FDA关于溶出的指导意见

1、Quality by DesignStipulate (postulate) key performance parameters early in development processDesign product & process to be robust for these parametersJanet Woodcock, M.D.May 19, 2004ICH Q6AICH Q8DissolutionSUPACBCSBA/BE12453Desired StateDesired State Current StateTesting toDocument QualityQuality

2、By DesignICH Q6A DECISION TREES #7: SETTING ACCEPTANCE CRITERIA FOR DRUG PRODUCT DISSOLUTIONWhat specific test conditions and acceptance criteria are appropriate? IRdissolution significantlyaffect BA?Develop test conditions and acceptance distinguish batches with unacceptable BAYESNOYESNOYESNODo cha

3、nges informulation ormanufacturing variables affect dissolution?Are these changes controlledby another procedure and acceptancecriterion?Adopt appropriate test conditionsand acceptance criteria without regard to discriminating power, topass clinically acceptable batches.Adopt test conditions and acc

4、eptance criteria which can distinguish these changes. Generally, single point acceptance criteria are acceptable. How?What?Why?Why?Why?And then, have CGMP problems?This can be catastrophic for the business and availability ofImportant drugsA Warning LetterMIT PHARMACEUTICAL MANUFACTURING INITIATIVE

5、(PHARMI) Average Cycle time 95 days Std dev(Cycle time) 100 days Exceptions increase cycle time by 50 % Exceptions increase variability by 100% Capacity Utilization of “System” LOWPERFORMANCE MEASUREVALUEPharmaceutical Manufacturing:Impact of Exceptions(Detailed Analysis of 2 Products)NEED FOR FUNDA

6、MENTAL TECHNOLOGYDissolution15 min30 min45 minAUCCmaxRef959698100100B96979710495C6284928455D8294958887E103103103112120F133553100102Test/Ref. MeanI. J. MacGilvery. Bioequivalence: A Canadian Regulatory Perspective. In, Pharmaceutical Bioequivalence. Eds. Welling, Tse, and Dighe. Marcel Dekker, Inc.,

7、New York, (1992).Modified release?High solubility?Rapid dissolution?Relationship betweenDisintegration - Dissolution?NoYesYesGenerally single-point dissolution acceptance criteriawith a lower limitGenerally disintegrationacceptance criteria withan upper limitEstablish drug releaseacceptance criteria

8、: ER: Multiple time pointMR: Two stage, parallel or sequentialYesNoNoNoYesHow?Test Test Comparison?Total Dissolution = Ft + Fl + Fs + Fs*DisintegrationDisintegrationTime (DT)TabletSurface (t)LargeFragments (l)SmallFragments (s)FtFlFsFs*After DTPrior to DT10# screenFraction dissolvedNote: Disintegrat

9、ion and dissolution process in a dissolution apparatus may differ from that in a disintegration apparatus (different hydrodynamics and other conditions)ICH Q6A DECISION TREES #7: SETTING ACCEPTANCE CRITERIA FOR DRUG PRODUCT DISSOLUTIONWhat specific test conditions and acceptance criteria are appropr

10、iate? IRdissolution significantlyaffect BA?Develop test conditions and acceptance distinguish batches with unacceptable BAYESNOYESNOYESNODo changes informulation ormanufacturing variables affect dissolution?Are these changes controlledby another procedure and acceptancecriterion?Adopt appropriate te

11、st conditionsand acceptance criteria without regard to discriminating power, topass clinically acceptable batches.Adopt test conditions and acceptance criteria which can distinguish these changes. Generally, single point acceptance criteria are acceptable. Overall Risk-based CMC: Why?Overall CMC Systems approach (e.g., link to morphic form, particle size, stability failure mechanisms) CMC: Why? Then How?Clin. Pharm.What?Design of Manufacturingand ControlsHow (reliable)?ProductDesign (Postulate -Conf