Validating Sterile Filtration: Overcome the Fear of Failure 3

Based on available data, long term filtrations may best be handled by 0.1-µm-rated filters, subject to validations being performed. However, in other cases, substituting 0.1-µm-rated for 0.2-µm-rated membranes may be unnecessary, and could result in significant penalties, including:
 Slower flow and processing rates, resulting in longer term operations.
 Higher costs for larger EFAs
 More leaching and extractables
 Higher product losses, due to adsorptive bonding to the ultimately greater filter area used.
A responsible choice requires that both the 0.1 µm-rated membranes and the 0.2 µm-rated membranes be validated.
If both types of filter prove appropriate, the higher pore size rating should be used to avoid the penalties of reduced flows. If, however, the validation data do not permit a clear resolution, the 0.1 µm-rated membranes should be used, since retention is more critical than flow rate or flux.
Below, we address some of the common sterile filtration concerns, requirements or practices that appear to be motivated by fear and can best be resolved by careful process validation.
“0.2-µm filters are penetrated by organisms. The industry is, therefore, required to switch to 0.1-µm-rated filters.”
In certain specific processes, 0.2-µm–rated filter can be penetrated by organisms, or by organisms which would normally be retained by such filters. In such cases, the flltrative removal of the organisms may well require the use of 0.1 µm–rated filters. Such instances are not new. Their occurrences have been considered by regulators for years, at least since the PDA and FDA held a special forum on this topic in 1995 [13].
   
Certain organisms, such as Burkholderia pickettii, Burkholderia cepacia, and Pseudomonas aerugenosa. shrink as a result of their immersion in fluid media that are only minimally nutritious for them [14]. Their reduction in size renders as invalid validations that use B. diminuta as a model. Brevundimonas diminuta can undergo shape alterations in minimally nutritious media but is not listed as undergoing size alterations occasioned by contacts with process fluids.
The fact that some microbes require 0.1-µm–rated filters to arrest them does not signify that all organisms are so disposed. The necessitated switch from 0.2-µm-rated to 0.1-µm–rated happens in only roughly 0.005% – 0.01 % of sterilizing grade filtration applications.
A mandated switch is therefore scientifically and statistically unfounded. Its promulgation may be shunned and process validation activities and data used as performance verification. Sole reliance on pore size ratings have been found obsolete anyway.
“Increasingly there are detectable but non-culturable organisms or L-forms or nano-bacteria in our processes.”
Conclusions cannot be made regarding the sterile filtration of microorganisms unless the methods of quantifying them by culturing and counting are available. Organisms such as the L-forms, nanobacteria, and “viable but non-culturable” entities may not be amenable to such analyses. Concerns about their presence may be justified, but without the means to cultivate and count them, it is impossible to attest to their complete absence.
It follows that a sterilizing filter can be judged only by its performance in the removal of identifiable and culturable organisms known to be present in the drug preparation [15]. The complex of influences governing the outcome of an intended sterilizing filtration necessitates a careful validation of the process, including that of the filter [4]. The very drug preparation of interest, the exact membrane type, the precise filtration conditions, and the specific organism type(s) of concern must be employed in the necessary validation.
“Redundant 0.2-µm filtration is necessary and should be used.”
Not necessarily. Again, proper process validation will disclose whether a single filter will do the job or not. However, there are some specific applications which traditionally, for whatever reason, utilize a second (redundant) filter as an “insurance filter,” i.e. if the first filter fails, the second may compensate. This holds, however, only when each filter has been validated to show specified retentivity.
Even so, the wisdom of the exercise deserves careful evaluation, as it assumes added costs for membrane EFA, increased leachables and extractables. The loss of drug product may needlessly be incurred by the filter’s heightened product hold-up, and unspecified adsorption.
    
“The maximum bioburden in front of a sterilizing filter should be 10 cfu per 100 mL of fluid.”
This is true if one wishes to accord with EMA regulations, and especially if one wishes to export product to Europe. The FDA makes no such stipulation, but bases its approval on process validation.
Seemingly in conflict, the two views arise from the same premise. The EMA regulation tries to establish the same sterility assurance level (SAL) for filtration as for thermal sterilization. EMA recognizes that, the greater the number of challenges, the more likely that at least one will succeed.
The FDA seems to agree, in that if the filter can sustain the removal of organism burdens far above those liable to be encountered in real life situations, it can assuredly withstand lesser insults. If, as the authors see it, the FDA’s massive challenge fails to breach the filter’s pores, it is needless to compel bioburden assessment in front of the filter. Filter validation would gainfully serve the intended purpose. Process validation, effectively conducted, would reliably demonstrate the filter action.