Risk Based Inspection (RBI) – Schedule M Point 4.9 (Microbiological detection levels for EM limits)
In RBI, inspectors focus more deeply on contamination control because failures can directly affect patient safety. Risk-based inspection planning typically varies the frequency, depth, and scope of review based on estimated risk to patients/product quality and compliance signals. PIC/S+1
Schedule M (Revised) point 4.9 requires that the manufacturer establish “levels of detection” of microbial contamination specifically to (1) set alert and action limits and (2) monitor trends in environmental cleanliness. It also provides recommended CFU limits (Table 3) for microbiological monitoring of clean areas in operation and clarifies these values are not specifications, but guidance information. This wording aligns with WHO sterile GMP guidance (TRS 961, Annex 6), which uses the same principle and example limits. World Health Organization
What “levels of detection” means in practice (what RBI checks)
Inspectors expect a documented Environmental Monitoring (EM) program that defines:
- Sampling methods appropriate to grades and operations (e.g., active air sampling, settle plates, contact plates/swabs, glove prints), with justified exposure times/locations.
- Detection capability and data quality: incubation conditions, media suitability, handling of plates, and controls that prevent false negatives/positives.
- Alert/action limit strategy: how limits are derived (baseline data from qualification, routine trends, process risk), and how Table 3 guidance is applied without treating it as a fixed “pass/fail spec.”
Trend monitoring and response (high RBI emphasis)
RBI doesn’t only ask “did you exceed limits?”—it asks “do you detect drift early?”
- Trending by room, grade, operation, shift, line, intervention type, and personnel.
- Defined triggers for trend investigations (repeated alerts, new organism types, seasonal spikes, recurring operator glove contamination).
- Robust investigation + CAPA: immediate containment, batch impact assessment, root-cause (HVAC, cleaning, gowning, behaviors), and effectiveness checks. (This expectation links tightly to Schedule M 4.10 on investigations when limits/trends occur.)
Common RBI gaps: using Table 3 as a rigid spec without site data, weak trending, “re-sample and close” investigations, and poor linkage between EM results and batch release review.