FDA has actively enforced its guidance on re-use of filters under GMP. An FDA Warning Letter to a sterile pharmaceutical
manufacturing facility has stated, "Failure to validate the extended re-use period of the (redacted) filters used for many
different injectable product formulations and batches. Validation rinse data was inadequate to support that ingredient residues
from the previous batch are removed... Your response (to the 483) failed to ensure that products (redacted) do not contain
unacceptable residues from prior batches of different products that used the same filters. The inspection found inadequate
validation rinse data to support that drug residue from the previous batch was removed. We are concerned of the possibility
of cross-contamination" (7).
Another FDA Warning Letter to a sterile ophthalmics manufacturer stated, "According to the establishment inspection report
you re-use sterilizing filters as long as they perform to the manufacturer's filter integrity standards of (redacted) or for
a maximum of your internal specification of 50 re-uses. We are concerned about the effectiveness of your filters after being
re-used and autoclaved 50 times. We understand that you conduct a filter integrity test by the (redacted) method before and
after each batch. However, in order to justify 50 re-uses, we would like to see bacterial retention validation studies using
product both upon the initial use of the filter and after the 50th re-use. Further, it is unclear to us whether you have conducted
filter extractable and leachable testing with product. If you have this data, provide it to us. If not, let us know when you
will be able to provide it to us" (8).
An FDA reviewer has stated publicly that reuse of sterilizing filters is "discouraged for sterile drug product," while
simultaneously recognizing that sterilizing-grade filter re-use is "common for API production" (9). The reviewer recommended,
"Microbial retention validation should incorporate multiple filtration and sterilization processes" and "correlate microbial
retention validation, filter integrity testing following multiple sterilization/filtration cycles, and sterility of API/product"
(10). FDA is now requesting that batch records indicate when sterile filters have been previously re-used, as stated in an
October 2008 483 observation (10).
Validation of filter re-use
Following PDA and FDA recommendations, a multiphase bacterial retention study program is indicated for validation of sterilizing
filtration with re-used filters. PDA Technical Report 26 (7, 8) and FDA's aseptic processing guidance (4) currently call for
preliminary bioburden studies of product or process fluid to determine suitability of conducting bacterial retention studies
on production filter membrane discs using either the standard bacterial challenge organism Brevundimonas diminuta (ATCC 19146) or a bioburden isolate under worst-case product and process conditions. These bacterial challenge tests should
include multiple filter membrane lots (typically three) and "at least one of the three membrane lots used for the bacterial
retention validation study should have a pre-study or pre-use physical integrity test value at or near the filter manufacturer's
test specification" (i.e., representing the least retentive membrane) (6).
A study of this extent would be sufficient to demonstrate the filter membrane's capability to sterilize the drug product or
process fluid on a single usage. The study would not, however, predict filter performance after multiple cleaning, resterilization,
and re-use cycles. Bacterial challenge should be conducted on production filters subject to actual, or preferably, worst-case
process conditions incorporating the full extent of multiple cleaning, rinsing, or resterilization and re-use cycles.
Re-use processes entailing multiple batches, either without inter-filter batch rinsing or with solvent rinsing between batches,
can often be scaled down and modeled at the bench. More complex re-use processes, however, such as those entailing multiple
cleaning and resterilization cycles, or drying between campaigns, are difficult to simulate in the laboratory with filter
discs, capsules, or even cartridges. In such cases, it is preferable to supplement the single batch disc challenge tests with
a series of bacterial challenges conducted on production filter cartridges that have been exposed to the full extent of actual
process use, cleaning, resterilization, and re-use cycles. Typical production cartridges are appropriate for this second phase
as "worst-case membrane" is assessed in the initial disc study and testing of used production cartridges serves to confirm
process compatibility as measured by maintenance of bacterial retention properties. Such tests may be the only means to determine
whether a filter's sterilizing properties remain unaffected by the multiple re-use process cycle conditions. Integrity tests
may be insufficient as demonstrated by the following case study.