Biopharmaceuticals commonly cannot be terminally sterilised, as such aseptic processing using sterilising grade filtration
is essential. Heat sterilisation, or any energetic input into biotech drug products, causes undesired product degradation
so the only available option is sterilised filtration of the biopharmaceutical fluid. Sterilising membrane filtration has
been used for decades, and there is a very high experience and expertise level within the industry. As such, the process is
reliable and well understood when properly validated. Filtration is also often required to reduce bioburden levels within
process streams to avoid potential biofilm formation; for example within purification steps and/or elevated endotoxin levels.
Getty/ Tom Nule
Process validation of sterilising grade filters is a fundamental task to ensure and verify the performance of the filter used
within the process conditions and fluid stream. Process validation means that the specified membrane filter is subjected to
a bacteria challenge test in accordance with ASTM 838-05, utilising the process parameters of the filtration process and,
if possible, the actual fluid product. If the fluid has properties that are detrimental to the challenge organisms, a placebo
as close as possible to the actual drug product, is required. The effect of the fluid stream on the organisms needs to be
tested using viability tests.
An additional validation test is chemical compatibility to check whether or not the filter membrane and construction is suited
for both the product to be filtered and the process conditions. Leachable and particulate matter tests may also be necessary
to determine any foreign subject matter release into the drug product. Often forgotten, but essential for biopharmaceutical
filtration, are unspecific adsorption studies, which not only determine the fouling rates of the membrane polymer, but also
the yield losses onto the filter membrane. These tests can be performed when filters are tested and scaled in filterability
trial work. When filters are in line steam sterilised, the sterilisation process requires qualification to prove that it does
not damage the filter. Other qualification data, such as gamma sterilisation robustness and efficiency, endotoxin level, integrity
test limits and oxidisable substances can be obtained from the filter manufacturer.
The author says...
Over-sterilisation is sometimes cited as a concern. Beside other key attributes, sterility is key to an injectable drug product;
therefore I would hesitate to utilise the word "over-sterilisation". Safety and sterilisation robustness are essential, and
one has to ensure that sterility is achieved by appropriate measurements, qualification and validation. If one wants to classify
something as "over sterilised", it could be through the use of either redundant filtration or filter ratings, which are inappropriate
for the application.
More important than adding filters or tighter pore sizes are process validation procedures, which verify that the filter does
what it is supposed to do: retain the organism level and species found in the upstream fluid and create a sterile effluent.
When a sterilising grade filter is properly validated and evidence has been obtained that it performs to required specifications,
why would one need a second one or move to a tighter pore size?
The only reason would be insurance, which creates an immediate insecurity notion. Another "over-sterilisation" aspect could
be the European restriction of a maximum 10 cfu/100 mL in front of a sterilising grade filter. Why are end-users of sterilising
grade filter bound to such a restriction, when the filters are commonly challenged with 107 organisms per cm2? If one utilises the example of a 1000 L volume with a bioburden of 10 cfu/100 mL being filtered through a 10 in. filter
element of 0.6 m2, the challenge would be 16 organisms per cm2, far below the validation challenge test level of 107 per cm2. That sounds very much like overkill!