Grow-Through and Penetration of the 0.2/0.22 "Sterilizing" Membranes - Pharmaceutical Technology

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Grow-Through and Penetration of the 0.2/0.22 "Sterilizing" Membranes


Pharmaceutical Technology


Grow-through concerns

Grow-through—although seemingly avoided by the time restriction set on filtrations—remains unresolved and an ongoing matter of concern, largely because its cause is still little understood and its control, therefore, is uncertain. Regardless, the possibilities of its occurrence ought never really pose a threat in pharmaceutical filtrations, given the requirement for validation. Whenever a terminal filter is used to sterilize a fluid, validation is required to demonstrate that the filter will perform satisfactorily, reliably, and repeatedly over the entire processing interval. Thereby, grow-through will be detected. Its occurrence being time dependent, its avoidance can be undertaken by expeditious filtrations, time restraints, larger effective filtration area (EFA), or filter change-outs. Likewise, other activities such as prolonged filling times will receive their needed documented experimental verification. Desired filter retentivity should thus be ensured by validation, regardless of the possibility of grow-through (7).

Awareness of organism size alterations

It was known, most likely among microbiologists, that the size of organisms could differ depending upon the stage of their development and upon how they were cultured. The classical work of Leahy and Sullivan on the cultivation of Brevundimonas diminuta should have made that evident to filtration practitioners (8). It seems, however, that those dealing with organisms in filtration processing contexts largely assumed that the cell sizes within a drug preparation essentially remained constant. It was partly for this reason that efforts were made to relate organism and pore sizes in the search for the "sterilizing" filter. Subsequent findings that the size of the organism did not necessarily remain constant during drug processing gave rise to the suggestion that 0.1 μm-rated membranes should be substituted for their 0.2/0.22 μm-rated counterparts that were considered "sterilizing filters" at the time.

It is now accepted that the physicochemistry of the suspending fluid may serve to alter the size of suspended organisms as a consequence of its limited nutritive power or as an expression of the Donnan equilibrium's response to ionic strengths.

Commonality of organism shrinkage and grow-through

What is of interest is that certain organisms undergo morphological diminution after exposure to particular drugs. This singular occurrence manifests itself in two different circumstances. One characterizes the "grow-through" phenomenon wherein after a filtration both the filter and its retained organisms are maintained wet by the drug preparation. In the second circumstance, the organisms are suspended for a time in a drug formulation awaiting the filtration step. The commonality is that the size alterations in each case seem consequent to contact with a drug. Unfortunately, the literature does not record the total contact time of the organism and drug in any of the reported cases. Also unknown is whether the same organism types have been involved in each of the exposures and whether under roughly the same conditions of temperature and so forth.

The authors surmise that the same phenomenon is being expressed in the two different situations. It is a purpose of this writing to encourage further investigation of the matter.

Pore size versus grow-through

Recent data secured by Sundaram et al. reveal that with regard to certain organisms, 0.2- and 0.22-μm-rated membranes provided sterile effluent and/or a high titer reduction only for various lengths of time before penetration occurred (9). Five 0.2-μm-rated nylon 66 filters were tested. Penetration times varied from 24 to 96 h, and the cumulative challenge at which penetration was first observed ranged from 1.2 X 107 to 1.1 X 108 cfu/cm2. Two 0.22-μm modified poly(vinylidene difluoride) (PVDF) hydrophilized filters showed bacterial penetration after 72 h, corresponding to a cumulative challenge level of 6.5–8.7 X 107 cfu/cm2. Two 0.2-μm-rated nylon 66 filters in series were unable to fully retain Ralstonia pickettii at 72 h, corresponding to a cumulative challenge of 2.4 X 107 cfu/cm2. The more extensive penetration of the nylon 66 membranes compared with that of the PVDF filters is in keeping with their greater degree of openness (10).


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