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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
hiop/Jfl17mlccllfic rvn11lcterist;rs oftbe drug substallce; (3) stnlisriclI/1I1efbods for comparing disso/llfioll profiles;
({ud (J) (/ prOCeII' to belp determine when din"olution testing is SfljJide1lt to grant (J woiver for 011 ill vivo
bim:qllit'lllcl1ct! st/ld). This t/ocumf!11f "Iso p1TJvides recommendations for dissolutiol1 tests to be/p eJlSflrc c011tillIIOliS drug prodfll1 fjllflliry IIl1d pnfo17JlfUlCe ofter m1ni1l portuppITJVol1ll0nllfnctliring chonges. SU1II1I10ry
il/fort/wlio" 01/ dissoillt iOlllllt'fbodology) IPP"ratlls) IIlId operllting conditiollS for dissolution testing of IR pmdlIffS is provided ill SIlIllIllIll)1 forlll ill Appelldix A. Tbis guidonce is ime1lded to comple1llelll tbe SUPAC - IR
gl/idnllce jar il/ill/slly: 1III111eililllr RelellS" Solid 01'111 Dosage FOl7l1s: Scilie-llp nlld Post-Appmvnl Challges:
Cbe1llistly, {\fulIlIjiltturiJlg IIlId COIlf1J/S, In Vitro Disso/llfiol1 Testing, IIlld 111 VIVO Bioequiullience
Dommen/alio/1, 11 1i//; jpeciji( IY'ji'l"f!Jl(e to the gel1f!f{lIioll ofdisso/mioll profilesfor CfJwpllmtive pmposes,
PAGE
BACKGROU":'JD
... 15
BlOPIIARMACEUTICS
CL\SSLFICA'rI ON SYSTE.M .... 16
SE1~rI1" G DISSOLUTION
SPFCiF1CATION$ ,.
BACKGROUND
. . 16
.16
C. Special Cases
. .17
.... 17
.17
DlSSOLUTI O~ PROHLE
CO" IPARI SO~S .....
.18
. .18
A.'-todcllndepellden t Approach
Usillg ~ Similarity Factor ...... 18
RFFFR E1'lCES
. , ..... 20
. ... 20
.......12
Disso/llliol1TechnologieslNOVEMBER 1997
Disso/lIfiollTechll%gies/NOVEMB ER 1997
Dissolution methodology and specifications developed by a sponsor are presented in the biophannaceutics section (2 1 CFR
320.24(b)(5)), and the chemistry, manufacturing, and controls secnon
(21 CFR J 14.50(d)(I)(ii)(a)) of an NDA. The dissolution characteristics of the drug product should be developed based on conside ration
of the pH solubility profile and pKa of the drug substance. The drug
permeabi lity or octanol/water partition coefficient measurement may
be useful in selecting the dissolution methodology and specifications.
The dissolution specifications are established in consultation with
and reference products (12 uni ts each) using the method approved
for the reference listed product is recommended. The Division of
Bioequivalence may also request submjssion of additional dissolution
testing data as a condition of approval, when scientifically justified.
l. US P Drug Product Dissolution Test Not Available;
Dissolution Test for Reference Listed NDA Drug Product Not
Publicly Available
In this instance, companltive dissolution testing using test and
reference products under a variety of test conditions is recolllmended. The test conditions may include different dissolution media (pH
I to 6.8), addition of surfactant, and use of apparatus I and 2 with
varying agitation. In all cases, profiles should be generated as previously recommended. The dissolution specifications are set based on
the available bioequivalence and other data.
C. Special Cases
I. Two- Point Dissolution Test
For poorly water soluble drug products (e.g., carbamaza pine),
dissolution testing at Illore than one time point for routine quality
control is recommended to ensu re in vivo product performance.
Altenliltively, a dissolution profile may be used for purposes of quality
control.
2. Two-Tiered Dissolution Test
To more accurately refl ect the physiologic conditions of the
gastrointestinal tract, two-tiered dissolution testing ill simulated
gastric Auid (SGF) with and without pepsin or simulated intestinal
flujd (S LF) with and without pancreatin may be employed to assess
batch-to-batch product quality provided the bioequivalence is
maintained.
Recent examples involving soft and hard gelatin capsules show a
decrease in the dissolution profile over time either in SGF or in SlF
without enzymes. This has been attributed to pellicle formation.
""hen the dissolution of aged or slower releasing capsules was carried
out in the presence of an enzyme (pepsin in SG F or pancreatin in
SIF), a significam increase in the dissolution was observed. In thjs
setting, multiple dissolution media Illay be necessary to adequately
assess product quality.
DISSOLUTION PROfilE
COMPARISONS
Until recen tly, si ngle- point dissolution tests and specifications
have been empl oyed in evaluating scale-u p and postapproval changes l
such JS (I) sca le-up, (2) manufacturing site changes, (3) componenr
and composition changes, and (4) equi pment and process cha nges. A
chan ged product may also be a lower strength of a pre\~ously
approved drug product. In the presence of certain minor changes, the
single-poinr dissolution test may be ,l(leq u<lte to ensu re unchanged
product quality and performance. For morc major changes, a dissolution profi le cOIllIW'isOIl performed under identical conditions for
the product before and after the challge(s) is recommend ed (see
SUPAC-IR). Dissolution profiles may be considered similar by vim,e
of (I) OI'erall profi le si mila rity and (2) similarity at evel)' dissoilltion
sample time point. The dissolution profile comp,lrison may be ca rried out usi ng model independent or model dependent methods.
f,
III,. ," I R, - T, I
V[ I ,.," R, [I 100
(postchange) and reference (prechange) product. It recommends dissolution profile comparisons using a model indcpclldenr approach
and the sim ilarity fuctor (/'2).
Dissolution Mediu1ll
Dissolution testing should be carried out under physiological conditions, if possible. This allows interpretation of dissolution data with regard to in vivo perforDisso/"/ltionTecim %giesINOVEMBER 1997
Agitlltion
In general, mild agimtion conditions should be maintained during
dissolution testing to allow maximulll discriminating power and to
Su Immediate Release ...(()nt;lIIud pagt 22
T&lidotioll
Validation of the dissolution apparatus/methodology
should include (I) the system suitabi lity test using calibrators; (2) deaeration, if necessary; (J) validatio n between
manual and automated procedures; and (4) validation of a
determinative step (i.e., analytical methods employed in
quantitative analysis of dissolution samples). This should
include all appropriate steps and procedures of analytical
methods validation.
REfERENCES
Amidon, C. L., H. i..nmt17las, V./~ Shah, and]. R. Crison, 1995,
"A Theoretical Basis For 0 Biop/Jarmaulltic Dnlg Classification:
The Comlotion of In Vitro Dnlg PrOflller Dissolmion and In Vivo
Bio/lVailability, ~ Pbannaulltical Rmarcb, 12:413-420.
FOil, 1995, Centn-for Dmg Evalulltion Ilnd Rmarcb, Gtlidance Jar
Industry: Immediate Rrllase Solid Oral Dosagt Forms. SealNlp and
Port-Approval Changts: Chrmistry, Mamifacturing and Controls, In
Vitro Disso/ution Tming, and In VIVO J/i()tqlliva/mu Domml1ltatlon
/SUPAC-IRJ, Nuvrmim- 1995.
Mtytr; M. c., A. B. Straughn, E. J. Jarvi, G. C. Wood, F. R. P(lsor, ami
V. I~ Shah, 1992, "Th( Bioeqlliva/t1ICt of Carban/oup;1/( Tabltts wit/J a
flirtory of Clinical Poi/11m, ~ PhlJnnoctmical Restarch, 9:1612- 1616.
Dissoilltio1lTecimoiogiesfNOVEMBER 1997
For Correspondence:
DI: V;nod P Shah
Offiu of PhamlOcellt;cal Science
Center for DnJg Evaluation and Research (COER)
Food and Dmg Adminirtrotion
Rockville, MD