In order to release the contents of the pressurized canister, the latter has to be actuated or triggered. The actuation produces a fine atom­ized spray of the drug substance which are eventually deposited in the lung region. MDIs remain as a first-line treatment for asthma and other pulmonary conditions such as chronic obstructive pul­monary disease. The greatest single limitation of MDI is the incon­sistent dosing that occurs with incorrect use of the inhaler. Hence, proper education on inhaler use is of critical importance especially for very young and elderly patients. For the MDI to deliver the drug eciently to the lower reaches of the respiratory tract, the patient must take a slow and deep breath to maximize passage of the aer­osol in the airway, followed by a breath-hold to allow deposition of the drug particles in the lungs. The many advantages of a MDI include its portability, multi-dose delivery capabilities as well as low risk of bacterial contamination. With modern technology, the newer generation of MDIs incorporates a metering valve with a smaller aperture. This generates aerosols of much finer particle size for many active drug substances. The drug substances are now dis­solved in hydrofluoroalkanes instead of being suspended in chloro­fluorocarbons as with the older technology. The hydrofluoroalkane­propelled aerosol has a lower velocity and gentler plume. Combined with the smaller particle size, this results in greater deposition in the inner reaches of the respiratory tract, and less deposition in the mouth-throat region. Deposition in the respiratory tract can also be increased and mouth-throat deposition reduced by the use of accessory devices such as a spacer. As the use of a spacer requires coordination of actuation with inhalation, education on the use of a spacer is also needed.

Whatever the method, the manufacture and filling should be car­ried out as far as possible in a closed system. Where the clean MDI components are exposed, the area should be supplied with filtered air, compliant with the requirements of at least a Grade D environ­ment with entry via airlocks. When a two-shot filling process is used, it is necessary to ensure that both shots are of the correct weight in order to achieve the correct composition. For this purpose, 100% weight checking at each stage is often desirable. In-process quality controls after filling should ensure the absence of undue leakage. Any leakage test should be performed in a way which avoids micro­bial contamination or residual moisture. Annex 10 of the PIC/S Guide to GMP for Medicinal Products provides special considera­tions in the manufacture of pressurized metered dose aerosol prepa­rations for inhalation.

At any pharmaceutical manufacturing facility, the inputs are the starting materials comprising the active pharmaceutical ingredi­ents, also referred to as the drug substances, and the excipients, sometimes referred to as the inactive pharmaceutical ingredients or packaging materials. The starting materials are kept at appro­priate storage areas within the warehouse. The initial step in the manufacture of a pharmaceutical product involves the weighing of APIs and excipients of approved quality, and this is followed by the actual manufacture of the product. The dierent production steps