This informal CPD article ‘Worst-Case or Worst Excuse? The Push for Realistic Aseptic Simulations’, was provided by Pharmalliance Consulting, who offer specialist support to pharmaceutical companies to maintain and increase quality compliance levels.
“Worst-case” conditions in aseptic simulations aren’t optional, they’re central. But not every company treats them that way. Inspectors are now zeroing in on how firms define and apply worst-case parameters in their media fills. When that part of the Aseptic Process Simulation (APS) is vague or absent, it’s one of the first things they call out.
What Inspectors Expect
Worst-case conditions can include:
• Maximum fill volumes and line speeds.
• Longest run durations and idle times.
• Challenging manual interventions by the least experienced qualified operators.
FDA inspectors are clear: these must be intentionally built into the APS, not just assumed. For example, in several 2023 inspections, firms were cited for running short, simplified simulations that didn’t match real production challenges.
Real-World Findings
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. At one facility, inspectors noted that the media fill excluded the most complex operator intervention, one that occurred in nearly every commercial batch. This oversight suggested that the media fill did not adequately challenge the aseptic process, potentially compromising the validation of the manufacturing operation.
A Trend Toward Data-Driven APS Design
Regulators are encouraging companies to use actual manufacturing data to define worst-case conditions. This includes analysing line downtime, run-time records, intervention logs, and EM data. The days of “best-guess” APS design are fading.
Including Atypical but Critical Interventions
One area that often gets missed is the inclusion of non-routine interventions that still occur with some frequency. For example, minor line stoppages, sensor resets, or manual component loading may happen during production but are left out of simulations for the sake of convenience. Inspectors have recently noted that omitting these scenarios can weaken the credibility of the validation effort. A media fill that doesn’t simulate these common “what if” moments may not demonstrate that the line can maintain sterility under real conditions.
Consistency Across Shifts and Operators
Some regulators have also begun looking at how consistently worst-case simulations are applied across shifts and operators. If an APS is only executed by the most experienced team during regular hours, it misses potential variability. A more complete picture includes weekend or night-shift operators and may involve scenarios that test different crew configurations. This also aligns with recent regulatory language about demonstrating process robustness, not just repeatability.
Bringing Quality and Operations Together
In some of the stronger APS programs reviewed by inspectors, QA and Operations work together from the start of simulation planning. QA brings oversight and documentation clarity, while Operations ensures the simulation mirrors the realities of day-to-day production. When these groups collaborate on defining worst-case elements, the outcome is usually more complete and better aligned with regulatory expectations. This type of partnership also helps ensure buy-in from operators who are responsible for executing the APS on the floor.
Conclusion
If your APS skips the hardest parts of the process, it won’t pass inspection. Worst-case isn’t just a theoretical concept, it’s what inspectors want to see challenged in real time. Better to simulate now than explain later!
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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.
Parental Drug Association, 2011. Technical Report No. 22 (Revised 2011) Process Simulation for Aseptically Filled Products, Maryland, United States of America.
