Most frequently asked questions on the revised EU GMP Annex 1 : Volume 2

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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1. What are the 2 major themes in the revised EU GMP Annex 1 involving primary packaging components?

The 2 major themes in the revision are:

1. Implementing a holistic Contamination Control Strategy (CCS) including comprehensive end-to-end control of the container closure system and,
2. Additional focus on Container Closure Integrity (CCI) due to its impact on the control of microbial ingress and particulates.

Regarding CCS, there is a larger focus on monitoring and reduction of particulates, microbial contaminants and sterility assurance.

Regarding CCI, which is critical for ensuring the sterility and overall quality of sterile medicinal products, the manufacturer must understand and mitigate the factors affecting the ability of a container and its closure system (such as vials, syringes, or ampoules) to maintain a sterile barrier against potential contaminants throughout the product's shelf life.

2. What is a CCS?

The CCS is probably the most significant part of the revised EU GMP Annex 1. A CCS is a high-level document that addresses how manufacturers plan to address and mitigate the risk of contamination to their products.The need for a CCS isn't new, but rather formalizes efforts required by sterile drug manufacturers to set out a plan for controlling contamination. However, the need to combine the various elements into one "strategy" document that describes how different elements interact may be new for some manufacturers.

3. Is West compliant with EU GMP Annex 1?

A deliberate and well-documented CCS is one of the new focuses in the EU GMP Annex 1 revision. Specifically, section 8.2 defines "Primary packaging containers and components should be cleaned using validated processes to ensure that particulate/pyrogen and bioburden contamination is appropriately controlled¹."West components may be part of the overarching sterile manufacturing process and contamination control strategy; however, it is the responsibility of the finished product (drug/biologic) manufacturer to comply with the regulation.High-quality, ready-to-use parenteral drug packaging components and systems from West have been leveraged by sterile drug manufacturers to support their contamination control strategies to great effect.

4. What are the 4 key considerations when assessing components for EU GMP Annex 1 readiness?

The 4 key considerations should be the product, the process, the protection, and the proof:

1. The Product: Manufacturers should assess the current packaging quality levels and the associated specifications for particulate, bioburden and endotoxin. Only then can it be determined if a tighter specification is required.
2. The Process: There is a need to know where the drug product is sterilized. How will components be introduced to the fill finish line? Will sealing occur in an aseptic environment? Only then can it be determined if the process meets requirements.
3. The Protection: Are the factors affecting CCI fully understood and mitigated and are there monitoring and testing plans in place over the shelf life of the product? Only then can you be reassured CCI is robust.
4. The Proof: Ensure your supplier has a satisfactory CCS which focuses on continual improvement and that there is supportive documentation available for your CCS.

5. Are there any other additions in the revision for consideration?

One of the new inclusions refers to extractables and leachables (E&L) due to the direct impact of E&L on patient safety. Extractables can be extremely toxic, so a toxicology assessment is needed for genotoxicants, irritants, sensitizers, and other toxicants. There is also an indirect impact on patient safety as impurities can interact with the drug product. Interactions could be chemical or physical which can lead to structural modifications of biotech products. An extractables profile from chemical characterization studies can help to address possible product quality impacts .

To speak with an Annex 1 expert, click here

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

¹ https://health.ec.europa.eu/system/files/2022-08/20220825_gmp-an1_en_0.pdf

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