Aseptic Process Simulation: Why the “Old” Media Fill Is No Longer Enough in the Annex 1 Era

For decades, many viewed the “Media Fill” as an exam to pass every six months: fill, incubate, hope everything remains clear, then get back to production. With the entry into force of the 2022 revision of EU GMP Annex 1, this view is obsolete—and dangerous. Today we speak of Aseptic Process Simulation (APS), a term that emphasizes the need to simulate not only the filling operation, but the entire aseptic process, its vulnerabilities, and its interactions with the Contamination Control Strategy (CCS).

The Paradigm Shift: From Test to Strategy

APS is not an isolated activity. New guidance (not only EU, but also PIC/S and WHO) requires APS to be designed on the basis of rigorous Quality Risk Management (QRM). It is no longer acceptable to say, “we do it as usual.” Instead, organizations must ask:

• What are the weak points of my process?
• What is the real “worst case” in terms of operator fatigue?
• Do the simulated interventions truly cover everyday risks?

Impact on Patient Safety

A well-designed APS is the final verification barrier before a process is considered safe for patients. A test performed under “ideal” conditions (rested operators, no failures, reduced speed) provides false reassurance. Annex 1 requires APS to challenge the process: difficult shifts, simulated mechanical breakdowns, and environmental limit conditions must be included.

Key Points for Pharma Professionals

• Zero Target: The acceptance criterion is unequivocal: zero contaminated units. Any growth is a failure requiring a thorough investigation.
• CCS Integration: APS verifies the effectiveness of the Contamination Control Strategy. If the CCS states that risks are mitigated by airflow patterns, APS must demonstrate this—even during invasive interventions.
• Technology-Specific Approach: Requirements differ depending on whether isolators, RABS, or manual processes are used. A one-size-fits-all approach no longer works.

FAQ: Frequently Asked Questions on APS

How often must Media Fills be performed?
The standard frequency is semi-annual for each line and each operating shift. Every qualified operator must participate in at least one APS per year.

Can units be discarded during APS?
Yes, but only if discarding is предусмотрed in production SOPs for that specific situation (e.g., initial setup). Discarding units “just to be safe” without procedural justification is a critical violation.

What happens if a single unit is found contaminated?
This constitutes an APS failure. It requires a formal investigation (Root Cause Analysis), corrective actions (CAPA), and the successful completion of three consecutive media fills before the process can be revalidated.

Conclusion

APS is the mirror of your sterile operations’ quality. Transforming it from a bureaucratic requirement into a scientific tool is the key to peace of mind—for you and, most importantly, for patients.

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