EU GMP Annex 1 (2022)

Annex 1 applies to the manufacture of sterile medicinal products — terminal sterilisation, aseptic processing, and the limited sterile manufacture of certain non-medicinal materials used in product. The 2022 revision was developed jointly between EMA, PIC/S and WHO so the same text governs EU manufacturers, PIC/S members (including UK, Australia, Canada, Singapore and others) and WHO-prequalified facilities.

Effective dates: 25 August 2023 for the body of the Annex; 25 August 2024 for the PUPSIT requirement (Section 8.87). Facilities and inspectorates have been operating under the revised Annex through 2024-2025.

The CCS is the single largest change. Annex 1 requires every sterile-manufacturing facility to maintain a documented, integrated Contamination Control Strategy that consolidates every existing control — facility and equipment design, utilities, personnel, environmental and personnel monitoring, process validation, sterilisation, materials, ongoing control — into one coherent strategy with documented links to the underlying risk assessments.

The CCS is not a collection of SOPs or a binder of risk assessments. It is a controlled document that demonstrates how the contamination risks have been collectively identified, assessed and controlled, and how each control is verified. It must be kept current and reviewed when the facility, process or product changes.

PUPSIT is integrity testing of sterilising-grade filters after they have been sterilised in place but before they are used to filter the product. The argument is that filter defects can be masked during filtration (by retained material or by wetting effects), so post-use integrity testing alone can miss a compromised filter.

Annex 1 makes PUPSIT the default. It can be omitted only where a documented risk assessment justifies the omission — typically because the filter design, the sterilisation method, or the process configuration makes PUPSIT impractical or itself introduces a contamination risk that exceeds the risk it would mitigate.

The PUPSIT requirement was deferred to 25 August 2024 to give industry time to retrofit lines. As of 2025, omissions must be supported by a documented, multidisciplinary risk assessment kept current with the CCS.

Annex 1 effectively makes isolators or RABS the default for new aseptic processing lines. Open aseptic processing in a traditional cleanroom remains permitted but is held to a higher justification bar — the operator must demonstrate why a barrier technology is not used and how the contamination risk is controlled to an equivalent level.

For isolators, Annex 1 prescribes Grade A inside the isolator with the background classification driven by the risk assessment (Grade D is often acceptable). For RABS, the background must be Grade B and the open-door interventions are scrutinised heavily.

EM under Annex 1 (2022) is explicitly QRM-driven. The locations, frequencies and methods are determined by a documented risk assessment based on the product, the process, the equipment and the personnel flows. The Annex retains the Grade A/B/C/D limits but is much more prescriptive about the use of trended data, alert and action limits, and the mandatory linkage of EM to the CCS.

Personnel monitoring (gowning qualification, ongoing glove print and gown sample monitoring) is held to the same standard — risk-based, trended and linked to the CCS.

APS expectations are sharply higher. The minimum size of each media fill remains at the historically-used range (typically a minimum of 5000-10000 units depending on the batch size, with statistical justification), but Annex 1 (2022) emphasises that the media fill must simulate worst-case interventions, the maximum permitted holding times, line stoppages, shift changes and operator fatigue.

Acceptance criterion: zero contaminated units for runs below 5000 (with investigation if any units fail); for 5000-10000 units one contaminated unit triggers investigation and any second triggers revalidation; above 10000 units, two contaminated units trigger investigation. Any contaminated unit must be investigated to root cause.

Annex 1 (2022) embeds ICH Q9 (now Q9(R1)) explicitly into every key decision: line design, gowning qualification frequency, EM plan design, intervention classification, APS design, validation strategy. The expectation is that risk assessments are written, current, multidisciplinary, and traceable to the CCS.

Personnel are treated as the highest-risk contamination source. Annex 1 requires risk-based gowning qualification, ongoing qualification (with a frequency justified by risk), restrictions on the number of operators in critical areas, and explicit consideration of fatigue and shift length in the CCS. Operators performing aseptic interventions must be qualified for each intervention type.

• CCS exists as a binder of references rather than an integrated document.
• PUPSIT omission risk assessment is one paragraph rather than a substantive analysis.
• EM plan is unchanged from pre-2022 frequency-based design.
• APS does not simulate worst-case hold times or interventions.
• Personnel qualification frequency is not risk-justified.
• Open aseptic interventions in RABS without justification of why a closed alternative was not used.
• Lack of trended data driving the CCS reviews.