FDA Guidance for Industry 1 Extended Release Solid Oral Dosage forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations

Development, Evaluation, and Application of In Vitro/In Vivo CorrelationsThis guidance provide.\ " 1"cco'IJ/mf!ndations to pharmm:ellticti/ sponson' 'wbo intend to develop dOCfIllIl 'llfatioll ill .mpp011ofllJl in Vih'o/in vivo cor'relatiol1 (lVrVC) fl1" {111 07'al extended reiease (ER) dmg prodllct for minllission in a 1Iew d17lg application (NOli), abbreviated lmv drug a/lplimtion (IINDII), 01' antibiotic dmg appliclltion (IIA 011).The gaidam:e preselllJ a comprehemive pe1:fpective 011 (1) '/IIetbods of developing an I Vl VC (lilt!eVlllllming its predictability; (2) /Ising {/II I V1VC to set dissoilltion specifications; 01111 (3) applying all I VIVC a:i II sll1Togate for in vivo bioequivalel1ce when it is 7lecesstl1"Y to docu-JIIent bioequival£'llce during tbe initial approval process or becallse of certain pre-01' postflpproval changes (e.g., j"o11J/ltiatioll, eqllipme17l, Pl"OceSS, find manu/act/wing site Cbll1lgCJ), BACKGROUND T he concept of IVIVC, particularly for ER dmg products, has been extensively discussed by phannaccutital scientists.The ability to predi ct, accurately ,mel precisely, expected bioavailability charocteristil~ for an ER product from dissolution profi le characteristics is a long sought after goal.Several workshops and publications have provided information in support of this goal.These are discussed briefly as follows:o A report from a 1987 ASCPT/DWAPSI FDA-sponsored workshop entitled Rep011 of Ibe l¥orkshop 01/ CR Dos(fge Forllls: Ismes (Ind COlln~"mies (1987) indicated that the state of science and technology at that time did not pennir consistently meaningful rvlVC for ER dosage forill s and encouraged lVJVC as a future objective.Dissolution testing was considered useful only for process control, stability, minor fonnubrion changes, and manufacturing site changes.o A USP pF Stimuli Article in July 1988 established the classification of IVIVC into Levels A, B ,mel C, which ,Ire currently in use.o A report frolll a 1990 ASCPT ID W APSI FDA-sponsored workshop entitl ed III vin~/bl VIVO Tesfing 11Ilt!Correlation for Oral COlln'olled/Modified Relwl' Dosllge POl'/IIS (J 990) concluded tha~ while the science and rechnologyIllay nor always permit meaningful rvrvc, the developmcnt of an IVIVC was an impol1anr objective on a product-by-product basis.Procedures for developmcnt, evaluation, and app lication of an IVIVC were described.Validation of dissolution specifications by a bioe-quivalence sUldy involving two batches of product witll dissolution profiles at the upper and lower dissolution specifications was sug6'C5ted.o US!' Chapter 1088 similarly describes techn iques appropriate for Level A, B, and C correlations and methods for establishing dissolution specifications, o Further infoonation related to IV1VCs was deve loped in a USP/AAPSIFDA-sponsored workshop, which resulted in a report entitled Workshop II Repol1: Scale-lip of 01'111 F,,•tel1lled Relellse Dosage Pomls (1993).T his report identified the objectives of an rvrvc to be the use of dissolution as a surrogate for bioequivalenl')' testing, as well as an aid in setting dissolution specifications.T he report concluded that dissolution may be used as a sensitive, rel iable, and reproducible surrogate for bioequivalence testi ng.The report gave support to the concepts of USP Chapter 1088 and further found that an IVIVC may be usefu l for changes orner than minor changes in fo rmu lation, equipment, process, manufacturing site, and batch size.