Navigating GMP Annex 1: How Single-Use Assemblies will Comply

What is Annex 1?

Annex 1 of EU GMP is a widely recognized guideline that sets forth the requirements for manufacturing sterile medicinal products, particularly those used in the biopharmaceutical industry. It plays a crucial role in ensuring product quality, patient safety, and regulatory compliance. One significant aspect influenced by Annex 1 is the use of single-use assemblies in fluid management processes. Annex 1 emphasizes the need for a risk-based approach to ensure the integrity and sterility of single-use systems used in fluid management processes. This article aims to provide an overview of GMP Annex 1, its applicability, and the necessary actions that biopharma industry stakeholders must take to comply with its requirements, particularly in relation to single-use assemblies.

Scope, Applicability and Impact on Single-Use Assemblies

GMP Annex 1, also known as the "Manufacture of Sterile Medicinal Products," is a guideline published by regulatory authorities, such as the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA). It outlines the principles and practices for the manufacture of sterile medicinal products to ensure their safety, efficacy, and quality as laid down in Commission Directive (EU) 2017/1572 for medical products for human use and veterinary use. 

Equipped to comply with Annex 1 with Single Use Support

To comply with GMP Annex 1, biopharma industry stakeholders must proactively evaluate their fluid management processes and single-use assemblies. This involves conducting thorough risk assessments, implementing robust quality management systems, validating and qualifying single-use systems, and establishing appropriate monitoring and control strategies. Regular training and documentation of procedures are also essential to ensure compliance with GMP Annex 1.

PUPSIT: Pre-Use Post Sterilization Integrity Test

According to the Annex 1, the integrity of the sterilized filter assembly should be verified by integrity testing before use to check for damage and loss of integrity caused by the filter preparation prior to use. The filter integrity testing procedure is called pre-use post sterilization integrity test or PUPSIT (8.87 in Annex 1).

PUPSIT is an important step in ensuring the sterility of the final product and is commonly used in the pharmaceutical, biotech, and medical device industries. Whenever sterile filtration is part of the filling process, pre-use post sterilization integrity must be implemented.

Read more: Annex 1 and the PUPSIT requirement

Single Use Support does supply biomanufacturers with a fully automated and modular system for filling and filtration, named RoSS.FILL. Its modularity results in process flexibility and scalability from few mL to hundreds of liters. It is possible to aliquot liquids into bottles and both 2D and 3D single-use bags of 10mL up to 1000L. A PUPSIT rack can be attached to automated aseptic filling platforms if sterile filtration is part of the manufacturer’s process. All of the required single-use assemblies to perform the filtration integrity test PUPSIT, can be supplied by Single Use Support.*

Annex 1 and beyond

Annex 1 sets minimum requirements for reducing contamination. However, it does not limit automated systems and further approaches to overperform. It primary goal is to best possible reduce operational errors due to human intervention and any other possible occurrences leading to product loss, bioburden, and leakages.

Single-use technologies are increasingly used on production lines and could help to ensure compliance. For example, single-use bioprocess containers make it easier to maintain sterility across powder and liquid transfers or open handling by manual filling.  Single use systems should be designed to reduce the need for manipulations and complexity of manual interventions. (8.132 of Annex 1). In detail this includes

• the interaction between the product and product contact surface (such as adsorption, or leachables and extractables)
• the fragile nature of the system compared with fixed reusable systems
• the performance of the pre- and post-use integrity testing for sterilizing grade filters
• the risk of holes and leakage
• the potential for compromising the system at the point of opening the outer packaging and
• the risk of particle contamination

 Single Use Support can provide customers with documentation, risk assessments and product specified information, such as data for extractables and leachables of single-use systems, proving how the company fulfills the criteria with its solutions.

Conclusion

GMP Annex 1 significantly impacts the use of single-use assemblies in fluid management processes within the biopharmaceutical industry. It requires manufacturers and stakeholders to adopt a risk-based approach, implement proper controls, and ensure the integrity and sterility of single-use systems. Compliance with GMP Annex 1 is essential to maintain product quality, meet regulatory requirements, and safeguard patient safety.

Single Use Support is pioneering the biopharmaceutical industry and is at the forefront of advancing fluid and cold chain solutions. The process solutions provider takes the same approach as Annex 1, that automated single-use technologies and closed and protected systems help reduce the risk of contamination. As a trusted partner to multiple biopharmaceutical manufacturers and contract development and manufacturing organizations, Single Use Support is here to offer guidance in achieving maximum product quality, patient safety and navigating GMP Annex 1.

^{* IRIS Single Use systems are developed product-specifically. All filter capsules available on the market can be installed. Filter types are selected depending on product and quantity. SUS takes the recommended redundancy into account. The use of high-pressure resistant material, such as braided silicone (platinum cured) tubing and the interconnection protection with Oetiker clamps enables leakage-free testing of the filter components prior to filtration at high pressures and filtration after testing. The recommended working pressure is determined during development of the assmenly and the feasibility of testing is ensured. The venting and flushing of the system is taken into account in the configuration. Each assemly is a custom solution for the manufacturers process}