- Annex 10 of EudraLex Volume 4, titled Manufacture of Pressurised Metered Dose Aerosol Preparations for Inhalation, provides specific Good Manufacturing Practice (GMP) guidance for the manufacture of pressurised metered-dose inhalers (pMDIs), which are commonly used for the treatment of respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD). These products deliver a precise dose of medication to the lungs using a propellant under pressure, and their production presents unique technical and quality challenges due to the complexity of both the formulation and delivery mechanism.
- A central theme of Annex 10 is the need for stringent control over the entire manufacturing process, given the high precision required in dose delivery, the volatility and pressure of the propellants, and the sensitivity of the inhaled route of administration. The annex emphasizes that all manufacturing operations—from formulation to filling and crimping, as well as labeling and packaging—must be carefully validated and controlled to ensure dose accuracy, consistency, and patient safety.
- The annex outlines the importance of controlling the quality of raw materials, especially the active pharmaceutical ingredient (API), propellants (typically hydrofluoroalkanes), and excipients. Because pMDIs contain substances under pressure and are inhaled directly into the lungs, the purity of all components is paramount, particularly regarding potential contaminants such as residual solvents, particulates, and moisture. Propellants must meet stringent pharmacopoeial and regulatory requirements, and special care must be taken to prevent contamination from lubricants or particulates generated during the manufacturing process.
- Equipment and facilities used in the manufacture of pMDIs must be designed to manage the risks associated with flammable or high-pressure gases, and to minimize the potential for product cross-contamination. The annex stresses the importance of closed systems to contain propellants and minimize environmental release or operator exposure. Equipment used for filling and crimping must be routinely checked and maintained to ensure dose uniformity and container closure integrity.
- The filling process itself is critical. There are two principal methods: cold filling and pressure filling, each requiring specific environmental conditions and safety measures. The annex requires that the fill volume, crimp integrity, and propellant pressure be closely monitored and controlled. This includes the use of automated check-weighing and leak-testing systems to detect under-filled or defective units before release.
- In addition to in-process controls, quality assurance and quality control (QA/QC) testing plays a vital role in ensuring product consistency and compliance. Testing includes not only content uniformity and delivered dose uniformity, but also aerodynamic particle size distribution (APSD)—a critical quality attribute for inhalation products, as it determines the drug’s deposition in the respiratory tract. The annex reinforces the need for stability testing under different conditions to support the shelf life of the product.
- Packaging and labeling operations must ensure that only correctly assembled and labeled products are released. Special attention must be paid to the labeling of strength, dosage instructions, and warnings, as errors in this area could have serious clinical consequences.
- Finally, the annex emphasizes personnel training, documentation, and the implementation of a robust quality management system. Staff must be trained in the unique properties and risks of pMDI manufacturing, including flammable propellant handling, aseptic technique (if applicable), and precise mechanical assembly. All steps of production and quality control must be fully documented and traceable to ensure compliance with regulatory requirements and facilitate investigations in case of deviations or complaints.
- In summary, EudraLex Volume 4 – Annex 10 offers comprehensive GMP guidance tailored to the production of pressurised metered-dose aerosol preparations for inhalation. It provides a framework for managing the specialized risks associated with pMDIs—from propellant handling to dose accuracy and device functionality—thereby ensuring the safety, efficacy, and reliability of these critical respiratory medicines for patients throughout the European Union.
