APR Sept/Oct 2023 - 113

« MICROBIOLOGY
In the new Annex 1, the batch size requirement is unchanged. The
typical number of units to be filled is a minimum of 5000 to 10000
units. For batch sizes that are smaller than 5000 units, the number of
containers filled should be at least equal to the production batch size
and should be sufficient to simulate all the activities and interventions
in the aseptic filling process.
Incubation and Assessment of Results
Filled APS containers should be agitated, swirled, or inverted before
incubation to ensure contact of the media with all interior surfaces
in the container. The number of reject containers during the APS
batch should not be more than the number of rejects during routine
production batches including, for example, those containers that are
rejected during the start-up of filling. All integral containers should be
incubated, including those with cosmetic defects and those that have
undergone non-destructive in-process control checks.
Where processes include materials that contact the product contact
surfaces but are then discarded (e.g., product flushes), the discarded
material should be simulated with nutrient media and be incubated
as part of the APS.
Clear containers should be used in APS to facilitate the inspection of
media for turbidity during incubation - opaque containers may be
substituted with clear containers of the same configuration. In the case
where such substitution is not possible, a suitable method of detection
of microbial contamination should be developed. Microorganisms
isolated from contaminated containers in APS must be identified to
the species level to help in the investigation and identification of root
cause of contamination source.
Filled media containers should be incubated with minimum delay
(the limit should be stated in protocol). The incubation conditions
and duration must be scientifically justified and validated to provide
an appropriate level of assurance of recovery of contaminating
microorganisms. This is typically seven days at 20 - 25˚C, followed by
seven more days at 30 - 35˚C.
Only trained and qualified personnel may perform the inspection of
incubated containers for any sign of microbial contamination. Positive
control tests should be performed on sterile (no growth) samples
of the filled containers at the end of incubation, using compendial
reference strains of microorganisms or local isolates.
The target for media fill is still zero contaminated units, but in the
new Annex 1 revision the investigation and revalidation strategy
based on batch sizes and number of contaminated units (stated in
the previous version) has been removed. Any contaminated unit is
now to be regarded as a failed APS, and an investigation to determine
the most probable root cause of the contamination, appropriate
corrective actions, and revalidation of APS is expected. In addition,
the company is also expected to quarantine any product batches
manufactured, pending the outcome of the investigation. If the root
cause is determined to be due to operator error, re-training and requalification
of the operators is required. Production can resume only
after the completion of the investigation and the revalidation of the
aseptic process by successful further APS batches.
The APS Batch records should contain records of details such as
reconciliation of container numbers, start and end times of batches,
interventions and process pauses, and the initials of the operators
involved in the interventions. Justification for filled and non-incubated
units, and all microbial data should be recorded in the batch record.
The new version of Annex 1 also includes paragraph 9.48, " An APS
run should be aborted only under circumstances in which written
procedures require commercial lots to be equally handled. " Criteria
for stopping or aborting production batches should be defined in
production and/or quality documentation, and APS batches should
only be stopped or aborted in accordance with the same criteria. An
investigation should be documented in all such cases.
When an aseptic process has not been in operation for an extended
period of time, a repeat of the initial three APS batches is required
before continuing manufacture. Repeat of the initial APS is also
required if there is a change to the process, equipment, procedures or
environment that have the potential to impact the sterility assurance
of the process or products, or if there are changes in the containers or
container closure combinations.
Conclusion
From our review of the new EU Annex 1 " Manufacture of Sterile
Medicinal Products, " there are more requirements related to Aseptic
Process Simulation
(APS) than in the previous version. Details
previously available in related guidance documents have now been
incorporated in the new GMP Rules.
More specific details of APS may be referenced in our articles published
in 20222,3
and references therein; many points covered in these articles
are relevant to the new EU Annex 1.
References
1.
European Commission, Brussels. " The Rules Governing Medicinal Products in the European
Union, Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal products for
Human and Veterinary Use " ; Annex 1 " Manufacture of Sterile Medicinal Products " , 2022
August 22, 58 pages ( " New EU Annex 1 " ). (Replaces " Rules Governing Medicinal Products
in the EU " , Volume 4 Good Manufacturing Practice; Annex 1 " Manufacture of Sterile
Medicinal Products " , 2009).
2.
3.
" Validation of Aseptic Processes by Media Filling " , R. Chai and D. Barber, ISPE Pharmaceutical
Engineering, 2022 March/April, vol 42 (2) pp.50-57.
" Considerations for Validating Aseptic Manufacturing Processes " , R. Chai and D. Barber,
A3_La Vague No 74, 2022 July, pp.12-16.
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