Risk-Based Approach

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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 lt 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., 110,000) 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