The revised EU GMP Annex 1 has been binding for the manufacture of sterile medicinal products since 25 August 2023. This short checklist names eight points that inspections typically focus on, and states for each one which evidence must be in place. Freely readable, without registration and without an email address.
Each point states the checkpoint question, the expected evidence and the gap we encounter most often in practice.
Question: is there a facility-wide CCS derived from the actual risks, and is its effectiveness assessed? The CCS is the centrepiece of the revised Annex 1: it brings together technical, organisational and procedural measures across the entire facility and justifies why they are sufficient in combination.
Evidence: a standalone, periodically reviewed document with risk linkage and effectiveness assessment.
Common gap: the CCS is an index of existing documents, without any assessment of the overall effect.
Question: are classification and qualification cleanly separated, and are both current? Classification follows ISO 14644-1 at rest and in operation; qualification additionally covers recovery time, pressure differentials, filter integrity and airflow visualisation for grade A.
Evidence: valid classification reports and requalification within the Annex 1 intervals, more frequent for grades A and B than for grades C and D.
Common gap: airflow visualisation from commissioning only, not repeated after structural or process changes.
Question: is the separation of operator and product implemented technically, and is the chosen solution justified? Annex 1 expects barrier technology to be considered; where it is in use, decontamination and tightness must be evidenced.
Evidence: validated decontamination cycle, isolator leak test, documented glove integrity testing, defined and trained interventions.
Common gap: glove testing without a defined frequency and without any link to the process simulation.
Question: are the product-contact media qualified and continuously monitored? This covers pharmaceutical water up to WFI, cleanroom air and compressed gases.
Evidence: water qualities to pharmacopoeia with sampling plan and trend analysis, qualified HVAC, filtered product-contact gases with tested filter integrity.
Common gap: compressed gases are treated as a technical utility; integrity testing of the gas filters is documented nowhere.
Question: does the simulation reflect the real process including worst-case conditions? Annex 1 provides for repetition normally every six months per aseptic process, line and shift.
Evidence: simulation records including everyday interventions and interruptions, defined acceptance criteria and an investigation of every contamination found.
Common gap: the simulated interventions are tidier than real operations, because the list was never gathered from the shop floor.
Question: is every person entering grade A or B qualified and regularly requalified? This includes gowning qualification as much as behaviour in the cleanroom.
Evidence: initial qualification including gowning qualification, periodic requalification, controlled access and the link to personnel monitoring.
Common gap: requalification runs purely by calendar, without reference to that person's monitoring results.
Question: does the monitoring derive from the CCS, or from habit? Every sampling location needs a rationale, grade A requires continuous particle monitoring.
Evidence: risk-based sampling plan with a rationale per location, defined alert and action limits, evaluated trends with documented response.
Common gap: trends are recorded but not evaluated; excursions end without root cause analysis.
Question: do the records for monitoring, process simulation and release withstand scrutiny? Data integrity requirements apply to exactly these records, on paper as well as in the system.
Evidence: attributable, legible, contemporaneous, original and accurate, plus complete, consistent, enduring and available; active audit trail with a defined review.
Common gap: the audit trail is active, but nobody reviews it; a review procedure is missing.
Eight points do not replace a gap analysis. They do show quickly whether the chain of evidence breaks at a point that audits examine regularly. Anyone who can evidence all eight stands on solid ground for Annex 1. Anyone who hesitates on two or three has already narrowed down where the work lies.
The detailed background to the Contamination Control Strategy is in our technical article on the revised Annex 1. How cleanroom and HVAC qualification works in practice is described on the corresponding service page.
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