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Risk-Based Approach

Process Simulation
Media Fills

10/22/02 OPS Advisory Committee/ Aseptic Processing/ Media Fill/ BUratani


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Process Simulation: Media Fill
Objective of media fill
to evaluate the capability of the aseptic process to produce
sterile drug product

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
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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
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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
Stresses full duration media fills for manually intensive
processes

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Manual Manipulation
start-up manipulations: weight checks, aseptic
assembly of equipment
aseptic sample collections
aseptic additions (e.g., charging containers and
closures, addition of sterile ingredients)
interventions (routine and non-routine)
operator fatigue

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Personnel

Number of personnel and their activities


shift changes and breaks

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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.
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Back up slides

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Criteria for removal of intervention 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.

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Media Fill Assessment
Mathematics/ statistical approach
acceptance limit of < 0.1% contaminated units at 95%
confidence level (approx. 1 in 5000).
It is therefore important that every unit should be accounted
for.
FDA agrees with PDA that the target should be zero
contaminated units regardless of size of run.
Intermittent incidents of low contamination (e.g., 1:10,000)
can be indicative of persistent problem and need for
requalification.
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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
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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.
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Acceptance Criteria
All units should be fully accounted for and reconciled:
All integral units should be incubated and counted as part of
media fill assessment.
Intervention units can be removed and not included as part of
the media fill assessment if they met the predetermined criteria
(specified in the SOP) as to the type of intervention and # of
units removed.

Non-integral units (container/closure defects) can be removed.

All removed units (intervention and c-c defects) must


be documented in media fill batch record.

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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 35C for 7 days
1 temp: 20- 25oC for 14 days
media: TSB aerobic organisms, FTM for anaerobic
organisms

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