Microbial medium simulation filling verification
The main content of Article 47 of the Sterile Appendix is as follows:
1. Validation of aseptic production processes should include a simulated filling test of the medium.
2. The medium should be selected according to the dosage form of the product and the selectivity, clarity, concentration, and suitability for sterilization of the medium.
3. Conventional aseptic production processes should be simulated as much as possible, including all key operations that affect the aseptic properties of the product, as well as various interventions and worst conditions that may occur during production.
4. For the first verification of the simulated filling test of the culture medium, three consecutive qualified tests should be performed in each shift.
5. After major changes to the air purification system, equipment, production process, and personnel, the simulated filling test of the medium should be repeated.
6. The medium simulation filling test should usually be carried out once every six months according to the production process, with at least one batch each time.
7. Specify the number of medium-simulated filling containers.
(This article mainly discusses the requirements of 3, 4, 5, and 6mediumReasonable choice of simulated filling verification time point.)
For aseptic production processes, aseptic process validation (medium simulation filling validation) can only demonstrate the performance of the aseptic process system (man-machine material method ring measurement) at a certain point in time (or medium simulation filling validation), and cannot guarantee that a good level of aseptic assurance will be maintained throughout different time periods.
In other words, the simulated filling verification of the culture medium can only prove the sterility assurance level in this verification stage, which indirectly reflects the sterility assurance ability of the current sterile process system.
Even if all the plant facilities, equipment parts, utensils, containers, and raw and auxiliary materials related to the sterility of sterile products have been effectively sterilized, when all these elements (man-machine material method ring measurement) are arranged and combined according to certain process regulations, there may still be the possibility that sterile conditions are not guaranteed or even the product may be contaminated.
Therefore, aseptic process validation (medium simulation filling validation) is a validation of the level of aseptic assurance throughout the entire aseptic production process.
First, the conventional aseptic production process should be simulated as much as possible, that is, the medium simulation filling verification should be carried out according to the conventional production process as much as possible.
Secondly, it should include all the key operations that affect the sterility of the product, as well as the various interventions and worst conditions that may occur during production.
What are the "worst conditions" in the "conventional aseptic manufacturing process"?
1. People, high-quality personnel who have undergone good training and qualification confirmation should tolerate the production process time and production environment conditions of conventional aseptic production processes, especially the possibility of night shifts, shifts, overtime, delayed shifts... and other production processes. And increase the number of filling personnel to exceed the number of personnel required for normal filling production, including the interference simulation situation of misoperation that is most likely to occur in personnel operation.
2. Machines, equipment, utensils, components... after cleaning, disinfection, sterilization, the storage time in the aseptic process area (preferably the use time) exceeds the control requirements or approaches the time limit of the control requirements. Simulate equipment failure, equipment maintenance, component adjustment, disassembly, replacement. Simulate the more demanding operating conditions of equipment process parameters (low speed, high speed, limit specifications of packaging containers).
3. Material, use growth-promoting medium, aseptic materials and liquid medicine are stored in the storage tank for the longest time before actual filling, aseptic materials need sterilization time interval, aseptic filtration to the maximum possible time required for filling and plugging, and storage time after filling.
4. Method, strictly implement all process regulations, inspection methods, and operating procedures, and select the harsh conditions within the SOP range to prove the sterility guarantee level of the worst conditions in the "simulated conventional aseptic production process".
5. Testing, inspection The testing conditions do not need to be repeated, mainly environmental monitoring, sterility inspection...
6. Ring, the longest time after cleaning, disinfection, and sterilization in a sterile environment (preferably the longest service time for dynamic production), the impact of environmental protection equipment failures and abnormal operations on the environment, such as opening and closing doors, etc. The worst conditions for the effect of initial, medium, and high-efficiency attenuation on the air supply volume. The impact of the maximum number of personnel on the environment.
In summary, we describe the aseptic process verification (medium simulation filling verification) (or re-verification) after the completion of a new project, after major deviation changes, after major maintenance, and after a long period of shutdown, separately from the semi-annual cycle of normal continuous production.
1. For the aseptic process verification (medium simulation filling verification) after the completion of the new project, after the major deviation change, after the major maintenance and replacement, and after the long-term shutdown, if it is equivalent to the first verification, the regulations require that "each shift should be carried out three consecutive qualified tests", I think a more accurate description should be "after the new project is completed, after the major deviation change, after the major maintenance and replacement, after the long-term shutdown" "before the production operation (or process verification) again" "simulation of conventional aseptic production process" "three batches of continuous production" simulation filling test, of course, according to the "importance of deviation change, maintenance and replacement criticality, and the length of shutdown time" for the necessary threat and risk assessment, it is completely possible to stipulate "culture medium simulation filling" Verification "1, 2, 3 times are acceptable.
2. Then for the regulations stipulating that "the simulated filling test of the culture medium should generally be carried out once every six months according to the production process, at least one batch each time", it should be understood that if there is no "major deviation change, major maintenance, long-term shutdown" phenomenon, it should be "carried out once every six months according to the production process, at least one batch each time", and as far as possible, the "worst conditions" simulated filling test of the culture medium should be carried out "between the batches of normal production products".
3. Periodic "medium simulation filling test" worst conditions still have to meet the various conditions mentioned earlier!
Then, the following conditions may not be considered the "worst conditions" in the "conventional aseptic production process":
1. Equipment, utensils, components... Just finished cleaning, disinfection, and sterilization (SIP), and started the simulated filling test of the culture medium. This is not the worst condition, this is the best condition.
2. Sterile materials and liquid medicine are not stored in the storage tank for the maximum time before actual filling, or the simulated filling process does not cover the maximum storage time.
3. The aseptic environment has just been cleaned, disinfected, and sterilized, and the simulated filling test of the medium begins. This is not the worst condition, but the best condition.
4. Also, the HVAC system has just been replaced with filters, and the equipment has just undergone daily maintenance and repairs. In theory, these are not "worst conditions", because these situations are all possible in the "conventional aseptic production process".
However, in many cases, the choice of the time point of the medium simulation filling test is still not considered so much, and it is impossible to take into account the simultaneous occurrence of various worst cases.
What we usually see is that in order to ensure the success of aseptic process verification (medium simulation filling verification), everyone will spare no effort to create "optimal" aseptic production conditions (not the worst conditions at all), without considering the possible "worst conditions"!
