7-log reduction and filter validation in accordance with ASTM F838-15a

To reduce the number of microbes in a liquid or on a surface, the liquid must be filtered or the surface must be cleaned or disinfected. To achieve results that are comparable and reproducible, the reduction in the number of microbes must be measured. This reduction is usually expressed logarithmically in terms of the LRV (log reduction value). Each unit of LRV means reduction by a power of ten. So an LRV of 1 means the microbes are reduced by 90 %. Out of an original population of 100 (10 x 10), only 10 microbes have survived. A reduction of 99 % (in other words LRV = 2) corresponds roughly to the effect of soap. In non-medical contexts, the term “disinfection” is used to describe a reduction of all microbes by a factor ≥ 4 orders of magnitude – in other words by 99.99 %. In this case, a maximum of one out of 10,000 microbes can survive. In medical contexts the requirements are stricter. According to the specifications of ASTM (American Society for Testing and Materials) and the FDA (Food and Drug Administration) the term “sterile filtration” can only be used when the LRV is at least 7.
 

LRV% reductionReduction from 100,000,000 microorganisms to
19010.000.000
2991.000.000
399,9100.000
499,9910.000
599,9991.000
699,9999100
799,9999910
899,9999991


The classification in terms of LRV is also used in relation to water hygiene. In medical settings, in particular, membrane filters are increasingly being used to filter drinking water. These filters are class 1 medical devices. The 0.2 µm pore size provides reliable protection against waterborne microbes. In accordance with the definition of sterile filtration, it leads to at least 7 log reduction of the test microbe Brevundimonas diminuta per square centimetre of filter area1, which means the microbes are reduced by 99.99999 %. Brevundimonas diminuta is the smallest of the waterborne bacteria. For this reason the authorities specify that it should be used as the test microbe: if a filter is able to hold back this microbe, it can be assumed that this filter is also capable of stopping larger pathogens like Legionella or Pseudomonas bacteria.

Filter validation – what has to be considered?

As with other processes in the pharmaceutical industry, it must be shown by means of validation that the filters do their job properly. This involves examining different aspects of filtration, such as bacterial retention (in accordance with ASTM F838-15a), filter integrity, release of particles from the membrane, chemical compatibility, etc.

The test of bacterial retention is effectively a performance test. It uses a standardised procedure to find out to what extent the filter can reduce the number of bacteria, the size of the reduction being expressed in logarithmic terms. In this test, the filter is inserted into the test apparatus and a defined solution of bacteria is then pressed through it. All components of the testing apparatus must be sterile and thus free from other microbes. The results of testing must be documented precisely.

Another aspect that plays a major role in the validation of filters is the service life - the time between installation and deinstallation of the filter. Testing also has to find out for how long the filter is able to stop bacteria, how resistant it is to chemical and physical influences and how certain it is that retrograde contamination can be avoided.

As well as the tests, which take place under laboratory conditions, it is important to check how the filter performs in practice. This is because other factors can play a critical role in practical use – factors like retrograde contamination, the behaviour of users, water quality and the specific hygiene environment. The filters are therefore tested in field studies in which they are used in everyday hospital conditions, for example in a transplant unit, over a longer period of time. Once a week, the water is tested for Legionella and Pseudomonas bacteria or other pathogens. To be sure that the sterile filters really are reliable throughout the recommended service life (four to eight weeks depending on the filter), field studies usually test them over longer periods.

 

1 U.S. Department of Health and Human Services Food and Drug Administration (FDA), C.f.D.E.a.R.C., Center for Biologics Evaluation and Research (CBER), Office of Regulatory Affairs (ORA), Guidance for Industry. Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice. Pharmaceutical CGMPs, 2004.