Annex 1 and the move to isolators: what modern sterile manufacturing requires
Europe’s revised sterile-manufacturing rules require a contamination control strategy and favour barrier technology. Why it matters beyond Europe.
In this article
Injectables, eye drops and vaccines must be sterile. The rules for making them were rewritten in Europe’s revised EU GMP Annex 1, and the changes are shaping sterile plants and machinery worldwide.
The timeline
Annex 1 was revised in August 2022. Most requirements took effect on 25 August 2023, and the point on lyophilisation (8.123) has applied since 25 August 2024.
The key requirements
- Contamination Control Strategy (CCS): a mandatory, facility-wide strategy identifying all critical control points.
- Barrier technology: restricted access barrier systems (RABS), isolators, robotics and continuous monitoring are named as options; isolators with vaporised hydrogen peroxide decontamination separate people from product most effectively.
- Grade A conditions in the critical zone, with unidirectional airflow.
- PUPSIT: filter integrity testing before and after use for sterile-filtered products, unless justified by risk assessment.
- Media fills: generally twice a year per process, line and shift, with every operator taking part and an expected result of zero contaminated units.
As the guideline puts it: “Monitoring or testing alone does not give assurance of sterility.” Sterility comes from design, procedures and qualified systems.
Why Pakistani plants are watching
Regulated export markets expect Annex 1-level sterile manufacturing, and DRAP has made PIC/S GMP its inspection reference (see our PIC/S article). At the 2025 International Pharma Convention, Syntegon Telstar Technologies presented on “Annex 1 compliance, a must for sterile production.”
Cleanroom grades in brief
Annex 1 defines four grades of clean area for sterile manufacturing:
| Grade | Typical use |
|---|---|
| A | The critical zone where the product or its container is open — filling, stoppering, aseptic connections |
| B | The background room for Grade A in conventional aseptic processing and RABS |
| C | Less critical steps, such as preparing solutions to be filtered |
| D | Handling of components after washing and other supporting steps |
The grade of the surrounding room depends on the technology. A Grade A zone protected by a RABS sits in a Grade B room, with operators gowned accordingly. An isolator keeps Grade A inside a sealed enclosure, so the room around it can be of a lower grade — which reduces gowning, simplifies operations and lowers contamination risk from people.
RABS or isolator?
| RABS | Isolator | |
|---|---|---|
| Separation of people | Physical barrier, room air shared | Fully sealed enclosure |
| Decontamination | Manual cleaning and disinfection | Automated, often vaporised hydrogen peroxide |
| Background room | Grade B | Lower grade |
| Changeover | Generally simpler | Longer, but more reproducible |
Both are acceptable under Annex 1 when properly designed and qualified. Isolators give the strongest separation; RABS can be a practical choice for upgrading existing lines.
The Contamination Control Strategy in practice
The CCS is a living document that ties everything together: facility design, airflow and pressure cascades, water and utility systems, raw materials and components, cleaning and disinfection, personnel training and gowning, environmental monitoring and the review of all the data these produce. Writing one often reveals gaps — an unmonitored transfer point, an untested assumption about cleaning — which is precisely its purpose.
People are the biggest risk
In aseptic processing, people are the main source of contamination: skin cells, hair and movement all shed particles and microorganisms. That is why Annex 1 places so much weight on gowning qualification, training in aseptic behaviour, limiting the number of people in clean areas and keeping interventions to a minimum. Barrier technology helps by putting a wall between the operator and the open product, but well-trained, disciplined staff remain essential with any technology.
What it means for investment
| Area | Typical upgrade |
|---|---|
| Filling | RABS or isolator-based lines |
| Cleanrooms | HVAC, airflow and monitoring systems |
| Quality | Environmental monitoring and documented CCS |
New sterile projects such as local insulin and vaccines will be built to these standards. Cleanroom and sterile-equipment suppliers exhibit at Pharma Asia 2026.
