For terminally sterilized products, the number of filter stages (i.e., the number of filters in series) should be determined based on factors such as the pre-filtration microbial contamination level and the impurity content of the feed solution. In most cases, a single-stage filtration is sufficient to meet the microbial contamination requirements of the feed solution prior to moist-heat sterilization. For high-risk, non-terminally sterilized products, a single-stage filtration can typically provide the required sterility assurance; however, in many instances, companies may opt for a dual-stage filtration configuration following a risk assessment to reduce the risk of filtration failure.
Generally, filtration utilizing two or more filters with identical or decreasing pore sizes is collectively referred to as sequential filtration. In a sequential filtration system, because the primary sterilizing-grade filter has the potential to fail, a second sterilizing-grade filter may be added upstream of the final sterilizing filter to prevent product loss. This configuration is termed a redundant filtration system, provided that sterility is maintained between the two filters and the microbial contamination level of the feed solution upstream of the first filter is generally controlled to ≤10 CFU/100 mL.
In a redundant filtration system, the filter located closest to the filling point is referred to as the primary filter, while the filter positioned upstream is referred to as the redundant filter.
It should be noted that a redundant filtration system must be distinguished from the following scenario: When bacterial breakthrough through a sterilizing-grade filter is suspected, two or more filters may also be connected in series. In this case, the two or more filters are effectively functioning as a single sterilizing filtration unit. Under such process conditions, all filters must meet the acceptance criteria for integrity testing.
Regulatory Requirements for Redundant Filtration
China
Measures should be taken to minimize the risks associated with sterilization by filtration. It is recommended to install a second sterilized sterilizing-grade filter to filter the solution again. The final sterilizing-grade filter should be positioned as close to the filling point as possible.
— Good Manufacturing Practice for Pharmaceutical Products (2010 Revision), Annex: Sterile Medicinal Products
United States
Use of redundant sterilizing filters should be considered in many cases. Whatever filter or combination of filters is used, validation should include microbiological challenges to simulate worst-case production conditions for the material to be filtered and integrity test results of the filters used for the study.
— FDA cGMP Sterile Drug Products Produced by Aseptic Processing 2004
European Union
Due to the potential additional risks of the filtration method as compared with other sterilization processes, a second filtration via a further sterilised micro-organism retaining filter, immediately prior to filling, may be advisable. The final sterile filtration should be carried out as close as possible to the filling point.
— EU GMP Annex 1 Manufacture of Sterile Medicinal Products 2008