Tuesday, 17 September 2013

Can Leptospira species penetrate sterilizing-grade filters?

(Leptospiral challenges for sterile filtration)

Leptospira  are Gram-negative aerobic spirochetes that are flexible, highly motile, and spiral-shaped with internal flagella. The bacteria measure 1μm in diameter and 10-20 μm in length. Leptospira  are obligate aerobes that use oxygen as the electron receptor and long-chain fatty acids as a major source of energy. While some of the Leptospira are harmless fresh-water saprophytes, other species are pathogenic and can cause leptosporosis, a significant disease in humans and animals.Leptospira  can occupy diverse environments and habitats; these bacteria are found throughout the world, except in Antarctica. Leptospiral contamination can occur in products sterilized by filtration. Heat sterilization of water eliminates this possibility. 

FDA is aware of a recent report  of Leptospira licerasiae contamination in cell cultures. There is no indication that this bacterium ultimately contaminated either the finished drug substance or drug product. This bacterium has been found to pass through 0.1 µm pore size rated sterilizing-grade membrane filters. While this specific species was the identified contaminant in this case, other Leptospira species also are capable of passing through 0.1 µm pore size rated filters. Compendial microbiological test methods typically used in association with upstream biotechnology and pharmaceutical production are not capable of detecting this type of bacteria.

Based on current information, Leptospira  contamination does not appear to occur frequently, and purification steps that follow cell culture in a typical biotechnology operation would be expected to prevent carryover to the finished drug substance. Testing of bulk drug substances produced in the reported cases did not detect Leptospira  spp., and no evidence of deleterious effects on in-process product were observed in the known case study. However, these types of bacteria can potentially:

  • penetrate sterilizing-grade membrane filters
  • be present in the manufacturing site environment
  • impact in-process production (e.g., production yields, impurity levels, process performance)
  • go undetected due to the limitations of current compendial bioburden tests in detecting this microbial genus

As a general principle, manufacturers should use sound risk management and be aware of unusual microbiota reported in the literature that may impact their manufacturing processes (e.g., cell culture biotechnology, conventional sterile drug manufacturing).

Manufacturers should assess their operations, be aware of potential risks, and apply appropriate risk management based on an understanding of possible or emerging contamination risks. As appropriate, preventive measures should be implemented during the product and process lifecycle.

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