Most frequently asked questions on the revised EU GMP Annex 1: Volume 1

In August 2022 the European Union revised its guidelines for sterile medicinal products for human and veterinary use. These guidelines came into effect on August 25, 2023. West has compiled the most frequently asked questions about Annex 1 and how it affects sterile drug manufacturers, which will be published across a multi-part series.

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EU GMP Annex 1 is a Good Manufacturing Practice (GMP) document published by the European Commission that is dedicated to the manufacture of sterile products. All pharmaceutical companies that produce sterile products for both human and animal health must comply with these regulations.

In August 2022, a comprehensive revision of EU GMP Annex 1 was released introducing significantly more stringent sterile manufacturing processes, including implementation of a contamination control strategy (CCS) and the recommended use of modern barrier technologies, such as restricted access barrier systems (RABS) and isolators, to reduce the risk of contamination.

The revised regulation became effective on August 25, 2023, with the exceptions of requirement for lyophilizers that are manually loaded or unloaded with no barrier technology separation to be sterilized before each load, which became effective one year later, on August 25, 2024.

This revision is a complete rewrite of the Annex and was a joint EU, PIC/S and WHO project, with U.S. FDA personnel actively involved.

The revised Annex 1 standards address advancements made in technology, regulatory expectations and industry practices in the manufacturing of sterile medicinal products. The revision aimed to enhance the clarity of the guidelines, ensure alignment with international standards, and incorporate new concepts that reflect modern risk management and quality assurance principles. Key reasons include:

• Technological Advancements
• Harmonization with international standards
• A risk-based approach
• Enhanced clarity & structure and inclusion of new concepts
• Response to industry feedback

These drive towards a lower level of contamination in finished drug product as contamination can have severe consequences for patients. Sterile drug product manufacturers will therefore need to prove to regulators that their packaging choices protect the drug product and the patient.

The revision introduces several significant changes aimed at improving the manufacturing and control of sterile medicinal products. Here are the key takeaways:

• Enhanced emphasis on quality risk management
• Introduction of the Contamination Control Strategy (CCS)
• Improved guidance on Aseptic Process Simulation (APS)
• Stricter environmental monitoring requirements
• Clarification on personnel qualification and training
• Focus on advanced technologies
• More detailed requirements for process validation
• Greater emphasis on data integrity
• Harmonization with international standards
• Expanded scope and applicability
• Increased focus on continuous improvement

All in all, the emphasis is on the sterile drug manufacturer to detail the risks and mitigations within their operations associated with contamination event opportunities. Also, there is additional emphasis on comprehensive end-to-end control of the container closure system and container closure integrity because of the impact that it has on control of microbial & particulate ingress.

There is an increased emphasis on personnel awareness, quality culture (behaviors) and controls, with a specific focus on principles involved in protection of sterile product during the manufacturing, packaging and distribution processes.

Yes, marketed drugs can be affected by the latest revisions as the updated guidelines apply to the manufacturing processes of all sterile medicinal products, including those already on the market. When reviewing the reasons for drug recalls, the FDA documented 36% of recalls are due to particulate or lack of sterility attributable to container closure.¹ This level of recalls forces the spotlight onto contamination control and is a consistent theme for regulatory agencies who are ever increasing their expectations around product quality.

An important aspect of the Annex 1 revision relates to the use of modern barrier technologies which aim to protect drug products from contamination. Such systems include isolators and restricted access barrier systems (RABS).

In the revised Annex, while using RABS and isolators is strongly encouraged, it is not mandated, and other options can be used if they are justified within the CCS. However, for new facilities or facility upgrades, there would need to be clear reasons why RABS or isolators weren’t the preferred options.

If you would like to read more about EU GMP Annex 1, click here