Attachment No. 10
to the Rules of Good Manufacturing Practice
MANUFACTURE OF DOSAGE AEROSOL MEDICINES UNDER PRESSURE FOR INHALATIONS
1. The manufacturing process of aerosol medicines under pressure with measuring valves intended for inhalations requires special attention due to the specific character of this pharmaceutical form. They shall be manufactured in conditions minimizing contamination by microorganisms and particles. It is also important to ensure the quality of the valve parts, and in case of suspensions — their homogeneity.
II. GENERAL REQUIREMENTS
2. (1) As a rule, two production and filling methods are used:
а) (a) a two-stage filling system (filling under pressure): a pharmaceutical substance is suspended in a propellant with a high boiling temperature; a dose of the suspension is poured into a container; a valve is inserted and crimped around; then a propellant with a high boiling temperature is introduced through the valve stem to obtain a finished medicine; the suspension of the pharmaceutical substance in the propellant is kept at quiet a low temperature to reduce losses due to evaporation;
b) (b) a single-stage filling process (cold filling): a pharmaceutical substance is suspended in a mixture of propellants; the suspension is kept under pressure or at a low temperature, or simultaneously under pressure and at a low temperature; then packages are filled with the suspension in a single step.
III. PREMISES AND EQUIPMENT
3. (2) If possible, the manufacturing and filling processes shall be performed in closed systems.
4. (3) The area where products or clean components are kept open shall be supplied with filtered air and shall meet the requirements to the process environment of at least class D. The area shall be entered through air chambers.
IV. MANUFACTURE AND QUALITY CONTROL
5. (4) Measuring valves for aerosols are more complex as compared to most devices used in the pharmaceutical industry. It shall be reflected in their specifications and taken into account in case of sampling and testing. It is particularly important to audit the pharmaceutical quality system of the manufacturer of measuring valves.
6. (5) All liquids (including gaseous propellents that are liquid or liquefied under pressure) shall be filtered to remove particles whose size exceeds 0.2 μm. When possible, it is recommended to perform additional filtration before the filling process.
7. (6) Containers and valves shall be cleaned according to a validated procedure that corresponds to the intended use of the medicine and ensures absence of any contamination, such as contamination by process auxiliary materials (e.g. lubricants) or microbial contamination. After cleaning valves shall be stored in clean sealed containers, it is also necessary to take precautionary measures preventing contamination during subsequent operations, e.g. during sampling. Packages shall be delivered to the filling line in a clean condition or shall be cleaned at the line just before the filling operation.
8. (7) It is necessary to ensure the homogeneity of the suspension at the filling point during the whole filling process.
9. (8) If the two-stage filling process is applied, it is required to ensure a definite weight of introduced substances at both stages in order to get the right composition. For this reason in many cases a 100% weight control at each stage is deemed reasonable.
10. (9) The control after filling shall confirm that there is no leakage. Checking for leakage shall be performed so as to avoid any microbial contamination or residual moisture.