D1S10-Mueller-v1.2-FINAL.pdf

1、1Melanie Mueller,PharmD PhDMaster ToxicologistDivision of Pharmacology/Toxicology Review(DPTR)Office of Safety and Clinical Evaluation(OSCE)Office of Generic Drugs(OGD)CDER/US FDAwww.fda.govStandardized Approaches for Determining Maximum Daily Dose(MDD)2Overview Background Definitions,Impact,Challen

2、ges CDER Internal MDD Alignment Efforts Importance of Alignment,Key Alignment Elements Feedback for Industry Summarywww.fda.gov3What is MDD?MDD is Numeric value(amount/day)calculated based on API amount reasonably administered in a day to most patients per drug labelingSuitable standard applicable t

3、o most patients indicated by drug labelingMultidisciplinary standard used during technical review of new and generic drugsNot intended to impact dosing in clinical practicewww.fda.govAPI=Active Pharmaceutical Ingredient4Why is MDD Important?MDD is critical During safety and quality review of new and

4、 generic drugs:To determine impurity control in drug substances and drug products To set acceptable limits for N-nitrosamine impurities To establish AET for extractables and leachables studies/reviews To establish excipient MDE posted on FDAs IID To ensure regulatory consistency across similar drugs

5、www.fda.govAET=analytical evaluation thresholdMDE=maximum daily exposureIID=Inactive Ingredient Database5What are the Challenges?MDD is a numeric value(e.g.,mg/day),drug labeling often does not list MDD as amount/day variables in drug labeling create calculation uncertainties:www.fda.govExamples of

6、Variables Listed in Dosage&Administration Section of Drug LabelingHighest recommended dose is 0.05 mg/kg/dayRecommended to apply a pea-size of gel to each of the five areas of the face dailyRecommended to apply one drop in the affected eye(s)twice a dayHighest recommended dose is 300 mg/m2/day6What