Manufacture of Liquids, Creams and Ointments: EU GMP Annex 9

In short: EU GMP Annex 9 sets out short, focused expectations for making liquids, creams and ointments, products that are easily contaminated by microbes. This guide is for production, QA and engineering staff and explains what the annex asks for and how to apply it on the shop floor.

Why these dosage forms need special care

Liquids, creams and ointments contain water or other media in which microbes can grow, and they are often made in open vessels. The annex therefore asks manufacturers to take special measures to prevent contamination of all kinds, not only microbial. It sits alongside EU GMP Part I Chapter 3 (Premises and Equipment) and Chapter 5 (Production).

Premises and equipment

• Closed systems. Closed processing and transfer protect the product. Where product or clean containers are exposed, the area should normally be ventilated with filtered air.
• Easy to clean and sanitise. Design and install tanks, containers, pipework and pumps for easy cleaning and, where necessary, sanitisation. Keep dead-legs to a minimum, since residues collect there and microbes can multiply.
• Materials of construction. Avoid glass apparatus wherever possible. High-quality stainless steel is usually the preferred material for product-contact parts.

Production

• Water. Specify and monitor both the chemical and the microbiological quality of process water, and maintain the water system to prevent microbial growth. After any chemical sanitisation, follow a validated flushing procedure so the sanitising agent is demonstrably removed. See high-purity water systems.
• Bulk deliveries. Check materials arriving by bulk tanker before unloading them into bulk storage tanks.
• Pipeline transfers. Take care that materials sent through pipelines reach the correct destination (for example, by line identification and verification before transfer).
• Shedding materials. Keep fibre-shedding items such as cardboard and wooden pallets out of areas where product or clean containers are exposed.
• Homogeneity during filling. Mixing and filling processes should be validated. Take particular care at the start of filling, after any stoppage and at the end, so that suspensions and mixtures stay uniform. See process validation.
• Hold of unpackaged product. If finished product is not packed immediately, define the maximum storage time and conditions and follow them.

Related practices

• Clean equipment between batches with a validated procedure: principles of cleaning validation.
• Compressed air that touches product or open containers is a contamination route: microbial contamination of compressed air.

Frequently asked questions

Does Annex 9 apply to sterile liquids? No. Annex 9 deals with non-sterile liquids, creams and ointments. Sterile products fall under Annex 1.

Is stainless steel mandatory? The annex says glass should be avoided where possible and that stainless steel is often the material of choice. It is a strong recommendation rather than a fixed rule, so justify any alternative.

What is a dead-leg and why does it matter? A dead-leg is a section of pipe or fitting where liquid stagnates. Residues and microbes build up there and are hard to clean, so designs should keep them to a minimum.

Where do I record batch and monitoring data? Keep batch records and monitoring data for at least 1 year after the expiry date of the respective product batch (EU GMP Part I Chapter 4 §4.11, or 5 years after QP certification if longer; 21 CFR 211.180(a)), and longer if local law or the marketing authorisation requires.

References

1. European Commission, EudraLex Volume 4, EU GMP Guidelines, Annex 9: Manufacture of Liquids, Creams and Ointments (current text published on health.ec.europa.eu; the annex carries no revision date).
2. European Commission, EudraLex Volume 4, Part I, Chapter 3 (Premises and Equipment), Chapter 4 (Documentation) §4.11 and Chapter 5 (Production).
3. US FDA, 21 CFR 211.180(a), General requirements for records.