Risk management and validation of liquid sterilizing filtration

With the promulgation and further implementation of GMP 2010, the risk management and verification of "sterilizing and filtering process" in the production of sterile drugs have drawn great attention from the pharmaceutical industry. The Validation Guide from a provider of sterilizing filters provides criteria for Validation of filters, including test data and standard values performed under laboratory conditions. For example, the time and number of times the filter can withstand sterilization, the maximum temperature and pressure difference tolerated by the filter, and chemical compatibility; Filter effluent and biosafety tests, as well as bacterial challenge and integrity test parameters under these conditions, etc.

3M Standard Validation Guide describes the filter validation project in detail, and ensures the consistency and stability of filter application and performance through strict validation, so as to achieve zero risk of sterilization filtration process. As for the sterilizing filtration in the specific liquid, the solvent, temperature, pressure and filtration time are different from the laboratory conditions, the "re-verification" under the process conditions must be carried out in accordance with the requirements of GMP. The validation content includes but is not limited to, the effect of the liquid on the sterilizing filter: Chemical Compatibility testing and Product-wet Integrity test; Aseptic filter material liquid impact: dissolution content test (Extractable testing) and Adsorption test (Adsorption testing); Influence of drug solution on Bacterial extraction on debacterifying filter: Bacterial viability test and Bacterial challenge testing. Due to the limitation of space, the principle and method of bacterial interception experiment are mainly introduced in this paper, so as to provide technical reference and theoretical basis for bacterial interception experiment.

Sterilization filtration process

The purpose of sterilization filtration is to remove bacteria from the raw pharmaceutical liquid through filtration. If the product cannot be final sterilized, a 0.22mm (smaller or with the same filtering effect) sterilizing filter is required. According to article 91 of The new GMP Appendix 1 "Chapter 13, Filtering non-final Sterilized Products", compared with other sterilization methods, sterilizing filter has the greatest risk. Therefore, it is advisable to install a second sterilized sterilizing filter to filter the liquid once more. FIG. 1 is a schematic diagram of the process flow of sterilizing filtration process. In general, deep filter elements are used for clarification filtration to remove impure substances in the material liquid and reduce the turbidity and biological load of the material liquid. The combination of pre-filtration and sterilizing filtration ensures the efficiency of sterilizing and the stability of filter core filtration. The first requirement of the regulations is to confirm that the filter adopted is "sterilizing level" when the method of sterilizing filtration is adopted. After this requirement is met, other aseptic safeguard measures in the method of sterilizing filtration are meaningful. The definition of whether the filter is a sterilizing level depends on the microbial retention ability of the filter, and the relevant standard method verification and process verification are completed. There is currently a lack of uniform standards for measuring pore size, which are of no practical significance for predicting microbial retention and comparing filters produced by different manufacturers. Therefore, microbial retention capacity is needed to define sterilizing grade filters (2010 edition - GMP Implementation Guide for Sterile Preparations). Thus it can be seen that the bacterial retention test is important for verifying the sterilizing filter element.