BFS uses sterilization filtration technology to sterilize, and the products are not terminally sterilized under normal conditions. Compared with other sterilization methods, the risk of sterilization filtration is the greatest, and the sterilization filter is the only measure for product sterilization in BFS. The correct selection and rational use of sterilization filters is an important part of the BFS aseptic process.
GMP has formulated relatively strict and specific specifications for the filtration and sterilization of non-terminally sterilized products and the selection and use of filtration: GMP Appendix I Article 75, the filtration and sterilization of non-terminally sterilized products shall meet the following requirements:
( 1) Products that can be terminally sterilized shall not be sterilized by filtration instead of sterilization. If the drug cannot be sterilized in its final packaging container, a 0.22 m (smaller or equal filtration efficiency) sterilizing filter can be used to filter the drug solution into the pre-sterilized container. Since the sterilization filter cannot remove all viruses or mycoplasma, heat treatment can be used to make up for the insufficiency of sterilization filtration.
(2) Measures should be taken to reduce the risk of filtration and sterilization. It is advisable to install a second sterile sterilization filter to filter the liquid again, and the final sterilization filter should be as close as possible to the filling point.
(3) After the sterilization filter is used, its integrity must be checked and recorded immediately by appropriate methods. Commonly used methods are bubble point test, diffusion flow test or pressure retention test.
(4) The filtration and sterilization process should be verified. In the verification, the time required to filter a certain amount of liquid medicine and the pressure on both sides of the filter should be determined. Any obvious deviation from normal time or pressure should be recorded and investigated, and the investigation results should be included in batch records.
(5) The use time limit of sterilizing filters of the same specification and model should be verified, and generally should not exceed 1 working day.
The FDA has also made clear requirements for the use and verification of sterile filters in the "Guidelines for Quality Management of Sterile Preparations Production": "No matter what filter is used or used in combination, verification should include simulating the worst production conditions of the material to be filtered. The microbiological challenge and the results of the integrity test of the filter used for this test. After correctly verifying the filtration operation for a given product, process, and filtration, it is important to ensure that the same filter is used in the production process. After a single batch is processed, Sterilized filters should be discarded as usual. However, when it can be proved that repeated use is reasonable, sterile filter verification should include the maximum number of batches. The integrity test of the filter can be carried out before treatment and should be carried out as usual after treatment."
The above specifications fully illustrate the importance of sterilization filters in aseptic processes. Sterilization filtration technology is a complex and comprehensive technology. It is by no means as simple as installing a 0.22 m filter to sterilize. Improper selection and use of the sterilization filter will cause microbial contamination of the product, resulting in product batch rejection or major phytotoxicity. Due to the particularity of the process, special attention should be paid to product contamination caused by endotoxin in the BFS process. Aseptic plastic packaging
(1) Bacterial endotoxin has strong heat resistance, 121℃/30 mm has no effect, 150℃ will not be lysed for several hours, 180℃/4 h, 250℃/45 mm can be completely destroyed. The control of microorganisms is the main content of the aseptic process. Terminal sterilization and heat treatment must not be regarded as reliable means to eliminate endotoxin pollution. The entire process of the process must be controlled to prevent product endotoxin from exceeding the standard.
(2) Bacterial endotoxin is small in size and can enter the filtrate through a sterilizing filter. The sterilization filter can only block bacteria, but not all endotoxins. Since the sterilization filter cannot achieve tangential flow, it is itself a pollution point that accumulates microorganisms. The carrying capacity of each sterilization filter has a certain limit. As the filtering capacity increases, the accumulation layer upstream of the filter As it increases, the risk of microorganisms passing through the filter increases. The use of sterilizing filters for overtime and overloading will increase the bacterial endotoxin content in the filtrate.
(3) Bacterial endotoxin is soluble in water and does not evaporate. In BFSI art, after system CII)/SII), flush the system with hot water for injection, and then dry it with clean compressed gas. Maximize the elimination of bacterial endotoxins in the system.
The sterilizing filter used in BFS cannot be selected simply by the filter pore size. The same 0.22 m filter may not be able to sterilize. Be sure to choose a sterile-grade filter and verify the sterilization effect. Similarly, the integrity test of the filter can only prove that the filter is intact, but cannot prove the sterilization effect of the filter. The process conditions such as temperature, pressure, and flow rate of the sterilization filter have an impact on the sterilization effect, so the process conditions of the sterilization filtration must be verified.
The SIP and integrity inspection of the sterilization filtration system is a standardized and highly procedural process that starts from the design. It is recommended to take a look at the "Procedures for Online Sterilization and Integrity Testing of Sterile Filtration Systems" by Millipore. It will be helpful for correct online sterilization and integrity testing of sterile filters.