Investigador

Lyophilization of Parenterals (7/93)
 

GUIDE TO INSPECTIONS OF LYOPHILIZATION OF PARENTERALS

 
Note: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does no confer any rights, privileges, benefits, or immunities for or on any person(s).
 
INTRODUCTION
 
Lyophilization or freeze drying is a process in which water isremoved 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, whichsimplifies 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 ofequipment
 
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.
 
oTransporting 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.
 
oComplete stoppering of the vials usually by hydraulic 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, inspections have disclosed potency, sterility and stability problems associated with themanufacture and control of lyophilized products. In order to provide guidance and information to investigators, some industry procedures and deficiencies associated with lyophilized products are identified in this Inspection Guide.
 
It is recognized that there is complex technology associated with the manufacture and control of a lyophilized pharmaceutical dosage form. Some of the importantaspects of these operations include: the formulation of solutions; filling of vials and validation of the filling operation; sterilization and engineering aspects of the lyophilizer; 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.
 
PRODUCTTYPE/FORMULATION
 
Products are manufactured in the lyophilized form due to their instability when in solution. Many of the antibiotics, such as some of the semi-synthetic penicillins, cephalosporins, and also some of the salts of erythromycin, doxycycline and chloramphenicol are made by the lyophilization process. Because they are antibiotics, low bioburden of these formulations would be expectedat the time of batching. However, some of the other dosage forms that are lyophilized, such as hydrocortisone sodium succinate, methylprednisolone sodium succinate and many of the biotechnology derived products, have no antibacterial effect when in solution.
 
For these types of products, bioburden should be minimal and the bioburden should be determined prior to sterilization of these bulk...