Annex 1 – Solutions for successful implementation and compliance with regulations

Annex 1 simply explained

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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