Food/ beverage and pharmaceutical customers frequently use microfiltration membranes for removal of microbial contamination in liquid or gas process streams. Microbial contaminants can be any of a variety of species of bacteria and yeast of varying size and concentration. Removal of these organisms is essential in the food/beverage industry to prevent product spoilage or food borne illness and in pharmaceuticals, contamination within a sterile parenteral drug (injectable) can lead to significant side effects such as infection, fever or death. Therefore, to provide products into these markets, filter manufacturers will conduct microbial retention tests with the filters to demonstrate the efficacy of microbial removal.
Biopharmaceutical Applications
Because many pharmaceuticals are damaged by heat, there is no process to sterilize these products in their final container. Thus it is critical that the process stream yield sterile product and that containers are filled and sealed in an extremely high-purity environment. In order to obtain
sterile effluent in the most critical applications, double layered membrane filters are typically used. The European Medicines Agency (EMEA) recommends 10 CFU (colony forming units – a count of viable bacteria) as the maximum acceptable bioburden prior to a sterile filter. For higher levels, a bacteria retentive prefilter should be used to reduce the bioburden. Multi-filter arrangements are routinely used in the industry to manufacture sterile products. PDA Technical report no. 26 (2008), Sterilizing Filtration of Liquids recommends a multi-filter approach to manufacture sterile products.
Sterile Filtration versus
Bioburden Reduction
Guidance for microbial removal is provided in the 2004 FDA Guidance Document for Industry on Sterile Drug Products produced by Aseptic Processing. Intended to provide non binding recommendations for biopharmaceutical processes, many aspects are also applicable to the food/beverage industry. By definition, a sterilizing grade filter is to have a rated pore size of 0.2 micron or smaller and should be validated for the reproducible removal of viable microorganisms from a process stream, resulting in sterile effluent under worst-case production conditions when liquid challenged with 107/cm2 of surface area of a specific test organisms. This challenge protocol was originally established by the Health Industry Manufacturer’s Association (HIMA) and subsequently published by ASTM (ASTM838-83, - 88, -05) and is often referred to as the HIMA test. The challenge level is orders of magnitude higher than would be expected in a sterilizing filtration process, thus providing a high degree of assurance of filter performance.
While the target organism for the biopharmaceutical industry is Brevundimonas diminuta, the test methodology can be applied to any micron rated membrane filter regardless of application. For example, a 0.45 micron rated membrane filter will not provide microbial free effluent when challenged with Brevundimonas diminuta, but may when challenged with Serratia marcescens. Neither Brevundamonas diminuta or Serratia marcescens have any significance for the food/beverage market, therefore more relevant organisms, such as Psuedomonas aruginosa (water borne contaminant) for 0.2 micron membranes and Lactobacillus brevis (found in dairy, wine and other food) for 0.45 micron membranes are chosen as test organisms.
Filters that have been validated for microbial removal exhibit much higher removal efficiencies than absolute rated particle filters, such as a pleated polypropylene filter. As a comparison, an “absolute-rated” Beta 5000 particle removal filter exhibits a removal efficiency of 99.98% of particles challenging a filter, while a sterilizing grade liquid filter exhibits a removal efficiency of >99.99999999% of micro-organisms challenging the filter. The removal efficiency of a membrane filter is expressed as the log reduction value (LRV) of target microbes, which are selected by virtue of their approximate size and relevance to the application.
Food/Beverage Applications
Microbiological quality is likely the most common food safety objective achieved by filtration. An important method for reducing the risk of microbial contamination is the HACCP (Hazard Analysis and Critical Control Point) principles published by the Food Safety and Inspection Service (FSIS) under the Department of Agriculture. HACCP is a systematic approach to identify and implement proactive programs to analyze, identify, control, monitor, correct, verify and document critical control points in the process control of the biological, chemical, and physical hazards associated with a particular food production process. In conjunction with the guidelines established under FDA CFR Title 21, food manufacturers have the necessary guidance to safeguard consumers.
In food/beverage applications, the criteria for effluent is not as rigorous as in the biopharmaceutical market since the goal is to achieve a low microbial load to downstream equipment or the product has microbial-static characteristics (i.e. alcohol in wine). In this case, the filters need to achieve only bioburden reduction, or significant removal of the microbial contamination. Using the same protocol as established in the FDA document on sterile drug products, the filter is challenged at 107 /cm2 of surface area of a specific test organism, which is equivalent to 1011 organisms for a typical 7 ft2 membrane filter. The quantity of viable organisms in the effluent is determined and subtracted from the 1011 value to determine the log reduction value. For example, if there were 1000 (103) in the effluent, you would get a LRV of 8 (1011- 103 = 108). Typically, an LRV value of 5 – 7 is deemed acceptable for food/beverage applications.
Cartridge Validation
In order for filter manufacturers to document the retentive potential of a filter, non destructive test procedures have been developed, including bubble point and diffusional flow. These tests can be correlated to bacterial retention utilizing the ASTM 838-05 methodology, and are designed to give you statistical confidence in the retentivity of the filter. In the process, integrity testing of
the filter(s) is generally performed prior to use as well as post-use to validate retention. Biopharmaceutical companies are required by the FDA to demonstrate efficacy of their processes and maintain documentation of each process. This validation is costly in terms of time and material and thus once locked-in, there is little incentive to change. Food/beverage producers typically do not require this level of governmental documentation and therefore generally only evaluate to a set of internal standards.
This technical brief was supplied by Graver Technologies. Browse our Graver product offering online here.
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