Achieving Successful Sterilizing Grade Filter Qualification
A review of field and laboratory bacterial retention validation data for a variety of fluids and challenge conditions suggests
that low surface tension fluids, such as many adjuvants and adjuvanted vaccines, present a higher risk of the occurrence of
a bacterial penetration event during sterilizing filter validation (Table 3). Among the classified solutions examined, liposome
solutions represent the highest risk, followed by lipid and finally surfactant solutions. B. diminuta bacteria loading above 1 x 108 CFU/cm2 (>10 times the minimum required challenge density) increases the chance of a penetrative event, as does a loading rate of
greater than 1 x 105 CFU/min. For liposome, lipid, and surfactant solutions, bacterial challenge using constant flow may present a higher risk
and we would hence recommend conducting validation studies and operating processes of low surface tension adjuvants and adjuvanted
vaccines at constant pressure.
Table 3. Summary of the results of metadata analysis. Risk is qualitatively defined here as the likelihood of an occurrence
of bacterial penetration during retention validation challenge.
The analysis discussed herein, along with published work by other filter manufacturers, strongly suggests that although bacterial
retention by sterilizing grade filters is most commonly achieved by size exclusion, it occasionally can be strongly influenced
by the nature of some feed solutions (surface tension, particle size), processing conditions (constant pressure versus constant
flow, temperature, operating pressure), membrane structure, and bacterial challenge test conditions (bacterial challenge load,
loading rate). Based on the reviewed data, clearly no single membrane is successful in all applications.
For the successful sterilizing filtration of adjuvants and adjuvanted vaccines, we recommend filter users consider the risk
of reduced bacterial retention very early in the process, i.e., when designing the formulation, the filtration operating conditions
and sequence, and when drafting the sterilizing filtration validation bacterial challenge test protocol. Several membrane
candidates for bacterial retention should be tested along with filterability studies, to arrive at the candidate offering
both complete bacterial retention and providing the highest filtration capacity for superior process economy. Because of the
impact of operating conditions on bacterial retention, it is important to maintain process consistency during scale-up and
to design the process with the end in mind.