Risk-based approach to setting sterile filtration microbial bioburden limits – Focus on biotech-derived products

Abstract

Holistic concepts should be applied that reduce risks prior to final bioburden testing and sterile filtration, based on enhanced process and product attribute understanding, which could be key to successful bioburden risk management.Key findings of this paper include:oBioburden control and monitoring prior to filter sterilization is necessary for any thermolabile parenteral drug product that cannot be terminally sterilized in the final container. The bioburden limit applied prior to filter sterilization, as recommended in the 2019 EMA guideline “The sterilisation of the medicinal product, active substance, excipient and primary container”, can be interpreted as a specification (i.e., pass/fail criterion) regardless of the sterilizing filter capacity and risk mitigation measures applied during manufacture. It is proposed to interpret the guidance given by the EMA as an action limit of ≤10 CFU/100 mL.oPre-filtration and post-filtration risks and control measures are inter-correlated and should be addressed via an integrated risk assessment. This includes selection of sample test volume, acceptable bioburden levels and sterilizing filter area.oA holistic approach to bioburden risk is recommended, using a two-tier system for low bioburden monitoring prior to sterilization. A low alert level (product/facility history) and a higher action level, at or below the EMA criterion would be appropriate. It is proposed that any excursion warrants a thorough investigation and a case-by-case assessment for product quality impact rather than default rejection.oThe paper describes how detectable bioburden may be mitigated through subsequent effective sterilizing filtration, if the potential for bacterial by-products and their impact on safety and protein stability is assessed.oAs the manufacturing process is highly controlled to limit the potential for bioburden growth prior to filter sterilization, sample volumes less than 100 mL and alternative acceptance levels to ≤10 CFU/100 mL can be justified on the basis of the actual sample subject to testing. This is particularly relevant for small volume product batches.oTesting of bioburden prior to sterile filtration is not the only measure to control the microbial status and to generate sterile product but is a monitoring tool to verify efficacy of the control measures.