A Risk-based Approach to Setting Sterile Filtration Bioburden Limits

Microbial control during the drug substance and drug product manufacturing process is critical for ensuring product quality and safety. For sterile biological drug products (finished dosage forms) typically manufactured by sterile filtration followed by aseptic processing, control of the microbial load at the sterile filtration step is an important component of the overall microbial control strategy. Both FDA and EMA regulatory guidelines stipulate that a maximum acceptable bioburden level, which is referred to as a pre-filtration bioburden level in this paper, should be stated at the point immediately prior to the sterile filtration step. The EMA guideline further states that a bioburden limit of no more than 10 colony-forming units (CFU) per 100 mL will be considered acceptable in most situations. The EMA guideline also states that a pre-filtration sample volume of less than 100 mL may be tested if justified. This paper introduces a risk-based method to establish pre-filtration bioburden acceptance levels and alternative test volumes. The relationship between bioburden risk, pre-filtration bioburden test limits, and sterile filtration process parameters, such as filtration volume, filter surface area, and microbial retention capacity of the sterilizing filter, was statistically determined. Taking into account the batch filtration volume, it is shown that pre-filtration bioburden test volumes and acceptance limits other than 10 CFU/100 mL may be justified, without compromise to sterility assurance. LAY ABSTRACT: In the manufacturing of sterile medicinal products, good manufacturing practice requires that bioburden be monitored before the final sterilization filtration step. High bioburden increases the challenge to the sterilizing filter and may also lead to other quality issues. Therefore a pre-filtration bioburden limit should be established. This paper introduces a risk-based method to establish such limit which may be different from what is recommended in regulatory guidelines.