Media Fills / Process
Simulation
Process Simulation: Media Fill
Objective of media fill
To evaluate the capability of the aseptic process to produce
sterile drug product
To learn how failures have to be evaluated and what
consequences they have
Use of risk-based approach in media fill design
Incorporate the same risk factors for contamination that
occur in production runs
Incorporate the worst case conditions that can occur in the
operation:
the process
the manufacturing environment, and
the operators
Critical Factors
Study Design - Accuracy of Simulation
simulate actual process as closely as possible, and
address worst-case conditions
Critical risk factors for contamination
duration and size of run
line speed: filling speeds
manual manipulations
personnel (number, shift changes,
fatigue)
routine and non-routine interventions
Size and Duration of Media Fill Run
Size: number of units filled should be sufficient to
reflect the effect of potential operator fatigue, and
adequately represent the maximum number of
interventions.
Duration: long enough to challenge or stress the
process, the environment, and the operators
Stressesfull duration media fills for manually
intensive processes
Personnel
Number of personnel and their activities
shift changes and breaks
Media Fill Assessment
Concept paper provides guidance for:
Criteria for removal of media fill units:
The interventions in media fill should simulate what
occurs in a commercial production run.
Where units can be removed as part of an intervention,
SOPs should include sufficient detail with respect to type
of intervention and number of units removed
Media fill records should document all interventions
performed and the number of units removed.
Unit accountability and reconciliation: integral and non-
integral units. Incubation of all integral units.
Unit Accountability and Reconciliation
Unit reconciliation, e.g.
# units filled = # units incubated + # units rejected for cause + # units for growth
promotion
Accountability for all units removed
during manual interventions
at final inspection, non-integral units with container-closure defects
All integral units (including units with cosmetic defects) should be incubated and
counted as part of media fill evaluation
Unit Inspection (container/closure defects)
Pre-incubation inspection: When a firm performs a
final production inspection of units immediately after
the media fill run, only those units found to be
defective in container/closure integrity can be
removed. Units with cosmetic defects should be
incubated and included as part of the media fill run.
Post-incubation inspection: Units found to be
damaged after the pre-incubation inspection should
be included as part of the media fill batch because
such units would also likely to have escaped
detection during normal production and be released
to the market.
Acceptance Criteria
When filling fewer than 5000 units, no contaminated units should
be detected. –
One (1) contaminated unit is considered cause for revalidation,
following an investigation. •
When filling from 5,000 to 10,000 units: --
One (1) contaminated unit should result in an investigation,
including consideration of a repeat media fill.
-- Two (2) contaminated units are considered cause for
revalidation, following investigation. • When filling more than
10,000 units: --
One (1) contaminated unit should result in an investigation. –
Two (2) contaminated units are considered cause for revalidation,
following investigation. acceptance limit of < 0.1% contaminated
units at 95% confidence level (approx. 1 in 5000).
FDA agrees with PDA that the target should be zero
contaminated units regardless of size of run.
Media and incubation temp
Temperature and media chosen should bases
on its ability to recover microorganism
normally found environmentally or in the
product bioburden.
Temp: 20-35oC
2 temp: 20-25oC for 7 days, followed by 30-35oC for 7 days
media: TSB aerobic organisms, FTM for anaerobic
organisms
Guide lines
Pharmaceutical regulations:
- Regulations: FDA “guidance for industry, sterile drug
products produced by aseptic processing – cGMP” -
- EU GMP Part I annex 1 –
- PIC/S PI 007-2 “recommendations on the validation of
aseptic process”
CONCLUSION
Even if all media fills are negative in a Company, it does
not necessarily indicate that no products were ever
possibly contaminated because the frequency
requirement of media fill testing is so minimal that it is
not statistically significant
A robust media fill programme is a necessary step to
validate process
Media fill testing is just one part of a necessary overall
quality assurance program (HVAC qualification, cleaning
procedure, sanitization, personnel training, …)
