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EU GMP guidelines for the manufacturing of sterile medicinal products

Annex 1 – Solutions for successful implementation and compliance with regulations

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Annex 1 at a glance

Annex 1 is part of the EU GMP guidelines. The revised EU Annex 1 came into effect in August 2023. It defines requirements for the manufacturing of sterile medicinal products with the goal of minimizing contamination risks and ensuring maximum patient safety. A Contamination Control Strategy (CCS) serves as the foundation for all processes, aiming to identify and mitigate potential risks. Cleanroom classification, barrier technologies such as isolators and RABS, and validated sterilization methods are essential to achieving compliance. Continuous environmental monitoring ensures sterility. Annex 1 applies to all manufacturers of sterile medicinal products in the EU, as well as exporters to the EU.

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Annex 1 simply explained

Regulation for the manufacture of sterile medicinal products

Expansion from originally 16 to now 58 pages

Preventing product contamination

Your challenges – Our solutions

Handling aid Annex 1 Syringe machine

Design and operational equipment

A wide range of innovative technologies help you master key production challenges. Whether it’s new acquisitions, modernization, process optimization to prevent contamination, or risk management – we offer carefully planned, field-tested solutions.

Filling and closing machine  4-headed  Filling and closing machine

Environmental and process monitoring

We support you in implementing continuous monitoring and documentation processes, ensuring data integrity in monitoring systems, as well as validation-compliant documentation and qualification. With solutions for real-time particle monitoring systems (e.g., BioTrak), we ensure efficient and compliant processes.

Glove intervention pharma machine, barrier technology

Barrier technology

Isolator technologies, RABS systems, and digital monitoring solutions enhance safety and efficiency in the production process. Our fully integrated solutions, including turnkey isolators and CSPE approaches, cover everything from flow optimization to fully integrated Factory Acceptance Testing (FAT) for maximum safety. Additionally, the intelligent use of robotics – leveraging software and automation, including AI – reduces glove interventions.

Pharmaceutical machines, production and specific technologies

Production and specific technologies

The validation and qualification of cleaning and disinfection processes are essential for safe production workflows. We offer solutions such as PUPSIT (Pre-Use Post-Sterilization Integrity Test), effective sterilization methods for freeze dryers, and automated loading and unloading systems to optimize efficiency and compliance.

Portrait Johannes Thomas Grobe
Dr. Johannes-Thomas Grobe, Chairman, OPTIMA pharma GmbH

Annex 1 defines the strict standards for the manufacture of sterile medicinal products – and with Optima as your partner, you benefit from decades of expertise and state-of-the-art technology to help you meet the highest quality requirements.

Dr. Johannes-Thomas Grobe, Chairman, OPTIMA pharma GmbH
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Whitepaper
Erfahrungen aus der Praxis

Annex 1: Expert knowledge and practical examples for download

Would you like to optimize your processes in compliance with Annex 1 and learn more about our expertise? We are happy to share our knowledge with you. Download our free whitepaper “Name” to gain valuable insights into our solutions and real-world experience.

Why OPTIMA?

Partnership
Competence
Safety

You can always rely on OPTIMA

Tailored Annex 1 solutions and support from concept to operation and beyond: With extensive practical experience, innovative technologies, and a holistic approach, we help you optimize your production processes—individually, efficiently, and with a focus on the bigger picture. For maximum safety in the manufacturing of your pharmaceutical products.

Ralf Wagner
Do you have any questions about our systems and turnkey solutions or would you like to discuss your specific requirements with us?
Ralf Wagner
Director Sales EUR/AMS, OPTIMA pharma
Ralf Wagner
Ralf Wagner
Director Sales EUR/AMS, OPTIMA pharma
+49 791 9495-2460 Write e-mail

Exciting blog articles on Annex 1

More blog posts

Frequently asked questions

  • Do OPTIMA machines comply with the "First Air" principles, and how does OPTIMA ensure that the design meets these requirements?
    The principles of Annex 1 are carefully examined and incorporated into the detailed design of all our machines. Various methods and tools are employed to ensure that "Second Air" is avoided, including Computational Fluid Dynamics (CFD) analysis, which visualizes airflow during production and process interventions. Complete turnkey lines with isolators and loading zones for freeze-drying systems can be dynamically simulated in a virtual environment. Through these simulations, the laminar flow can be analyzed and optimized concerning First and Second Air within the project. As a result, system optimizations are already implemented during the engineering phase. Pharmaceutical companies and CDMOs can integrate Optima's flow simulations into their Contamination Control Strategy (CCS) to document facility optimization. The collected data and insights are demonstrated using a specific mock-up model, discussed in detail, and individually agreed upon with the customer.
     
  • Is the use of isolators the only option for production according to Annex 1?
    According to Annex 1, §4.3, isolators are the preferred solution. The use of isolators in sterile manufacturing is a highly secure option which has significantly increased in recent years. However, an open RABS system is still permitted. In general, the choice of containment concept for a filling line should be based on a clearly defined Contamination Control Strategy (CCS). This ensures that all regulatory requirements are met and that appropriate contamination control measures are implemented. Special attention must also be given to handling both direct and indirect product-contact parts to minimize contamination risks and ensure compliance with Annex 1 guidelines.
     
  • What is Optima's philosophy regarding glove minimization?
    According to EU Annex 1 regulations, glove interventions in isolators should be avoided whenever possible. Every glove attached to an isolator presents an inherent risk due to its mere existence. However, it is important to first consider the risk assessment of glove interventions, as the level of risk can vary significantly. For example, a glove intervention in the dosing area, where open containers are present, carries a much higher risk compared to a glove intervention after crimping, where the containers are already sealed. Therefore, not all glove interventions pose the same level of risk. To reduce or eliminate glove interventions in a risk-based and customer-specific manner, Optima follows a philosophy that incorporates a portfolio of glove-minimizing solutions. Instead of offering a single machine type, Optima provides a range of diverse solutions that are compatible with almost all machine types and configurations. The "appropriate" solution is always tailored to the individual customer, depending on the process, budget, and operational philosophy of the company. Technology options should reflect these varied customer requirements.
     
  • Is the Pre-Use Post-Sterilization Integrity Test (PUPSIT) mandatory for product filters?
    Pre-Use Post-Sterilization Integrity Tests (PUPSIT) are now mandatory for product filters under the revised Annex 1 (§8.82 ff.). In certain cases, PUPSIT may be omitted, but this must be justifiably documented within the framework of the Contamination Control Strategy (CCS).
     
  • Where is the air speed measured, i.e., what is defined as the "working position?"
    Air speed is typically measured 300 mm below the CG membrane, which corresponds to the current industry standard. Alternative measurement positions are possible, but depend on individual circumstances and must be agreed upon based on the specific technical solution. Air speed is set according to DIN EN ISO 14644-3 and documented during qualification.
     

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Portrait Ralf Wagner
Do you have questions or specific requirements? Talk to Optima's experts about your project.
Ralf Wagner
Director Sales EUR/AMS, OPTIMA pharma
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