Sterilization grade filters

Liquid product is fed to the BFS machine from a holding tank or vessel. The pathway is sterilized in place prior to receiving product, and product is sterilized by means of in-line sterilizing-grade filters. There is usually more than one stage of sterile filtration required on the product pathway. 

Hydrophilic and hydrophobic sterilizing-grade filters are used throughout the BPS process for the sterilization of product and air, respectively. Pilters used should be... 

The earliest commercially available filters were manufactured in two pore sizes 0.45 and 0.8 pm. The 0.45 pm-rated membranes were considered to be sterilizing-grade filters and were successfully used in the sterile filtration of pharmaceuticals and parenterals. The membrane filters were qualified using Serratia marcescens, a standard bacterium, having dimensions of 0.6 x 1 pm. However, in the late 1960s it became apparent that the matrix of the 0.45 pm-rated filters could be penetrated by some pseudomonad-like organisms (1). For sterile filtration applications in the 1990s, 0.2 pm-rated membranes are the industry standard in the manufacture of sterile parenterals and pharmaceuticals. 

Although Brevundimonas (Pseudomonas) diminuta (ATCC 19146) is most commonly used for sterilizing-grade filter validation, in certain applications other bacteria are used. For example, when it is necessary to demonstrate removal of mycoplasma in applications involving sera and tissue culture media, membranes having a smaller pore size rating, eg, 0.1 Jim, are frequendy used. For these membranes, Picholeplasma laidlawii may be employed for validation purposes (9). 

MacDonald, W. D., Pelletier, C. A., Gasper, D. L. Practical methods for the microbial validation of sterilizing-grade filters used in aseptic processing. J Parenter Sci Tech 43 268-270 (1989). 

Levy, R. V., Souza, K. S., Neville, C. B. The matrix approach Microbial retention testing of sterilizing-grade filters with final parenteral products, part 1. Pharm Tech 14 161-173 (1990). 

The test should have been correlated with a bacterial challenge test (BDT). The FDA considers a sterilizing grade filter as one that produces a sterile filtrate when challenged with 10 Pseudomonas diminuta per cm2 of filter surface. 

Some large proteins such as fibrinogen or Factor VIII can demonstrate retention by the sterilizing grade filters. The effect of solution properties such as pH, ionic strength, temperature, and operation parameters such as TMP on retention should be understood to minimize the loss of the product protein. 

Hydrophilic and hydrophobic sterilization grade filters are used throughout the BFS process for the sterilization of product and air, respectively. Filters should be purchased from an approved supplier and should be certified as meeting the regulatory requirements for sterilizing grade filters. By definition this means that the filter will have full bacterial retention when subjected to an aqueous challenge of Brevundimonas diminuta (ATCC 19146) at a minimum concentration of 1 X 10 cfu/cm of filter surface area. 

Particulates are critical in sterile filtration, specifically of injectables. The USP 24 United States Pharmacopoeia) and BP British Pharmacopoeia) quote specific limits of particulate level contaminations for defined particle sizes. These limits have to be kept and, therefore, the particulate release of sterilizing grade filters has to meet these requirements. Filters are routinely tested by evaluating the filtrate with laser particle counters. Such tests are also performed with the actual product under process conditions to proove that the product, but especially process conditions, do not result in an increased level of particulates within the filtrate. 

Whilst the vast majority of parenteral products are rendered sterile either by moist heat sterilization or by filtration through sterilizing grade filters, other methods of sterilization should be considered, particularly in the development of non-aqueous formulations or novel drug delivery systems. For implants, for example, gamma irradiation is an option that should be explored early on in development. 

The manufacture of parenteral products is focussed at all times on the requirement for sterility of the finished product. Despite the fact that the regulators are clear in their preference for products to be terminally sterilized, the vast majority of parenterals are filtered through sterilizing grade filters and filled aseptically, primarily because stability considerations preclude the use of moist heat sterilization. The statistical limitations of sterility testing a sample... 

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