A Practical Approach to Root Cause Analysis
Production and quality teams immediately escalate the issue. Sterile production managers convene to assess the situation, and urgent decisions are made. Often, the areas where the APS was performed are placed under quarantine. Commercial sterile production may continue only until the current batches are completed, but no new batches are started until the cause of the positive APS result has been determined.
Typically, a special “war room” is set up, and a team of subject matter experts (SMEs) and quality representatives is assembled to begin the investigation.
Why It Matters
A failed APS has immediate and significant operational and regulatory consequences.
First, all sterile products are considered part of the investigation until the root cause is identified. As a result, product release is suspended.
Second, regulatory authorities must be notified. In Belgium, for example, companies are required to inform the Federal Agency for Medicines and Health Products that production of the affected product has been temporarily suspended due to a failed APS and that a root cause investigation is underway.
Finally, lengthy investigations can lead to production downtime, supply risks, regulatory scrutiny, and higher operational costs. For manufacturers of sterile products, the pressure to quickly and accurately identify the root cause is therefore enormous.
Typical Pitfalls in APS Investigations
In practice, there are several challenges that often complicate the root cause investigation following a failed APS.
- Unclear scope of the investigation: At the start of the investigation, the scope is often broad. If the investigation is not structured, teams may struggle to determine which products, processes, or production lines are actually affected.
- Lack of cross-functional expertise: A comprehensive root cause analysis requires expertise from multiple disciplines, including microbiology, engineering, quality, and manufacturing. Without the right expertise, investigations may overlook critical factors.
- Insufficient environmental data: Investigations sometimes lack supporting data on environmental monitoring or airflow analysis, making it difficult to identify the actual source of the contamination.
- Delayed coordination and decision-making: Without structured meetings and clear responsibilities, investigations can lose momentum, and corrective actions may be delayed.
- Delays in coordination and decision-making: Without structured meetings and clear responsibilities, investigations can lose momentum and corrective actions may be delayed.
Normec Advipro’s Approach in Practice
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1.
Rapid setup of the investigation
A structured investigation framework is established immediately. SMEs and quality representatives form a dedicated investigation team, which often operates from a central “war room.”
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2.
Broad initial assessment of the scope
At the start of the investigation, all sterile products are considered to be within the scope until there is sufficient evidence to narrow the scope of the investigation.
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3.
Structured investigation management
Daily meetings at various levels help monitor progress, track action items, and ensure accountability within the teams.
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4.
Technical Support for the Investigation
Technical investigations focus on identifying potential contamination pathways. Data from environmental monitoring are evaluated, and, if relevant, additional studies are conducted, such as air visualization studies (AVS) and microbial sampling.
As evidence is gathered, the scope of the investigation can be gradually refined, allowing certain production lines to resume operations while corrective and preventive actions (CAPAs) are implemented.
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5.
Resumption of Production
Before commercial production can resume, several conditions must be met.
Three consecutive successful APS runs should be completed to demonstrate that the process is back under control. In addition, regulatory authorities should provide a positive recommendation before commercial manufacturing resumes.
Practical Recommendations
Based on our experience supporting manufacturers of sterile products, there are several approaches that can significantly improve APS investigations.
Begin the root cause analysis immediately: by engaging the investigation team quickly, production downtime is minimized and crucial data is captured while events are still fresh in everyone’s memory.
Use structured investigation management: Daily progress meetings and clear action tracking help maintain momentum and prevent delays.
Include airflow and environmental surveys where relevant: Visualization of airflow and microbial sampling can reveal contamination pathways that are not immediately visible.
Concluding Thoughts
A structured investigation approach, supported by the right expertise and technical tools, can significantly improve both the speed and quality of the root cause analysis following a failed APS.
If your organization is facing a complex investigation into sterile manufacturing, Normec Advipro’s experienced experts can support you with investigation management, technical studies, and the implementation of corrective actions. Normec Advipro’s MoVE team also provides support for air visualization studies (AVS) and environmental monitoring.
Meet our Normec expert:
Evelien Fossépré
Project Engineer
Evelien Fossépré is a consultant at Normec Advipro and specializes in sterile manufacturing and infection control. She is a certified QP with leadership experience in packaging and sterile preparation and has a QA background in the sterile department. In addition, she has experience supporting pharmaceutical manufacturers with investigations and validation activities, helping companies strengthen their regulatory compliance and operational reliability.
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