Overview Of Lyophilization Of Pharmaceutical Products
There are several pharmaceutical products, notably some antibiotics, that are classified as parenteral as they are unstable for prolonged periods as aqueous solutions. Parenteral products are those that cannot be administered orally or by the alimentary canal. They have to be administered by intravenous or intramuscular injection.
Freeze-drying, technically known as lyophilisation, is a process employed in many industries to remove water from perishable materials without applying heat, and to make the material convenient for transport. The process is commonly applied, for example to instant coffee powder to help retain the flavour of the coffee and prolong its shelf life. It is applied to pharmaceutical drugs that would be destroyed if the water were to be removed by heating. Lyophilization completely removes any moisture from the drug, so that when sealed, it is chemically stable and has a much greater shelf life than the original drug. The following are examples of drugs that can be lyophilized.
Lyophilization offers the following advantages:
- Ease of processing a liquid, which simplifies aseptic handling
- Enhanced stability of a dry powder
- Removal of water without excessive heating of the product
- Enhanced product stability in a dry state
- Rapid and easy dissolution of reconstituted product
Disadvantages of lyophilization include:
- Increased handling and processing time
- Need for sterile diluent upon reconstitution
- Cost and complexity of equipment
The Lyophilization Process
The lyophilisation process for pharmaceutical products usually comprises the following steps:
- Dissolving the drug and excipients in a suitable solvent, generally water for injection (WFI).
- Sterilizing the bulk solution by passing it through a 0.22 micron bacteria-retentive filter.
- Filling into individual sterile containers or vials and partially stoppering the containers under aseptic conditions.
- Transporting the partially stoppered containers to the lyophilizer and loading into the chamber under aseptic conditions.
- Freezing the solution, typically to between -50 and -90°C by placing the partially stoppered containers on cooled shelves in a freeze-drying chamber or pre-freezing in another chamber.
- Applying a vacuum to the chamber and heating the shelves in order to evaporate (sublimate) the water from the frozen state.
- Complete stoppering of the vials usually by hydraulic or screw rod stoppering mechanisms installed in the lyophilizers.
The lyophilizer is a specialist equipment fitted out for the whole process of freezing, applying a vacuum to sublimate the solvent, and stoppering the vials. Critical to the whole process is ensuring that a sterile environment is maintained throughout. Sterilization of the equipment is usually performed with steam at pressure, in a similar way to an autoclave. However, particularly in the case of older equipment, there may be some parts that are not amenable to such treatment – plumbing responsible for injection of nitrogen, or vacuum lines. For this reason sterilization by using ethylene oxide may also be employed. It is important that the product is tested sufficiently to ensure that stability and sterility is maintained up to the point where the sample is reconstituted prior to injection. If the product is to be analysed, sterile water must be used to reconstitute the drug as bacteriostatic water can kill any contaminants that may be present in the sample. Bacteriostatic water contains typically less than 1% by volume benzyl alcohol which acts as a preservative, and is routinely used for reconstituting injectable drugs.
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