fDA Guidance for Industry Dissolution Testing of …

1 ' Vorking Group Members: II.. f lui, - lnme. j . IIsII, jll III, IIllsell"- jlllS bllll'Slll,* HelrY MIIiIIWsli, fDA Guidance for Industry 1. 111111 Millry, Ilrry 1lllrllrl, 1m lIy,* ""Iu, 11111, elr jll hi 111,1, Dissolution Testing of Immediate 11.,1 1111111,* 111111,111. IlIlr I. WIIIIIIS. Release Solid Oral Dosage forms 'Tb(l' IIIJ/(;IfiIIIl/s OflTTrntJy HI u:ttb lIN FDA.."'/; ;;.'/:"'", fl11"Tf1pfltttktu:t Jh~uM he IIdtirrsud 7iJis gllidl/I/ce is df'lleloped jar immedil/Ie "lease (lR) dosl/ge j017I1S I/Ild is illtrnded 10 prrruide (/) gel/eml 1'(!r0711111/!Iftintiol1S for dissolmiol1 Testing ; (2) approaches for settillg tlisso/lllion specifications feinted to the Deparnncnt of J-Iealth and hiop/Jfl17mlccllfic rvn11lcterist;rs oftbe drug substallce; (3) stnlisriclI/1I1efbods for comparing disso/llfioll profiles; Human Services ({ud (J) (/ prOCeII' to belp determine when din"olution Testing is SfljJide1lt to grant (J woiver for 011 ill vivo Food and Drug Administration CClltt.))))))}

2 !r for Dmg E\'aluatiol1 and bim:qllit'lllcl1ct! st/ld). This t/ocumf!11f "Iso p1 TJvides recommendations for dissolutiol1 tests to be/p eJlSflrc c011till- Research (CDER). IIOliS drug prodfll1 fjllflliry IIl1d pnfo17 JlfUlCe ofter m1ni1l portuppITJVol1ll0nllfnctliring chonges. SU1II1I10ry August 1997. il/fort/wlio" 01/ dissoillt iOlllllt'fbodology) IPP"ratlls) IIlId operllting conditiollS for Dissolution Testing of IR pmd- BPI. lIffS is provided ill SIlIllIllIll)1 forlll ill Appelldix A. Tbis guidonce is ime1lded to comple1llelll tbe SUPAC - IR. TABLE OF. gl/idnllce jar il/ill/slly: 1 III111eililllr RelellS" Solid 01'111 Dosage FOl7l1s: Scilie-llp nlld Post-Appmvnl Challges: CONTENTS PAGE. Cbe1llistly, {\fulIlIjiltturiJlg IIlId COIlf1 J/S, In Vitro Disso/llfiol1 Testing , IIlld 111 VIVO Bioequiullience BACKGROU":'JD .. 15. Dommen/alio/1, 11 1i//; jpeciji( IY'ji'l"f!Jl(e to the gel1f!f{lIioll ofdisso/mioll profilesfor CfJwpllmtive pmposes, BlOPIIARMACEUTICS. CL\SSLFICA'rI ON.}}

3 16. SE1~rI1" G Dissolution . SPFCiF1 CATION$ ,.. 16. A. Approaches for Setting BACKGROUND Specifications for a New Chemical I!:mil), ..16. D. rug absorption from a solid dosage New drug applications (NDAs) submitted to G. Approaches for Selring form afte r oral administration the Food and Drug Administration (FDA) con- D is'iolution SllCcifications for Generic productS ..17. depends on the release of the drug tain bioavailability data and in vitro Dissolution C. Special Cases .. 17. subst:1t1ce from the drug product, data, that, together with chemistry, manufactur- D ..\bpping or Response Surface the Dissolution or solubilization of the drug ing, and controls (CMC) data, characteri ze the \ Iethoooiogy .. ,..17. under physiological conditions, and the penne- quality and perfonnance of the drug prodUCT. In E. In \,,,o ln Vitro Correiations ..I8. ability ,lcross the gastrointestinal tract. Because vitro Dissolution data are generall), obmined from E \~1 lid:ltion and \ 'crification of of the critical nature of the first nYo of these batches that have been used in pil'Oml clinical SI>ccifications.

4 18. steps, in vitro Dissolution Illay be reJevanr to the andlor bioavailability srudies and from other DlSSOLUTI O~ PROHLE. CO" IPARI SO~S ..18. prediction of in vivo performance. Based on this human studies conducted during product devel- A. '-todcllndepellden t Approach general consideration, in vitro Dissolution tests opment. Acceptable bioequivalence data and Usillg ~ Similarity Factor .. 18. for immediate release solid oral dosage fonns, comparable in \;tro Dissolution and CMC data n. \1odel Indel>endent Multi\'lIri3le such as tablets and capsules, are used to (I) assess are required for appro",,1 of abbreviated new Confidence Rc ~,'ion Procedure .. 19. d,e lot-to-Iot quality of a drug product; (2) guide drug applications (ANDAs) (2 1 CFR ) ). C. Modd Depcndcl11 Approaches .19. development of new fomlUlationsj and (3) ensure The in \;tro specifications for generic products DISSOLlJT'ION AND SUPAC IR 19. continuing product quality and performance should be established based on a Dissolution pro- BIOWMVERS.

5 , .. 20. after certain changes, such as changes in the for- file. For new dmg applications, as well as generic Apl>endix A .. 20. mulation, the manufacturing process, the site of drug applications, the Dissolution specifications RFFFR E1'lCES ..12. manufacture, and the scale-up of the manufacrur- should be based on acceptable clinical, bioavail- 'Th,s gllidn"rr hIlS bUll prtparrd by fht ing process, ability, and/or bioequivalencc batches. Rdfllst &''f!C1 t WorkiNg Group oftht BiophonNoctuti($. Current knowledge about the solubili ty, Once the specifications are esmblished in an Cf)()rtlil1lJrillg C"mmltttt In tht Cmu,. permeability, Dissolution , and pharmacokinetics NDI\, the Dissolution specifications for batch-to- for Ot'lIg eVlJllIIllirm and Rtstllrch of a drug product should be considered in defin- (COER) lit the Food 11111/ Drug batch quality assurance are published in the Ad",i/l;Strllt101l. This guitumu document ing Dissolution test specifications for the drug United States Pharmacopeia (USP) as compendi- l"fprtmm tht Agrngr OIrTnlf thillking Oil the Dissolution tmlllg of "",ntdiate approval process.

6 This know ledge should also al standards, which become the official specific-a- nlellst sQ/ill uml dosRgt fflnns. It dots I/ot be used to ensure continued equivalence of the tions for all subsequent IR products wid, the CI"tIlIC or (/Jllfn lilly rights for ( "" 011 fmy perso" (md d()t$ lIot opn-ntt to product, as well as to ensure the product's same- same active ingredients. In general, these com- himl FDA or tht public. All ness under certain scale-up and postapproval pendial Dissolution standards are single-point Illttrndriw approach mllJ ht lIstd If SItCh ftppronch JarisjitJ. changes. Dissolution tests, not profiles. fbt nqllirnlll'lIIs of tbr npp!uuNt Stal:tlle, continued next page ngu/auul/s, ar both. Disso/llliol1 TechnologieslNOVEMBER 1997. FDA Immediate Release Guidance .. continued BIDPHARMACEUTICS based on the performancc of acceptable bioequivalence batches of the drug product. The NDA Dissolution specifications should be based CLASSIFICATION SYSTEM on experience gai ned during the dmg development process and the Based on drug solubility and permeability, thc following in vitro performance of appropriate test batches.)))

7 In the case of a Biopharmaceutics Classification System (BCS) is recolllmended in generic drug product, the Dissolution spccitiC< arc generally the the literature (Amidon 1995): same as thc refercnce listed drug (RLD). The specifications are con- Casc I: High Solubility - High Pcnneabi lity Drugs firmed by Testing the Dissolution performance of the generic dmg Case 2: Loll' Solubility - Iligh Penneability Drugs product frolll an acceptable bioequivalence srudy. If the Dissolution of Case 3: High Solubility - Low Pcrmeability Drugs the generic product is substantially different compared to that of the Casc 4: Low Solubi lity - Low Pcnneability Drugs reference listed dmg :mel the in vivo data remain acceptable, a differ- This classification can be used as a basis for setting in VilTO disso- ent Dissolution specification for the generic product may be set. Once lution specifications and ca ll also provide a basis for predicting ~le ,I Dissolution specification is set, the dl1lg product should comply wid, likelihood of achieving a successful in vivo-i n vitro correlation that specification throughout its shclf life.

8 (IVIVC). The solubility of a drug is determined by dissolving cl,e The International Conference on Ilannonisation (lCI-I) QIA. highest unit dose of the drug in 250 mL of bufTer adjusted between guideli ne (Stabili ty "Iesting of New Drug Substances and Drug pH and A drug substance is considered highly soluble wh:n Products) has recommended that for an NDA, three batches (two the dosclsolubility volullle of solution are less than or equ<l l to 1)0. pilot and one smallcr scale) be placed into stabi lity testi ng. These mL. J ligh-permcabiliry drubTS arc genenl ily those With, an extent of hatches also Jllay be lIsed to set Dissolution specifications when a SUIt- absorption that is greater than 90% in the absence 01documented able bioequivalence relationship exists between these batches and inst:1bili ty in the gastrointestinal tracr or those whose pemlcabi ~ i ry both cl,e pivotal clinical trial batch and the drug product intended for has bcen detennined experimentally. The BCS suggests that for high the market.

9 Solubility, high penneabili ty (c,lse I) drugs and in some inst:lJlces for Th ree caragorics of Dissolution test specifications for immediate high solubili ty, low permeability (case 3) drugs, 85% Dissolution in release dmg products are described in the Guidance . IICI in 15 minutes can ensure that the bioavailability of the Single-poinr specifications drug is not limi ted by Dissolution . in these cases, the ra te limiting step As a rounne quality control test. (For highly soluble and rapidly for drug absorption is emptying. dissolving drug products.). The mean T50% residence (em ptying) time is 15-20 min- specifications utes under fasting conditions. Based on this infonnation, a conserva- I. For the quality of the drug product. tive conclusion is that a drug product undergoing 85% Dissolution in 2. As a rourine qua lity control test for certain types of drug 15 minutes under mild Dissolution test conditions in lICi products ( , slow dissolving or poorly water soluble drug product behaves like a solunon and generally should not have any bioavail- like carbamazepine).

10 Ability problems. If the Dissolution is slower than gastric emptyi ng, a Dissolution profile comparison Dissolution profile with multiple time points in Illultimedia is recolll- I. For .Iccepting product sameness under 5 UPAC-related mended. changes. In the case of low solubility/high penneabil ity drugs (case 2), drug 2. ~Io waive bioequivalence requi rements for lower strengths of a Dissolution may be the rate limiting step for drug absorption and an dosage fonn. rVTVC may be expected. A Dissolution profile in multiple media is 3. To support wa ivers fot other bioequivalence requirements. recommended fo r drug products in this category. In the case of high In the funlre, a two-time point approach may be llseful, both to solubi lity/low permeability drugs (case 3), permeability is the rate characterize a drug product and to serve as quality control controlling step and a limited TVTVC may be possible, depending on speci fi cation. the relative rates of Dissolution and intestinal transit.