This informal CPD article ‘Risk-Based Approaches to Aseptic Process Simulation’, was provided by Pharmalliance Consulting, who offer specialist support to pharmaceutical companies to maintain and increase quality compliance levels.
Introduction
In aseptic manufacturing, there is no room for error. Even the slightest contamination can put patients at risk. That is why Aseptic Process Simulation (APS), also known as media fills, is so important. It tests whether aseptic techniques, personnel, and processes are working as they should.
EU Annex 1 encourages a risk-based approach to APS. Instead of following a standard checklist, manufacturers need to design media fills that reflect real risks in their production environment. A well-designed APS is not just about meeting regulations. It helps identify weak points before they turn into serious contamination issues.
Designing a Compliant Aseptic Process Simulation
A strong APS should mirror actual production and push the process to its limits. The goal is to:
- Simulate normal and worst-case scenario operations as realistically as possible.
- Test how the process holds up under stress, such as frequent interventions or long hold times.
Annex 1 requires that all testing conditions be backed by a risk assessment. Key factors to consider include:
- Using full-scale batch sizes to reflect real production.
- Involving both experienced and new operators to assess consistency.
- Running tests under normal conditions and right after cleaning to check for variability.
- Simulating routine interventions, like equipment adjustments or minor breakdowns.
- Performing runs at the slowest and fastest line speeds to understand process risks at different operating conditions.
Selecting the Right Growth Media
The success of an APS depends on choosing the right growth media to detect contamination. EU Annex 1 states that APS media must:
- Be capable of growing a wide range of microorganisms typically found in pharmaceutical environments.
- Undergo Growth Promotion Testing (GPT) before and after use to confirm effectiveness.
- Handled carefully to avoid false positives.
Commonly used media include:
- Soybean Casein Digest Medium (SCDM), which supports bacteria, yeast, and mold growth.
- Tryptic Soy Broth (TSB), a high-nutrient medium for detecting aerobic bacteria and fungi.
Before use, media must be tested to ensure suitability. After APS, incubated units should be re-tested to confirm they remain viable.
Defining APS Acceptance Criteria
EU Annex 1 sets strict limits on contamination in APS results:
- For batches under 5,000 units: No contamination is allowed. Any failure requires immediate investigation.
- For batches between 5,000 and 10,000 units: A single contaminated unit is acceptable. Anything more requires a full root cause analysis.
- For batches over 10,000 units: Up to two contaminated units are allowed. Any contamination must still be investigated.
If a media fill fails, production must stop until:
- The root cause of failure is identified.
- Corrective and Preventative Actions (CAPAs) are put in place.
- A Re-validation confirms that the issue has been resolved.
Conclusion
APS is more than just a box to check for regulatory compliance. It's a vital step in ensuring the sterility of pharmaceutical products. Taking a risk-based approach allows manufacturers to focus on real-world contamination risks, not just following a set of rules. When APS is done right, it helps identify potential issues early, improves the overall process, and, most importantly, ensures patient safety.
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References:
The European Commission, 2022. EU Annex 1, Brussels, Belgium.
