GUIDE TO INSPECTIONS OF LYOPHILIZATION

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GUIDE TO INSPECTIONS OF
LYOPHILIZATION OF PARENTERALS
July, 1993
Introduction
Lyophilization or freeze drying is a process in which water is removed from a product after it is frozen and placed under a vacuum, allowing the ice to change directly from solid to vapor without passing through a liquid phase. The process consists of three separate, unique, and interdependent processes; freezing, primary drying (sublimation), and secondary drying (desorption).
The advantages of lyophilization include:
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 generally includes the following steps:
o Dissolving the drug and excipients in a suitable solvent, generally water for injection (WFI).
o Sterilizing the bulk solution by passing it through a 0.22 micron bacteria-retentive filter.
o Filling into individual sterile containers and partially stoppering the containers under aseptic conditions.
o Transporting the partially stoppered containers to the lyophilizer and loading into the chamber under aseptic conditions.
o Freezing the solution by placing the partially stoppered containers on cooled shelves in a freeze-drying chamber or pre-freezing in another chamber.
o Applying a vacuum to the chamber and heating the shelves in order to evaporate the water from the frozen state.
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o Complete stoppering of the vials usually bp;`hyd'ra~*,l~;ic or screw rod stoppering mechanisms installed in` the lyophilizers.
There are many new parenteral products, including anti-infectives, biotechnology derived products, and in-vitro diagnostics which are manufactured as lyophilized products. Additionally,;.irtspections have disclosed potency, sterility and stability problems associated with the manufacture and control of lyophilized products: i~ In order to provide guidance and information to investigators, somd.industry
procedures and deficiencies associated with lyophilized=~praducts are identified in this Inspection Guide.
It is recognized that there is complex technology associated;with the manufacture and control of a lyophilized pharmaceutical0dros`age form. Some of the important aspects of these operationsii~de:
the formulation of solutions; filling of vials and validation' of the filling operation; sterilization and
engineering aspects of t:he lyophilizes; scale-up and validation of the lyophilization cycle; and testing
of the end product. This discussion will address some of the problems associated with the manufacture
and control of a lyophilized dosage form.