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Background There has been an evolution of our understanding of membranes and of membrane filtration over the half-century of their use. Their early successes in producing sterile filtrates led to the optimistic belief that such membranes were absolute; and that they unquestionably removed from pharmaceutical preparations the organisms commonly suspended therein. 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 passage through the filters.
Brevundimonas diminuta B. diminuta (ATCC 19146), previously classified as Pseudimonas diminuta, came to serve as the model organism for pharmaceutical filtration. These microbes, suspended in a penicillinase solution were found to penetrate 0.45 µm-rated membranes, the “sterilizing membranes” 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 suspensions absent penicillinase (Bowman et al. 1967). The rationalization was that the organisms were removed by adsorptive arrests to the filter surfaces (as well as by sieving) unless protein competitively pre-empted the adsorptive sites. As a consequence, the adsorptive sequestration mechanism came to be recognized. Adsorption is governed by filtration conditions, such as the challenge density, the ionic strength of the solution, possibly the temperature/viscosity, and most importantly by the applied differential pressure. Dependence upon such various influences, by definition, signifies the nonabsoluteness of filters and of filtration (Tanny et at. 1979). Absoluteness would mean freedom from such dependencies. However, so reliable is the sterilizing removal of B. diminuta by 0.2
(0.22) µm-rated membranes that these membranes have come to be designated as the “sterilizing filters”. The capture of B. diminuta by 0.45 µm-rated membranes is still popularly attributed by some to sieve retention occasioned by the smaller pores of the 0.45 µm-rated filters pore-size distribution.
Sterilizing Filter Designation Filter manufacturers are entitled to designate their 0.2 (0.22) µm-rated membrane products as being “sterilizing filters” if they are capable of withstanding challenges of 1 x 107 B. diminuta organisms per square centimeters of membrane surface (HIMA 1982). The challenge is normally performed using a suspension of a suitable concentration of B. diminuta in from 2 to 20 liters (usually) of saline lactose broth, employing about one bar (15 psi) differential pressure for the filtration. There is no industry-wide standard method. Given the possibility of adsorptive sequestration and of the resulting influences of the several conditions of the filtration on the outcome of the organism/membrane confrontation, the FDA insists that users of membranes designated by their manufacturers as “sterilizing filters”, experimentally demonstrate the sterilizing proclivities under “worse case conditions”, under the severest conditions of the processing operation (FDA 1996). 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 is involved. As stated, the model organism is the B. diminuta grown under stipulated conditions (Leahy and Sullivan 1979, Fennington and Howard 1997). The present definition of “sterilizing filter” is, then, referenced in terms of this organisms size and its adsorptive proclivities.
Bubble Point Correlations To Retention Efforts have been made to match the B. diminuta size to the 0.2 µm-rated pore size; a relationship 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 been
developed between organism retention levels and bubble point integrity test values that are indicative of a filters largest pores (Johnston and Meltzer 1970) (See Figure 1). On the basis of this correlation, a particular filter can be designated as a “sterilizing filter” given a sufficiency of B. diminuta retention. The bubble point will differ for each polymeric type, but for any type the label 0.2 (0.22) applies to membrane that completely retains the B. diminuta challenge. The numerical value should not be entertained seriously. It is a vestigial sign only. There is, then, an identity between the bubble point measurement and the affixing of the 0.2 (0.22) µm label based on B. diminuta retention. Again, it is evident that the appellation “sterilizing filter” is defined in terms of B. diminuta removals. Its arrest by filters depends upon its particle size/pore size relationship and upon its capability to adsorb to the membrane polymer under the selected filtration conditions. It is hardly likely to serve as a universal model for all other microbes, of whatever size, and under all other filtration conditions. Still there is often surprise when filters with the 0.2 or 0.22 µm designations fail to retain organisms. Improper imputations of poor filter quality may be made, as if the action of the “sterilizing filter” were absolute and independent of the organisms involved, of the nature of the suspending fluid, and of the filtration conditions.
Smaller Organisms There is increasing concern that organisms smaller than B. diminuta may be present in certain pharmaceutical preparations. The 0.2 µm-rated membranes may not perform as sterilizing filters for the smaller organisms. Organisms present in Water for Injection may, on account of the poor nutritional environment, be reduced in size (Gould 1997). L-form organisms, devoid of their more rigid outer membranes, may be capable of negotiating the tortuous pore paths of filters (Thomas et al. 1997). They are not retained by 0.2 µm-rated filters (Hargreaves 1996). Also, nanobacteria have been found in sera. Additionally, there is the threat of the unknown posed by viable but unculturable microbes (Colwell 1993).
Substitution of 0.1 for 0.2 Membranes It has been suggested that such smaller organisms may be better restrained from passage by 0.1 µm-rated filters. It is advanced, therefore, the 0.1 µm-rated membrane should replace the 0.2 µm-rated as the sterilizing filter. As an alternative to the use of 0.1 µm-rated membranes, the use of two 0.2 µm-rated filters in series is also suggested. Jornitz et al. (1999) indicate, however, that double 0.2 µmrated membranes, aside from augmenting adsorption effects, are not likely to be as efficient as the 0.1 µm-rated membrane. It is advocated that substitution of 0.1 µm-rated filters for their 0.2 rated counterparts, however prudently intended, should not be implemented unless the need is experimentally indicated. Such substitutions may involve filtration problems and would most likely compel revalidations. Whether the interchange of 0.1 and 0.2 µm-rated filters requires revalidation deserves consideration. The finer pored membrane structures may be more promotive of adsorptive sequestration since they offer more pore surface area. Viscosity effects may become enhanced; flow rates being reduced. Borderline incompatibilities may become exaggerated, added solid/liquid interfaces manifesting themselves. Additionally, the narrower pores may undergo wetting with greater reluctance, almost all the newer membrane polymeric materials of construction being borderline in their hydrophilicity. This could occasion an increase in (false) integrity test failures, usually caused by incomplete wetting of the pore surfaces. Steam-in-place failures could increase. These could eventuate from the greater impediment to the penetration of narrower apertures by steam (Young et al., 1994), and by its more ready condensation upon increased surface areas (Steere and Meltzer 1993). Above all, the improved, hoped for organism retention would require documented experimental confirmation. This means validation. There are, as stated, applications for which the 0.1 µm-rated filters are clearly indicated. Risk assessments for other applications are appropriate. There are, however, penalties in flow
rates and potentially in throughputs to be considered. Figure 1-14, illustrates the dramatic decrease in flux, for at least one type of membrane, that results when a 0.45 µm-rated filter is substituted for by a 0.2-and then by a 0.1 µm-rated membrane. The flux decreases respectively from 22 to 8, and then to 2 mL/cm2/min at (15 psi) one bar differential pressure. Some of this loss, but hardly all, can perhaps be compensated for by improved filter design. However, tighter filter design will ineluctably result in flow rate diminution. Reliance upon thinner membranes should be made with caution. They are more prone to imperfections. Additionally, the use of prefilters to minimize increased flow-blocking particle accretions on the tighter membranes could be necessitated. The application of 0.1 µm-rated membranes has its uses. The exercise should not, however, receive cavalier endorsements; it has its costs.
Minimum Bubble Point Ratios Filter manufacturers ascertain the proper water bubble point value for their type of filter that accords with the required 1 x 107 cfu retention per cm2 of filter surface. In filter
manufacture it is common to provide a safety margin by furnishing customers with membranes of higher-than-minimum water bubble points. The penalty imposed on the filter user by this insurance is a somewhat lower rate of flow. The classic situation involves a filter
manufacturers determining the minimum bubble point for water, its translation to the product bubble point, and the testing of the filter for integrity. The integrity tests ascertain the ratio of the water/product bubble points. This is useful in determining whether the product bubble point meets the minimum allowable test value or not (Report 26). Three filter specimens are used in the integrity testing. At least one should have a bubble point value close to the minimum. Otherwise, the level set will reflect an unnecessarily high value. This, in turn, means that the filter user will not be entitled to employ filters with lower integrity values. Following such an evaluation, the filter purveyor will be enjoined from selling for that validated application filters having bubble points between the minimum and chose of the tested value.
Filter Manufactures Choice The minimum accepted bubble point is that which correlates to the required organism retention level. It would seem to be in the filters manufacturers interest to provide membranes with as close a value to the minimum bubble point as possible so as not to exclude from use filters still possessed of a sufficiency of retention but having bubble points lower than that tested in the validation. However, there is a problem. Many filter manufacturers have until now elected to produce membrane with higher than minimum bubble points, both as a safety factor for users and perhaps in connection with minimizing scrap rates. Filter manufacturers, therefore, must make a choice. One option lies with furnishing membranes having lower but acceptable bubble points consonant with the minimum water bubble point and its matching organism retention abilities. This would avoid precluding the use of membranes whose water bubble point automatically sets the product bubble point as that of the filter used in the validation. A second possibility is for the filter manufacturer to designate a new minimum bubble point specification for the membrane he now regularly produces. To be sure, this would forego offering filters of lower bubble points but still above those representing the correlation to the required organism retentions. The safety factor of higher values would automatically inhere. The cost to the filter manufacturer would be minimal if his product is consistent in its bubble point value. The scrap rate, too, would reflect the constancy of manufacture, but the cutoff level would be that of the (higher) new minimum setting. Implications that this change in catalogue specifications implies a corrective to previous lower bubble point values would be inappropriate.
Implications of Higher Minimum Bubble Points How the filter producers address their problem, essentially a business decision, need not concern the user. Most prefer to offer membrane having bubble points closer to the minimum value stipulated in their product descriptions. At least one filter manufacturer, however, has elected to specify a new minimum water-wet bubble point for his product. The new range,
routinely manufactured, is sanctioned by its being above the filter manufacturers minimum value, the level at which that filter type retains 1 x 107 cfu/cm2 of filter surface. Redefining the minimum bubble point of the membrane being offered to the drug industry, in effect a change in the catalogue listing, in no way modifies the adequacy of the value actually determined by the filter manufacturer, if the value changed is higher than the previously stated value. Even then one should not take such changed and new value for granted. In filter production, membranes are produced within a specified bubble point range, an upper (maximum) and lower (minimum) bubble point value. An upward shift of this specified band may excessively elevate the upper limit, thereby changing filter performance. One is called upon to supply evidence that the filters performance did not change, i.e. beside the achievement of a sterile effluent, certain other properties have to be evaluated, as for example described in PDA Technical Report 26. The adsorptivity should be evaluated; same for flow rates, pressure conditions, extractable levels, etc. When the bubble point is changed now to a higher level, one has to ask whether this will influence the pore size and pore size distribution, and with it the flow rate and, therefore, contact time or time to filter the required batch volume. If, because of increased contact time between the solution and the filter, the adsorptive effect could be heightened, the product could change in respect to its activity, potency and strength. Changes in the process, of equipment settings or parameters have to be evaluated in respect to their potential adverse effect on the process and/or drug product. Therefore, a change of integrity test value of a sterilizing grade filter, even to a higher assurance level, requires testing to achieve documented evidence that it will not have adverse effects. Either way, filter users will have at their disposable microporous membranes dedicated to sterile filtrations from which minimum product bubble point can be arrived at with confidence.
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