This informal CPD article ‘When Media Fills Miss the Mark: What Inspectors Are Finding in APS Programs’, was provided by Pharmalliance Consulting, who offer specialist support to pharmaceutical companies to maintain and increase quality compliance levels.
Media fills are supposed to prove that your aseptic process works. But for many companies, this key validation step is falling short, and inspectors are noticing. Over the past two years, regulators have made it clear that an Aseptic Process Simulation (APS) that doesn’t reflect the real process is no validation at all.
What “Representative” Really Means
Inspectors are looking for media fills that match the full scope of production. That includes:
- Batch sizes that match the largest commercial runs.
- Real-time simulation of interventions like line adjustments or component reloads.
- Matching fill speeds and durations to actual production.
The Problem with “Sanitised” Simulations
It’s not just about time or scale. Inspectors have also flagged media fills where key interventions were left out or performed in ways that don’t reflect the real thing. In one case, investigators discovered that a facility's media fills did not accurately simulate commercial operations; the aseptic operations during media fills were not sufficiently representative of the actual manufacturing processes for injectable suspensions.
Lessons from Recent Warnings
In another instance, the FDA cited a facility for failing to simulate worst-case scenarios during its Aseptic Process Simulations (APS). The firm did not demonstrate simulations that included the largest number of container units aseptically filled, the longest filling durations, or the performance of identified interventions by fully qualified aseptic filling operators. This omission underscored the necessity of incorporating worst-case conditions into APS to ensure the robustness of aseptic processes.
Involvement of Routine Operators
One area that continues to be flagged in inspections is the use of non-routine or overly experienced personnel during media fills. Regulators expect APS runs to include the actual operators who conduct day-to-day filling activities, including newer or less experienced staff. This helps to capture real variation in technique and reinforces the purpose of the simulation, to reflect real working conditions. In several inspections, authorities have criticised companies for using only senior technicians during media fills, which may not reveal procedural lapses seen in typical operations.
Environmental Monitoring During APS
Another issue that has come up frequently is how companies handle environmental monitoring during media fills. Some firms either reduce sampling or skip certain points entirely, viewing the simulation as separate from production. But regulators have made it clear that full environmental monitoring must be maintained during APS, just as it would be during commercial batches. This includes viable and non-viable particle monitoring in critical zones. Missing this step can raise questions about how the firm would detect or respond to contamination during a real run.
Conclusion
A media fill that doesn’t reflect real risks won’t hold up during an inspection. By making APS conditions match actual production challenges, companies can avoid the most common findings and ensure their aseptic process is truly validated.
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References
U.S. Food and Drug Administration, 2023. Warning Letters Database, United States of America.
The European Commission, 2022. EU Annex 1, Brussels, Belgium.
International Society for Pharmaceutical Engineering, 2023. FDA Regulatory Panel: 2023 ISPE Aseptic Conference, Maryland, United States of America.
