Risk-Based Approach

1. Risk-Based Approach Process Simulation Media Fills 10/22/02 OPS Advisory Committee/ Aseptic Processing/ Media Fill/ BUratani

2. 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

3. 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

4. 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

5. 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

6. Personnel • Number of personnel and their activities • shift changes and breaks

7. 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.

9. Back up slides

10. 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.

11. 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.

12. 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

13. 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 includedas 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.

14. 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.

15. 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