APR Sept/Oct 2023 - 40

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BIOPHARMACEUTICAL
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* Type of media to be used with rationale
* Number and types of interventions
* Number, identity and roles of personnel
* Environmental monitoring to be performed
* Accountability of units filled
*
Incubation conditions and durations
*
Inspection of units - pre-incubation, post incubation
and intermediate
* Acceptance criteria
* Conditions of exclusion of vials from incubation (this should
be rare)
* Growth promotion
* Conditions for invalidating/cancelling - decision
making authority
* Personnel training requirements
* Details about batch record to be used
* Documentation requirements for the final report
Batch Record
A detailed batch record (BR) written in the same format as the
production BR with the same data recording and verification/sign off
requirements should be in place.
An additional section detailing the step-by-step performance of the
Interventions should be a part of this BR. All interventions performed
(planned and unplanned) with details such as time, operators involved,
duration, the identity of the tray filled, any line stoppages, sample
units removed, should be clearly documented. All results should be a
part of the batch record including:
* Environmental and personnel monitoring results
* Number of units filled, number of units incubated,
full accountability
* Number of units rejected pre-incubation with cause
for rejection
* Results of inspection - number of units positive for growth, tray
identity, detailed investigation with root cause and corrective/
preventive actions
* Growth promotion of media after incubation
* Record of activities and occurrences during the APS
* Any deviations/OOS
* A Final Report which evaluates the entire aseptic process
simulation and formulates a conclusion on the acceptability of
the APS is required.
* Quality unit oversight of the entire process including
observation in real time
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| September/October 2023
Points to Consider for APS
* Number of APS - for new line/process a minimum of three (3)
APS are required. For ongoing requalification - minimum semiannual.
If different processes are performed on the same line,
each process has to be re-evaluated semi-annually.
* Container closure - if multiple sizes of containers of the same
type and in same process are used, a bracketing approach
(smallest-largest) may be used.
* Filling speed-generally should be set at production filling
range. However, if higher or lower speeds present " worst
case " conditions those may be used. For example, bracketing
approach of highest speed with smallest unit (operational
challenge-PM generation) or slowest speed with largest vial
(larger neck size - maximum exposure) may be used.
* Fill volume- container need not be filled to full capacity.
Amount of media should be sufficient to contact all container-
closure surfaces when inverted and allow for detection of
microbial growth.
* Media used - most common medium used is Soybean Casein
Digest Medium (SCDM). This medium is capable of supporting the
growth of aerobic microorganisms commonly found in the clean
room environment and personnel samples. If the process being
validated is anaerobic then Fluid Thioglycolate Medium (FTM)
may be used.
*
Inert gassing - Typically nitrogen or other inert gases are used to
protect oxygen-sensitive products and also to provide positive
pressure for transfer. For APS the nitrogen should be replaced by
air using the same method of delivery and at the same steps.
Duration and Number of Units Filled
The duration should simulate the longest fill or be representative
of routine operations. The duration should be sufficient to allow all
interventions and process steps to be executed. Number of units filled
during APS should be based on contamination risk and sufficient to
simulate the process. Generally, 5,000-10,000 units are considered
acceptable for average production runs.1
* For production batches less than 5,000 units, the APS batch
should be equal to the production batch size.
* For production batches of 5,000 to 10,000 units, the APS batch
should be comparable in size (5,000-10,000 units).
* For production batches >10,000 units, the APS batch should be
> 10,000 units with several approaches to the batch size and
filling process.
Interventions
Activities performed by personnel in proximity to the aseptic fill zone
are called Interventions. Some of these are unavoidable and part of
the process. However, Interventions in aseptic processes should be
APR Sept/Oct 2023

Table of Contents for the Digital Edition of APR Sept/Oct 2023
