation filling should include the maximum and minimum production speeds.
The filling volume does not need to be the same as the conventional filling volume in reality; but there should be enough filling volume to have sufficient contact with the surface of the seal of the container and to visually detect the growth of microorganisms after culture.
The challenging test is based on daily production disturbances, such as work shift rotation, monitoring activities, filling line assembly, weighing adjustment, adding stoppers, handling bottle pouring, sampling, environmental monitoring, etc.; non-daily disturbances such as equipment failure, filling line blockage, stopper blockage, track adjustment, removal/replacement of damaged parts, etc.
When culturing, the container must be turned upside down or rotated to ensure that all surfaces, including the inner surface of the container, are in complete contact with the culture medium; the container filled with the culture medium is visually inspected for microbial growth after culturing; the integrity of the contaminated ampoule should be checked by approved procedures for evidence of damage to the container or seal; visual inspection should be performed by qualified personnel
The range of results should comply with relevant regulatory requirements; The evaluation of results should identify all contaminated microorganisms received at least to genus and preferably to species when the source of contamination can be identified, regardless of whether the warning line or action limit is exceeded; For all test sizes, intermittent incidents of microbial contamination may suggest the presence of low-level contamination that should be investigated. Investigation of serious failures should include sterility assurance effects on batches produced since the last successful medium filling.
Clearance and cleaning should take appropriate measures after the completion of the medium filling to ensure that the medium filling verification does not pose a risk of contamination to subsequent production; the medium has appropriate treatment methods.
The medium filling implementation period should pay attention to the maximum time that the filling or sub-filling equipment, components, storage tanks, sterile materials, liquid or powder can be placed before actual filling, and the filling equipment, filling components, storage tanks, and sterile materials with the longest allowable storage time should be used to participate in the medium filling; the medium stored in the storage tank after aseptic filtration should be filled after the maximum storage time of the product at the time of actual production.
Medium simulation filling verification is only the performance of the aseptic process system at a certain point in time, including the environment, equipment, procedures and personnel, and cannot guarantee that the same level of microbial assurance can be exhibited in different time periods. Therefore, in order to ensure the production of aseptic products, it is possible to maintain the level of aseptic processes by controlling and verifying all relevant processes, such as environmental monitoring, personnel confirmation and cleaning and sterilization verification. Therefore, it is also very important to verify the relevant cleaning and sterilization processes separately to ensure the quality of the products produced by aseptic processes.
Author: Yin Zhiyong, Source: Dandelion
