Sterile Filter Validation – Question and Answers

A sterile filter is generally intended for the elimination of harmful particles and microbes from process fluid. The fibre-shedding characteristics of filters should be minimal and the filter system must be inert; the filter system should not add or remove anything from the fluid, even though it may not be regarded as a contaminant at first glance. Extractable leachable study, Filter compatibility, bacterial challenge tests and physical integrity tests are the major tests to be performed during filter validation.

What are the factors which affects filter performance? Factors that can affect filter performance generally include (1) viscosity and surface tension of the product to be filtered, (2) pH, (3) compatibility of the material or formulation components with the filter itself, (4) pressures, (5) flow rates, (6) maximum use time, (7) temperature, (8) osmolality, (9) and the effects of hydraulic shock.

Why a challenge concentration of 107 organisms per cm2 of effective filtration area is generally used in filter validation for bacterial retention study. It’s a guidance requirement. According to “Sterile Drug Products Produced by Aseptic Processing —Current Good Manufacturing Practice” - “A challenge concentration of at least 107 organisms per cm2 of effective filtration area should generally be used, resulting in no passage of the challenge microorganism. The challenge concentration used for validation is intended to provide a margin of safety well beyond what would be expected in production”.

What is the maximum accepted bioburden level? With reference to the EMA Human and Veterinary Notes for Guidance on Manufacture of the Finished Dosage Form (CPMP/QWP/486/95 and EMEA/CVMP/126/95) a bioburden limit of no more than 10 CFU/100 ml is specified. When a prefilter is installed, this value should also be achieved prior to the prefilter. Higher bioburden limits should not be justified by the higher capacity of two consecutive bacteria retaining filters.

Why is filter validation important to drug development?  Filter validation plays an essential role in the drug development process. It’s required by the regulatory bodies in support of product submissions that require a sterilizing filter. Anything that is aseptically manufactured and goes through a sterilizing filter needs to be validated through my department.

Why Brevundamonas dimuta is used for filter validation (Bacterial retention study)?  Brevundamonas dimuta  is well-characterized, well-known and well-standardized. Use of this microorganism provides several advantages v It is Generally regarded as nonpathogenic to humans, ordinary microbiology laboratories can use it without major biohazard concerns; v  It can be consistently cultured under controlled conditions to yield very small, mono dispersed cells with a narrow size distribution. These can penetrate 0.45 m filters reproducibly in small numbers at high challenge levels, thus representing a potential worst-case challenge.

What are the main parameters for sterile filter validation 1.Integrity Testing (Bubble point) 2.Filter Compatibility 3.Bacterial retention 4.Extractables & Leachable 5.Preservative binding