The revised version of EU GMP Annex 1 was published in 2022 and has applied since 25 August 2023. Only section 8.123, on the design of lyophiliser loading and unloading and the frequency of their sterilisation, has applied since 25 August 2024. The Annex applies to the manufacture of sterile medicinal products. Its principles can also be used for other products; the Annex gives certain liquids, creams and ointments, and low-bioburden biological intermediates as examples. Manufacturers who do this should document which principles they apply. In practice, some GMP laboratories also use it as a reference. For technical managers, qualification managers and project managers, the question is therefore less whether the Annex is relevant and more where exactly it affects their own equipment and facilities.
The Contamination Control Strategy as the common thread
The most important structural change is the Contamination Control Strategy (CCS). It requires a manufacturer to describe and assess its measures against microbial, particulate and pyrogen contamination as one coherent system rather than in isolation.
For technical systems, this means that the cleanroom, HVAC system, water system, compressed air supply, sterilisation processes and monitoring are no longer separate topics. They are building blocks of a shared strategy. The CCS should be able to explain what each system contributes to contamination control, how that contribution is demonstrated and how weaknesses are detected. The basis for this is documented quality risk management. Decisions on design, qualification scope and monitoring should be justified on the basis of risk.
In practice, this is often where the first gap appears. The technical documents exist, but they are not linked to the CCS. An inspector who asks for the rationale behind a particular monitoring location expects a traceable path from the risk assessment to the measure.
Cleanroom and HVAC
Classification is only one part of qualification
Annex 1 treats the classification of a cleanroom as part of its qualification. Classification assesses air cleanliness by measuring the total particle concentration and compares it with the intended cleanroom grade (A to D). Measurements are taken at rest and in (simulated) operation, and the limits are given in Table 1 of the Annex. Qualification as a whole goes further. It shows that the room and the HVAC system are designed, installed and operated so that the required conditions are reliably achieved. This includes filter integrity, air volumes, differential pressures, airflow direction and recovery times, among other things. Qualification should also be clearly differentiated from routine environmental monitoring.
If you file a classification report as complete evidence of qualification, or present monitoring data as qualification, you can rightly expect questions in an audit. How the qualification stages build on each other is described in the article DQ, IQ, OQ, PQ explained.
Airflow, pressure cascades and recovery times
The Annex places particular emphasis on demonstrating that the airflow in critical zones actually protects the product. Airflow visualisation studies (smoke studies) should show that air in grade A areas flows in a directed way away from the critical point, and that interventions by personnel do not disturb this flow in an unfavourable way. The studies should be performed at rest and in operation, for example with simulated interventions. The video recordings are retained, and the outcome is documented and taken into account when the environmental monitoring programme is set up.
For adjacent rooms of different grades, the Annex gives a differential pressure of at least 10 Pa as a guidance value. Differential pressures identified as critical should be continuously monitored and recorded, and a warning system should indicate any drop immediately. Other differential pressures are monitored and recorded at regular intervals. Recovery times are also part of qualification. This is the time a room needs after operations end, or after a disturbance, to return to the at-rest particle limits. The Annex gives a guidance value of < 20 min for this. The acceptance criteria should be defined and justified in advance.
Environmental monitoring
Environmental monitoring for particles and microorganisms is not just a routine programme. It is a tool of the CCS. Sampling locations, frequencies and methods should be derived from a risk assessment. Action limits must not exceed the maximum values in Tables 5 and 6 of the Annex. Alert levels are based on the results of qualification and are reviewed periodically against trend data. In grade A areas, particles should be monitored continuously for the full duration of critical operations, including equipment assembly. For grade B, the Annex recommends a similar system.
The technically relevant points are the selection and qualification of the monitoring systems, the positioning of the sampling probes, the data integrity of the records and the evaluation of trends. If trend analyses exist only on paper and do not feed into decisions, inspectors regularly notice.
Water, steam and gases
Utilities are also in focus. Water systems should be designed, operated and monitored so that microbial contamination is prevented and the risk of biofilm formation is minimised. Aspects such as circulation, dead legs and materials are part of qualification, and sanitisation follows a defined schedule. For pure steam used as a direct sterilising agent, the condensate should meet the monograph for Water for Injections of the relevant pharmacopoeia. A sampling schedule ensures that representative steam is analysed on a regular basis.
Gases and compressed air that come into direct contact with the product or product-contact surfaces should be supplied in a suitable quality. Gases used in aseptic processes should be filtered at the point of use through a sterilising-grade filter with a nominal pore size of no more than 0.22 µm. Where the filter is used on a batch basis or as a product vessel vent filter, it should be integrity tested. The Annex also calls for periodic microbial monitoring of the gas at the point of use. With compressed air in particular, product contact in existing facilities is often underestimated, so it is worth looking at every point of use. It has proven useful to specify the required compressed air quality in the URS as classes according to ISO 8573-1.
Barrier systems
According to Annex 1, RABS and isolators are beneficial in assuring the required conditions and in minimising microbial contamination from direct interventions in the critical zone. Their use should be considered in the CCS, and any alternative approach should be justified. For isolators, glove integrity should be tested at least at the beginning and end of each batch or campaign; for RABS, at periodic intervals. The isolator itself is leak tested at defined intervals. Decontamination includes a sporicidal agent, for example vaporised hydrogen peroxide. It must also be demonstrated that unidirectional airflow is maintained across the whole of the grade A area.
The role of documentation and risk assessment
Many Annex 1 requirements are not new, but they are now enforced much more consistently. The difference often lies in the depth of justification. Inspectors expect decisions on design, qualification scope and monitoring to be derived from risk assessments in a traceable way, and they expect these assessments to be kept up to date. A well-maintained traceability matrix helps to show the path from the requirement through the risk assessment to the test evidence.
A practical approach: the gap analysis
For existing facilities, a structured gap analysis has proven useful. It provides a sound basis for prioritisation and budget planning.
- Define the scope: Which rooms, systems and processes fall under the Annex, or should be aligned with it voluntarily?
- Take stock: Collect the existing URS, qualification reports, risk assessments, SOPs and monitoring concepts.
- Compare: Set the requirements against what exists, topic by topic. Use one row per system, rated “met”, “partially met” or “open”.
- Assess the risk of the gaps: Not every gap has the same impact. Address gaps with a direct effect on product protection first.
- Action plan: Define actions with owners and deadlines, and manage technical changes through change control.
- Link to the CCS: Transfer the results and rationales into the Contamination Control Strategy.
A simplified structure for the comparison table could look like this:
| System | Topic | Existing evidence | Rating | Action |
|---|---|---|---|---|
| Cleanroom / HVAC | Airflow visualisation, grade A | Study available, without interventions | partially met | Extend study to include interventions |
| Compressed air | Product contact | List of points of use incomplete | open | Record points of use, check filters |
| Monitoring | Rationale for sampling locations | Location plan without risk assessment | partially met | Complete the risk assessment |
The example rows are for illustration only. The actual topics depend on your facility and your product portfolio.
What about medical devices?
Annex 1 is not binding for medical devices. ISO 13485 applies instead, in the EU through the MDR’s requirements for the quality management system. For the US market, the QMSR (21 CFR Part 820) applies, which has incorporated ISO 13485 by reference since 2 February 2026. Risk management follows ISO 14971, and cleanrooms are classified according to ISO 14644-1 classes, such as ISO 7 or ISO 8, supplemented by the company’s own SOPs. In practice, Annex 1 is still often used as a point of reference, but without cleanroom grades A to D.
Conclusion
Annex 1 shifts the focus from individual pieces of evidence to coherent contamination control justified on the basis of risk. For technical systems, this means that qualification, monitoring and documentation must not merely exist. They must be linked with each other and with the CCS. If you approach a gap analysis in a structured way, you will see early on where evidence is missing and where only the rationale needs sharpening. You can find support with assessment and implementation under GMP consulting.