Annex 1: From Theory to Practice as a Central Standard for Aseptic Processes
Last updated: 29 January 2026
As Annex 1 of the EU-GMP Guideline (“Manufacture of Sterile Medicinal Products”), Annex 1 specifies the requirements for the manufacture of sterile medicinal products and defines detailed regulatory expectations, protection objectives, control principles, and verification methods. Another important point is Container-Closure Integrity (CCI) and the associated requirement for 100% integrity testing of blow-fill-seal (BFS) containers sealed by fusion. The specifications address manufacturers, equipment suppliers, and service providers involved in aseptic processes, combining structural, technical, and organizational requirements into a consistent quality framework.
Scope and Basic Principles
The guideline applies to the manufacture of sterile medicinal products - both aseptically filled and terminally sterilized - and includes fully automated production lines as well as processes with partial manual interventions. Core principles can also be transferred to other sterile applications. It requires every process to be analyzed along potential contamination pathways and technical and organizational measures to be aligned so that risks are systematically contained. Particular attention is given to the interaction between spatial design, air handling systems, and material logistics, as these areas present numerous transfer possibilities. Additionally, the guideline requires a closely monitored control environment in which cleanroom classes, cleaning concepts, and process parameters are clearly defined, monitored, and documented. The principles of complete documentation and continuous improvement form the methodological framework that ensures manufacturing processes remain under control permanently, not just qualified once.
Core Elements of the Contamination Control Strategy
The Contamination Control Strategy (CCS) is at the heart of the regulation and demands comprehensive preventive planning. In the Annex 1 glossary, CCS is defined as a planned set of controls for microorganisms, endotoxins/pyrogens, and particles, derived from the current understanding of the product and process, designed to secure process performance and product quality. Each process chain must be systematically analyzed to identify critical control points. Then, action packages are implemented, combining physical barriers, technical solutions, and procedural rules. Typical CCS components include:
- closed production zones and barrier systems
- standardized hygiene routines and clothing requirements
- validated cleaning and disinfection procedures
The guideline also requires monitoring mechanisms to record particulate and microbiological data and enable trend analyses.
Process Design, Machinery, and Technical Requirements
In process design, minimizing direct human intervention plays a central role. The requirements favor closed systems, automatic controls, and technologies where contact risks are reduced. Engineering measures include airflow concepts, pressure zones, filter standards, and physical separation of material and personnel flow. The regulation also requires traceable validation of technical equipment, including suitability tests, routine function checks, and documentation proving reliable operation. For machine manufacturers, this results in requirements concerning design, cleanability, and accessibility for inspection. The Blow-Fill-Seal (BFS) technology by Rommelag is the optimal solution, as the containers are formed, filled, and sealed directly within the system. Using BFS technology, the Annex 1 requirement for minimal human intervention and closed process operation can be ideally implemented. In particular, the local Grade A air protection of the critical filling zone can lead to significantly reduced cleanroom requirements in the background area (e.g., Grade C). Such technology offers numerous advantages by minimizing interaction points and thus contamination risks, ensuring high process reliability through a fully automated, closed process.
Validation, Simulation, and Release Criteria
The guideline requires solid evidence that aseptic processes can consistently deliver sterile products. Validations are based on comprehensive tests covering both individual processes and entire systems. Aseptic process simulations (e.g., media fills) are considered central tools for identifying potential weaknesses. Qualification of rooms, air-handling systems, and control instruments is also required. The release of production runs must be tied to clearly defined criteria, including microbiological and particulate indicators. Through recurring testing and trend analysis, process control remains verifiable.
Personnel Rules, Training, and Organizational Aspects
Human behavior remains a major source of contamination; therefore, the guideline sets strict requirements for personnel qualification and conduct. Personnel may only work in aseptic areas after targeted training and qualification. Clothing requirements, cleanroom behavior, and regular competency assessments are part of the organizational protection system. The guideline also requires clear assignment of responsibilities - duties for operations, quality assurance, and maintenance must be clearly defined.
Impact on Manufacturers, Suppliers, and Technology Providers
The requirements lead to tangible changes in production planning, investment decisions, and supply chain coordination. Manufacturers are required to maintain CCS documentation, establish validation programs, and operate monitoring concepts. Suppliers - such as producers of primary packaging materials or cleaning chemicals - must evaluate their products within the risk context of aseptic production. Overall, the regulation fosters greater integration of technical, procedural, and organizational solutions across the entire value chain.
Innovation and Technology Trends in Implementation
In practice, the regulation encourages technologies that reduce direct interaction and enhance monitoring. Barrier systems, isolators, and automated filling platforms are gaining importance as they provide a stable separation between product and operators. In this context, BFS technology serves not only as an automated filling platform but as a particularly advanced aseptic filling technology that has met the current regulatory trend (closed systems, barriers) for decades. Meanwhile, the growing use of digital technologies leads to new forms of monitoring and analysis: networked sensors, continuous data logging, and automated trend evaluations enable faster response to deviations.
Checkpoints for Practical Implementation
For practical implementation, a step-by-step approach is recommended: first, perform a gap analysis to identify existing deviations from the requirements. Then, set priorities, plan actions, and define responsibilities. Typical measures include modifications to building and ventilation systems, the introduction of closed process lines, updating SOPs, and intensive employee training. Finally, validation, monitoring, and an audit cycle follow to ensure compliance.
Conclusion: Significance for Quality and Product Safety
The existing guideline defines a consistent, practice-oriented framework for the manufacture of sterile products. By linking risk management, technology, and organization, it creates a foundation that makes processes plannable, controllable, and auditable. In the long term, this orientation promotes more reliable processes that meet the requirements of authorities, customers, and end users to a high degree.