医药冷冻干燥技术.pdf

Pharmaceutical Freeze Drying: The Lyophilization Process Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 1 Outline I. What is freeze drying? II. Reasons for freeze drying III. Steps in freeze drying A. Freezing B. Primary Drying C. Secondary Drying IV. Case Studies V. Pros and Cons of Freeze Drying Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 2 I. What is Freeze Drying? • Definition of Freeze Drying “To dry (as food) in a frozen state under high vacuum esp. for preservation” (Webster Dictionary) “ ... a means of drying, achieved by freezing the wet substance and causing ice to sublime directly to vapor by exposing it to a low partial pressure of water vapor” (Sterile Pharmaceutical Manufacturing - Applications for the 1990’s) Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 3 II. Reasons for Freeze Drying? • Material chemically unstable in solution • Low temperature drying process • Compatible with protein pharmaceuticals • The amorphous form of the drug is desirable (i.e., solubility) • Low particulate contamination • Compatible with aseptic/sterile processing Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 4 Pharmaceutical Freeze Drying Involves: 1. Dissolving the drug and excipients in a suitable solvent, generally water. 2. Sterilizing the bulk solution by passing it through a bacteria-retentive filter. 3. Filling into individual sterile containers. 4. Freezing the solution by placing the open containers on cooled shelves in a freeze drying chamber or pre-freezing in another chamber. 5. Applying Vacuum to the chamber and heating the shelves in order to sublime ice. Nathaniel Mi