APR Sept/Oct 2023 - 112

» MICROBIOLOGY
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2.
Bracketing or matrix approach can be used for various
container/closure combinations for the same or different
products if process equivalence is scientifically justified. The
matrix approach is acceptable for a range of product/container
sizes. For example, the largest (longest time to fill) and smallest
(fastest speed of filling machine) containers should be included
in the APS protocol, together with an intermediate container
size/filling speed if there are more than three product/
container sizes in the matrix.
3. Maximum hold time for products and equipment during the
APS. Supplementary microbiological testing of items such as
wrapped sterilized containers, or wrapped sterilized filling
machine components should be used to support maximum
holding times of containers or equipment (as stated in the
batch record or production SOP).
4. The media fill volume in the container should be sufficient
to contact all the interior surfaces that could potentially be
the site of contamination in the sterile product. Additionally,
there needs to be sufficient headspace in the filled container
to support potential microbial growth.
5.
Inert gas used in routine operation should be substituted
with equivalent flow of air to support microbial growth. An
exception is when detection of anaerobic microorganisms
is intended.
6. The nutrient media selected should be capable of growing a
group of reference microorganisms stated in pharmacopeia,
for example USP, and growth promotion testing of such
microorganisms needs to be confirmed for the media batches
used. The array of microorganisms should also include
representative local microorganism isolates.
7. The detection methods for environmental microbial
contamination should be reliable and validated. Common
methods are active air sampling, contact plates, and settle
plates. The contact plates typically need to incorporate an
agent to neutralize disinfectant residues.
8. The APS should be of sufficient duration to challenge
the entire process, and include all necessary operators,
all interventions, shift changes and the capability of the
operational environment to produce a sterile product. For
example, if the media fill batch size is to be smaller than
routine batch size, the filling may be divided into sections,
and the line may be paused temporarily in between the filling
sections to achieve the desired overall APS duration.
9. Filling operation shifts that extend or change personnel must
capture operator fatigue and include the shift changeover(s)
as shift changeover involves entry of new personnel and
increased activities in the room. The APS should be designed to
capture factors that pose a risk to product sterility and qualify
the maximum time the operators can work in the cleanroom.
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10. Interventions done when the process is idle such as shift
changeover, recharging dispensing vessels, introduction of
additional equipment etc., should be included in APS.
11. Environmental monitoring is to be performed for the entire
duration of APS, as required for routine production.
12. For campaign manufacturing, APS batches are to be
performed at the beginning and at the end of each campaign
to simulate contamination risks during the campaign run. The
objective is to demonstrate that the campaign duration does
not pose any risk to the product.
13. Routine APS is required, but " End of production APS " may be
used for additional investigative purposes if justification is
provided. If used, it must be demonstrated that the product
residue does not inhibit microbial growth.
For sterile active substance preparation, the media batch size should
be large enough to represent routine operation and sufficient
to simulate worst case interventions. Simulated material such as
surrogate materials or growth media are to be subjected to microbial
growth evaluation. The surrogate material selected should be
similar in physical characteristics and rheological properties to the
material it is to replace in the APS. Additionally, the most important
selection criteria is that the surrogate material should not jeopardize
the recovery of microorganisms, i.e., should not be bactericidal
or bacteriostatic to the positive growth control organisms when
suspended in the APS medium.
Similar to the previous version of the Annex 1, the new Annex 1
states that APS is required for initial validation of a sterile facility, and
also after significant modification of facilities, operational practices,
and services or equipment that may have an impact on the sterility
assurance of the product. The initial requirement is three successful
consecutive batches of APS, and subsequently, six monthly periodic
revalidation batches for each aseptic process, filling line and shift. The
new Annex 1 offers that all operators should participate in at least one
successful APS annually. It is also recommended to perform an APS
prior to line shut down or long period of inactivity, to demonstrate that
the batches made before the planned shutdown/period of inactivity
did not have contamination issues during processing.
As small-scale manual aseptic compounding and filling processes
have higher risk of contamination than an automated process, the
qualification requirements for operators are more stringent. It is
expected that each operator should take part in three successful
consecutive initial APS batches, followed by revalidation by
participation in one successful APS approximately every six months.
This is commensurate with the higher level of risk associated with
manual aseptic filling processes. Again, the APS batch size needs to
mimic the actual manual filling production operation, and also in this
case, all the container sizes and equipment train need to be included
in APS.
APR Sept/Oct 2023

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