- Annex 9 of EudraLex Volume 4, titled Manufacture of Liquids, Creams and Ointments, provides specialized Good Manufacturing Practice (GMP) guidelines for the production of non-sterile semi-solid and liquid pharmaceutical dosage forms, such as oral solutions, topical creams, gels, lotions, ointments, and suspensions. These dosage forms are widely used and present unique formulation, processing, and contamination control challenges, which are addressed comprehensively in this annex.
- The annex begins by acknowledging that liquids, creams, and ointments are often prone to microbial growth and cross-contamination, particularly because they may contain water or other ingredients that can support microbial proliferation. Therefore, cleanliness, hygiene, and environmental control are emphasized as critical components of the manufacturing process. Facilities must be designed and maintained to allow for effective cleaning and to prevent cross-contamination between different product types, especially when manufacturing multiple products with similar appearance or strong pharmacological activity.
- Annex 9 emphasizes the importance of dedicated or campaign-based production for certain types of products, especially those containing sensitizing or potent active substances. Where shared facilities are used, cleaning validation becomes essential to demonstrate that residues from previous batches are removed to acceptable levels. Cleaning procedures must be well-documented and strictly followed to avoid carry-over contamination.
- A key focus of Annex 9 is the control of raw materials and excipients, particularly with regard to microbiological quality. Water used in the production of liquids and creams must meet specific microbial and chemical standards (e.g., purified water or water for injection, depending on the intended use). Ingredients that support microbial growth must be protected during storage and manufacturing, and the final product should include appropriate preservatives unless the product is sterile or produced under aseptic conditions.
- The annex provides guidance on the design and operation of equipment such as mixing tanks, homogenizers, mills, and filling machines. Equipment must be capable of ensuring uniform mixing, particle size reduction (if necessary), and prevention of aeration or foam formation. Transfer lines and holding tanks should be designed to minimize dead legs and stagnation points where microbial growth could occur. Equipment should be easy to clean and maintain, with preference given to closed systems that reduce the risk of contamination.
- Batch manufacturing processes must be clearly defined and controlled. This includes the order and rate of addition of ingredients, mixing time, temperature control, and sampling procedures. For suspensions or emulsions, maintaining physical stability during manufacture and throughout the product’s shelf life is a critical consideration. The annex also highlights the importance of in-process controls, such as checking for homogeneity, pH, viscosity, particle size distribution, and appearance to ensure product quality and consistency.
- Filling and packaging operations must be carefully controlled to avoid product degradation and contamination. Containers, closures, and packaging materials must be suitable for the product type and must not interact adversely with the formulation. The annex emphasizes the need for environmental monitoring and cleanliness, especially in areas where the product is exposed prior to packaging. In the case of topical products, the packaging process must also ensure that the product can be used hygienically by patients and healthcare professionals.
- Finally, labeling and documentation are given special attention. All processes must be traceable, and batch records should provide complete details of all stages of production and quality control. Labels must include critical information such as usage instructions, storage conditions, expiry dates, and warnings.
- In summary, EudraLex Volume 4 – Annex 9 provides a detailed GMP framework for the manufacture of liquids, creams, and ointments, tailored to the specific needs and risks associated with these dosage forms. It supports manufacturers in ensuring microbiological integrity, physical stability, and batch uniformity, thereby helping to maintain product safety, efficacy, and compliance with EU pharmaceutical regulations.
Further reading:
- EudraLex – Volume 4 – Good Manufacturing Practice (GMP) guidelines
- EudraLex – The Rules Governing Medicinal Products in the European Union, Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use Annex 9: Manufacture of Liquids, Creams and Ointments
