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Guidance for IndustryNasal Spray and Inhalation Solution, Suspension, and Spray Drug Products — Chemistry, Manufacturing, and Controls Documentation`U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER)July 2002CMCGuidance for IndustryNasal Spray and Inhalation Solution, Suspension, and Spray Drug Products — Chemistry, Manufacturing, and Controls DocumentationAdditional copies are available from:Office of Training and Communications Division of Drug Information, HFD-240 Center for Drug Evaluation and Research Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 (Tel) 301-827-4573 http://www.fda.gov/cder/guidance/index.htmU.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER)July 2002CMCTABLE OF CONTENTS I. INTRODUCTION................................................................................................................. 1II. BACKGROUND................................................................................................................... 2A. Nasal Sprays .........................................................................................................................2B. Inhalation Solutions and Suspensions...................................................................................3C. Inhalation Sprays..................................................................................................................3III. DRUG PRODUCT............................................................................................................ 5A. Formulation Components.....................................................................................................5B. Formulation Composition.....................................................................................................5C. Specifications for the Formulation Components...................................................................5D. Manufacturer........................................................................................................................9E.Method of Manufacture and Packaging................................................................................9F. Specifications for the Drug Product....................................................................................10G. Container Closure Systems.................................................................................................22H.Drug Product Stability........................................................................................................27IV. DRUG PRODUCT CHARACTERIZATION STUDIES................................................32A.Priming and Repriming in Various Orientations................................................................33B.Effect of Resting Time.........................................................................................................33C.Temperature Cycling..........................................................................................................33D.In Vitro Dose Proportionality .............................................................................................34E.Cleaning Instructions..........................................................................................................34F.Device Robustness...............................................................................................................34G.Effect of Dosing Orientation...............................................................................................34H.Effect of Varying Flow Rates ..............................................................................................35I.Profiling of Sprays Near Container Exhaustion (Tail Off Characteristics)..........................35J.Effect of Storage on the Particle Size Distribution..............................................................35K.Plume Geometry .................................................................................................................36L.Preservative Effectiveness and Sterility Maintenance .........................................................36M.Characterization of Nebulizer Specified in the Labeling.....................................................36N.Photostability......................................................................................................................36O.Stability of Primary (Unprotected) Package........................................................................37V.LABELING CONSIDERATIONS....................................................................................37A.Nasal and Inhalation Spray Drug Products.........................................................................37B.Inhalation Solutions and Suspensions.................................................................................40GLOSSARY OF TERMS............................................。