Many are familiar with it – but few are prepared: the revised EU GMP Annex 1 has been in force since 25 August 2023, and the transition period for freeze dryers ended in August 2024. Since then, the new guideline for the manufacture of sterile drugs has been the subject of discussion in the pharmaceutical industry – albeit often only among experts. In the day-to-day operations of many pharmaceutical plant operators and planners, however, there is still a surprising lack of urgency – but that could change at a moment's notice with a visit from the authorities.
‘Protection of vested rights’ is often the argument used to explain why the new requirements have not yet been actively addressed. After all, existing plants may continue to be operated – provided that no changes are made. But this is precisely the crux of the matter: anyone who intervenes in existing processes, modernises or replans now will no longer be able to avoid the stricter requirements of the new Annex 1.
What is new – and what specifically will change in day-to-day operations?
The revised Annex 1 guideline is more comprehensive and precise. The text has been expanded and is divided into ten clearly structured sections. The key changes primarily concern:
- the contamination control strategy (CCS): the CCS is the centrepiece of the new Annex 1. Operators must demonstrate a consistent strategy for avoiding contamination in their facilities and processes – from the delivery of raw materials to bottling. This includes, among other things, environmental monitoring, cleaning validation, material flows, personal hygiene and technical barriers (RABS, isolators). What was previously considered ‘best practice’ is now a mandatory standard. Not only do facilities have to be safe, but safety must be documented in a traceable manner at all times.
- Quality risk management (QRM): Risk management is also being tightened: operators must systematically assess hazards throughout the entire product life cycle and regularly update their measures. The higher the risk of contamination, the stricter the requirements.
- cleanroom and environmental monitoring: Another key change concerns cleanroom planning and qualification. New requirements include the mandatory visualisation of airflows during cleanroom qualification and the more precise requirements for lock concepts and material flows. The specifications for personnel hygiene have become stricter (e.g. sterile protective clothing in classes A/B) – as a result, the lock concept must be reconsidered.
What does this mean for pharmaceutical plant operators?
The first step is to ask yourself honestly: What specifically affects me now? And what will only affect me when I start planning a new project?
Immediate action is required for:
- Sterilisation processes: These must function daily and verifiably, for example through leak tests.
- Data integrity: All process documentation must be ALCOA-compliant – in other words, it must be traceable, legible, timely and unalterable.
- Cleanroom monitoring: Existing facilities in particular should be critically examined – is the existing technology still Annex 1 compliant?
Long-term measures:
- Review and, if necessary, adaptation of the entire CCS and QRM
- Planning of future facilities strictly in accordance with Annex 1
- Training and awareness-raising among personnel
- Evaluation of technological optimisations (RABS, isolators, automation)
What will change for suppliers and outfitters of pharmaceutical plants?
The new Annex 1 will also be a crucial test for manufacturers and suppliers of pharmaceutical equipment. In the future, suppliers should be involved in the planning much earlier – keyword: Design Qualification (DQ). This phase of qualification was neglected for a long time, but is now becoming extremely important. This is because errors in the specification cost a lot of time and money later on.
Suppliers should prepare for the following requirements:
- Proof of CCS conformity of their products
- Support with DQ and specification creation
- Interface capability to IT systems (e.g. for data integrity)
- Consulting expertise on Annex 1-compliant solutions (e.g. lock concepts, flow visualisation)
