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Consideration on Sterilizing Grade Liquid Filtration

Consideration on Sterilizing Grade Liquid Filtration



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Published by MWJornitz
Paper describes parameters which are relevant when chosing a sterilizing grade membrane filter within biopharmaceutical processing.
Paper describes parameters which are relevant when chosing a sterilizing grade membrane filter within biopharmaceutical processing.

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Published by: MWJornitz on Oct 22, 2008
Copyright:Attribution Non-commercial


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Consideration on Sterilizing Grade Liquid Filtration – Pore Size and Filtration Sterilization -
 M.W. Jornitz, K. Kawamura, PhD and T. H. Meltzer, PhD
 There has been an evolution of our understanding of membranes and of membranefiltration over the half-century of their use. Their early successes in producing sterile liquidfiltrates led to the optimistic belief that such membranes were absolute; and that theyunquestionably removed from pharmaceutical preparations the organisms commonly suspendedtherein. The filtrative action was seen to result from sieve retention, the mechanism whereby particles (organisms) larger in size than the pores become spatially restrained from passagethrough the filters. Nevertheless recent findings show that adsorptive sequestration plays a role infiltrative sterilization, which in itself can be influenced by the drug product properties to befiltered. Appropriate process and filter validation is required to determine the performance of afilter and its function (PDA Technical Report 26).
Microbial Retention and Brevundimonas diminuta
 B. diminuta (ATCC 19146)
, previously classified as
 Pseudimonas diminuta,
came toserve as the model organism for pharmaceutical filtration. These microbes, suspended in a penicillinase solution were found to penetrate 0.45 µm-rated membranes, the “sterilizingmembranes” at the time, but were restrained by the tighter 0.2 µm filters devised for that very purpose. However, the invoking of the sieve retention mechanism was called into question because the 0.45 µm-rated membrane did remove these organisms from aqueous suspensionsabsent penicillinase (Bowman et al. 1967). The rationalization was that the organisms wereremoved by adsorptive arrests to the filter surfaces (as well as by sieving) unless proteincompetitively pre-empted the adsorptive sites. As a consequence, the adsorptive sequestrationmechanism came to be recognized.
 Adsorption is governed by filtration conditions, such as the challenge density, the ionicstrength of the solution, possibly the temperature/viscosity, and most importantly by the applieddifferential pressure (Mittleman et al. 1998). Dependence upon such various influences, bydefinition, signifies the non-absoluteness of filters and of filtration (Tanny et al. 1979).Absoluteness would mean freedom from such dependencies. However, so reliable is thesterilizing removal of 
 B. diminuta
 by 0.2 (0.22) µm-rated membranes that these membranes havecome to be designated as the “sterilizing filters”, whereby the use of a 0.45 µm rated membranecan also result in a sterile filtrate, depending on the process conditions. Therefore onlyappropriate process validation enables to determine the required performance of a filter independent of its pore size designation. Pore size designation becomes a mere logisticalnecessity or an indicator for the filter manufacturer and user.
Sterilizing Grade Filter Rating
 Filter manufacturers designate their filters 0.2 (0.22) µm-rated membrane products if theyare capable of withstanding challenges of 1 x 10
organisms per square centimetersof membrane surface (HIMA 1982, ASTM 1988). The challenge is normally performed using asuspension of a suitable concentration of 
in from 2 to 20 liters (usually) of salinelactose broth, employing about 2 bar (30 psi) differential pressure for the filtration. Withstandingthe challenge test does not necessarily mean that such filter membranes are of 0.2 µm rating. Asin Figure 1. membranes designated 0.2 µm can be of larger pore size and still result in a sterileeffluent, when challenged as stated above. Adsorptive capture may be the effective in this case.Given the possibility of adsorptive sequestration and of the resulting influences of the severalconditions of the filtration on the outcome of the organism/membrane confrontation, the FDAinsists that users of membranes designated by their manufacturers as 0.2 µm or “sterilizingfilters”, experimentally demonstrate the sterilizing proclivities under “worse case conditions”,under the severest conditions of the processing operation (PDA/FDA 1995).
 This FDA requirement, thus, in itself recognizes that a membrane that sterilizes under one set of circumstances may not so perform under another even when the same organism isinvolved. As stated, the model organism is the
 B. diminuta
grown under stipulated conditions(Leahy and Sullivan 1978, Fennington and Howard 1997). The present definition of “sterilizingfilter” is, then, referenced in terms of this organism
s size and its adsorptive proclivities.
Pore Size Distribution 0.2 micron
Different Filter Manufacturers
min. averagemax.00,20,40,60,8Pore Size (µm)F1F2F3F4F5F6
 Figure 1.: Pore size distribution measured with Coulter Porometer of 0.2 µm rated filter membranes
Bubble Point Correlations and Retention Ratings
 Efforts have been made to match the
size to the 0.2 µm-rated pore size; arelationship expressive of the sieve retention mechanism. The results are clouded if only because pore-size ratings are innocent of any measurement standards. However, correlations have beendeveloped between organism retention levels and bubble point integrity test values that areindicative of a filter 
s largest pores (Johnston and Meltzer 1979) (See Figure 2).

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