Certain active ingredients and products that cannot be terminally sterilised may be subjected to filtration through microbial retentive materials. The suitability of filters of such materials should have been demonstrated by means of a microbial challenge test using a suitable test microorganism. A suspension of Pseudomonas diminuta (ATCC 19146, NCIMB 11091) may be suitable. It is recommended that a challenge of at least 107 CFU per cm2 of active filter surface is used and that the suspension is prepared in tryptone soya broth which, after passage through the filter, is collected aseptically and incubated aerobically at 32°. Such membrane filters are nominally rated 0.22 µm or 0.2 µm. It must be ascertained whether the filtration parameters employed in manufacturing the product will significantly influence microbial retention efficiency. Some of the other factors in validation of the filtration process include product compatibility, absorption of drug, preservative and/or other additives, release of contaminants from the filter and initial effluent endotoxin content.
Since the effectiveness of the filtration process is also influenced by the microbial burden of the solution to be filtered, the determination of the microbiological quality of solutions prior to filtration is also an important aspect of validation of the process in addition to other parameters such as pressures, flow rates, and filter unit characteristics. The production process and environment should be designed to minimize microbial contamination and should be regularly subjected to appropriate monitoring procedures. The equipment, containers, and closures and, where possible, the ingredients should be subjected to an appropriate sterilization process. It is recommended that the filtration process is carried out as close as possible to the filling point. Attention should be given to the filter capacity, batch size and duration of filtration.
The filter should not be used for a longer period than has been approved by validation of the combination of the filter and the product in question. The operations following filtration should be carried out under aseptic conditions. The integrity of an assembled sterilizing filter should be verified before use and confirmed after use by carrying out tests appropriate to the type of filter used and the stage of testing, e.g., bubble-point, pressure hold or diffusion rate tests. Due to the potential additional risks of the filtration method as compared with other sterilization processes, a pre-filtration through a bacteria-retentive filter (e.g. 0.45 µm pore size) may be necessary in cases where a low bioburden cannot be ensured by other means.
Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of Pharmaceutical Guidelines, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
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