`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`202107Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`

`

`
`
`NDA 202-107
`
`KorlymTM (Mifepristone) Tablets
`
`Corcept Therapeutics
`
`Xavier Ysern, PhD
`
`ONDQA/ DNDQA III/ Branch VII
`
`(Clinical Review Division: DMEP)
`
`NDA 202—107 CMC Review # 2 Page 1 of 14
`
`Reference ID: 3072819
`
`

`

`Colnmentlflotel]:
`
`fiflowmgsecfimupniududiown
`hue Reviewuashonldfielfieeto
`
`eiflH'thyuAlfl-Shifii-U
`
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`convutim
`TomniuflyhaveMSWotdnpdm
`fieTableofConlentsv-flhflieconect
`paginafiomflickonceanywhueinlhe
`Tableot‘CoanIeTahleot'Conluns
`Maintaining-Mingus
`
`
`
`rl'able of ContentsL ___________________________
`
`Table of Contents.........................................................................................................................................................2
`
`Chemistry Review Data Sheet ....................................................................................................................................3
`
`The Executive Summary .............................................................................................................................................6
`
`I. Recommendations __________________________________________________________________________________________________________________________________________________ 6
`
`A. Recommendation and Conclusion on Approvabilily.......................................................................................6
`
`B. Recounnendati-onPhase4 (Post—Marketing) Commitments,Agi'eements, and/orRiskManagement
`Steps, ifApprovable ........................................................................................................................................6
`
`IL Summary ofChemisuy Assessment ..................................................................................................................... 6
`
`A. Description ofthe Drug Pmduct(s) and Drug Substance(s)..............................................................................6
`
`B. DesuiptionofHowtheDmngductisIntendedtobeUsed..........................................................................7
`
`C. Basis for Approvabilily or Not-Approval Recommendation ............................................................................8
`
`111 Administiative ........................................................................................................................................................9
`
`A. Reviewer’s Signature........................................................................................................................................9
`B. Endorsement Block ...........................................................................................................................................9
`
`C. CC Block ..........................................................................................................................................................9
`
`Chemistry Assessment
`
`I. Review OfCommon Technical Document—Quality (Ctd—Q) Module 3.2: Body OfData
`
`S
`
`DRUG SUBSTANCE [Mifepristone’
`
`3. i 334.
`p DRUG PRODUCT [Korlymn‘ (mifepn'stone) Tablets] ............................................................................... 10
`A APPENDICES.............................................................................................................................................. 10
`
`R REGIONAL INFORMATION_____________________________________________________________________________________________________________________ 10
`
`IL Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ............................................................... 10
`
`A. Labeling & Package Insert............................................................................................................................. 10
`
`B. EnvironmlalAssesmnentOtClaimOfCategoricalExchlsion.................................................................... 10
`
`III. ListOfDeficienciesToBeComunmicated None
`
`NDA 202—107 CMC Review it 2 Page 2 of 14
`
`Reference ID: 3072819
`
`

`

`FRI?“
`
`w
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`F'A'H
`
`W
`
`1. NBA:
`
`202-107
`
`2' ”VIEW’Ii ——————2— ——————————————————————————————————————————————————— -\
`17-Jan-2012
`
`
`
`/
`, Commut [Hotel]:
`IClremlstryRevlewData SheelL _______________________ x gummy...“ on,
`fiiu-hhu-fllhehfiehqfl
`Hone-emudomm,
`
`hmmumumu
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`‘ Miriam Thislnin
`nastiest-Madman:
`”mama-mu
`p-loflllmv'l'dou—Iafim
`
`Cornmont [Honest]:
`Add the review number for this
`
`review. AI reviews for an AlllDA
`should be numbered sequentially
`'
`assigned reviewer is
`
`6. SUBMISSIONS) BEING REVIEWED:I _________________________________________
`
`5) Reviewed
`
`SM"'
`Original
`Amendmt (Proprietary name)
`Amendment (Labeling/PackageInsertandContainer—Carton)
`
`Document Date
`15-Apr-2011
`l9—Apr-201 1
`25-Apr-2011
`
`7. km & ADDRESS or APPLICANTL
`
`Name: Corcept Therapeutics
`Address:
`149 Commonwealth Dr., Marlo Park, CA 94025
`Representative: Luana Staiger
`Telephone:
`650 678 7230 (email: lstaiger@corcep.com)
`
`‘\
`
`\\
`
`\
`
`
`
`
`
`8.IDRUG manner NAME/CODEITYPEzL _______________________________________ J"
`
`Nunezl ____________________I:oilyrpmnaiéeeqsioysuaylsas ____________ ,I’
`'
`a)
`ell-Proprietary Name (USAN) _____________W____________________________
`b)
`Namd#l ________________________-; _______________________________
`c)
`(Denim
`Submission Priorily (0NDC only):
`“lg-m 137941---- ..............Upséflswfelznsllafieq ................
`Won PliorilyE _____________________________________________ 3‘ \
`
`\\
`
`‘
`
`
`
`
`Comment [“14]:
`
`FuONDCuemly Bacillus“?
`
`
`
`
`
`
`(“War-my) m
`Our-merit [Hotels]:
`
`
`Thesecion sluld include:
`m
`Comment [Hotels]:
`Rehr lo FDA Form 356i: oraviable
`
`refererm
`
`\
`
`10- PHARMACOL CATEGORYLSIMcMmdmeWmm _____________
`reduce the efi'ects fhypercortisolism '
`'
`ts with undogemms \
`gLn‘ng‘s Syndrome]o
`mpahen
`
`\\
`
`NDA 202-107 CMC Review it 2 Page 3 of 14
`
`Reference ID: 3072819
`
`

`

`
`
`Chemistry Review Data Sheet
`
`12.
`
`GTE/POTEN
`
`300
`
`
`11.b08AG1-:1-‘om¢ ____________ 12111131 __________________________________________ mlmm:
`Rafa b the ODE! Dal: Md:
`Manual (Genelal itiulMPPist
`CYE ----------n-Ig‘ ---------------------------- -\‘ Wmmhwlmfnwnm).
`mm
`
`
`as needed or.
`naval doom fonns
`
`
`13. hour]: 0F Annmnsmnmi _ 95a! _______________________________________ X
`... .1mm"W
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`".
`Coll-lilies. ForW, lyopllizod
`\ www.ma
`14 chmsmt _________ 3g ________________________________________ .
`
`
`
`16. kZHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA, MOLECULAR
`wucmt ________________________
`
`Mfeplistone
`RmmelUclafcomnynamezRUm
`Fonmla:ngI-135NO7
`
`Mw: 429.60 g/mol
`
`CAS #2 84371-65—3
`
`Comment [Note19]:
`
`
`
`(mlmwniggwfiozaw
`N
`due Wading] ll
`"10/
`fiffllfi.“
`
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`
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`
`llB—[pMylmfimM}l7fl-hy¢oxy—l7(l1xopynybesha4,9—dim-m ammo name)
`im$$_fi.mfl“
`
`17. REIATEINSUPPORTINGW ______________________________________
`
`A. DMFs:
`
`
`
`
`
`_Bgv_igv!_
`IA)A|
`mmleted 1‘1
`I
`\
`1 W m
`I
`
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`
`ItemRefaenced
`
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`
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`
`4
`
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`
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`
`
`
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`
`'flstpage.ifpoasi1|e.soasb
`
`«nila'n lasagna-medians. If
`|!\
`05-Jan-2012 03-m-'fl|eslmd1leisla9eflhana
`
`
`
` lAciioncodes fotDMF Table:
`l—DMFReviewetl
`Imuommammam
`
`
`
`
`0|hercodesindimtewhyfl1eDMFwasnotmviewed,asfollows:
`2—TypelDMF
`3—Reviewedplevimslyandmrevision-elnstmview
`4-Suflicientinfonmfioninapplimfion
`S—Aufllmilytotefiemnoematganted
`6—DMl-‘notavailable
`7—Other(explainulder"Cmmnmts")
`
`’mmmmmN/Aamkmmmmmmmmmmmmmmm
`reviewed)
`
`WellieDMFdidmtneedbbe
`mauled)
`
`
`
`NDAZOZ-IO'I CMCReview#2 155940114
`
`Reference ID: 3072819
`
`

`

` CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`APPLICATION #
`
`DESCRIPTION
`
`CONSULTS/ CMC
`RECOMMENDATION -w
`RELATED mmvs
`————
`I_ A table
`12—Jan—2012—
`_———
`
`Comment [Note26]:
`
`The daleoflesponse and
`recommendalim should be holed.
`‘l'helypesofoonsdlsonelaled
`reviewslhatslnddbenoledareas
`
`nw”aecble
`
`21—Oct—2011 CarolHo ' RPh
`
`follows:
`
`DMEPA
`Methods Validation
`Revalidalion by Agency laboratories is
`
`not recommended
`EA
`Ace e table
`Part ofthis review
`
`Tiadename‘
`
`.
`
`—'_———
`DMEPA: Division of Medication Error Prevention and Risk Managemmt.
`
`NDA 202—107 CMC Review it 2 Page 5 of 14
`
`Reference ID: 3072819
`
`

`

`FRI.“
`w}
`
`W811
`
`1. Recommendations
`
`CHEMISTRY REVIEW
`
`Executive Summary Section
`
`The Chemistry Review for NBA 202-107
`
`A. Recommendation and Conclusion on ApprovaliilflyL
`
`meCMCpointofviewthisapplieutionisreconmiendedfiirAPPROVAL.Allpendingissueshavebeen
`satisfactorilyresolved
`
`Basedontliestabilitydatasubmitted,anupiiyof24monthsfmdiugpmductpackagedinHDPEbotfles
`mmmderfliemoommendedstoragecondifions: Storeat25 C(77 F);excursionsperniittedtn
`-
`F) [see USP CmitmlledRoomTemperature]. Piotectfiommfisture.
`
`B. Recommendation on Phase 4 (Post—Marketing) Commitments, Agreements, and/or Risk
`Management Steps, it' Approvalile
`
`None.
`
`11. bummryot’ChemistryAssessmentsL ___________________________________________
`
`I
`I
`I
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`I
`I
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`I
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`I
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`\
`\
`
`_‘
`A. [Description oftlie Drug Pmducus) andDrllgSllbstancdsi ___________________________ \
`I
`I
`I
`I
`
`Drug Substance Mifepristone
`
`\
`
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`
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`
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`Mum-dingy?”
`
`Comment [Mount]:
`
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`WBWW
`ornotapprovablefiomadiaiiistry
`mmpaspeetive.
`
`\
`
`Comment [Nolan]:
`
`'l'liismyisinhirledbpullw
`muwumm
`dilingtlnduiiistryrwha) This
`mmuhothuoi'flifimb
`tliereview-idashndvaloudocmt
`
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`3-one (IUPAC nann), niolectflarfomiiila%;fi0-, andniolecularweight42960glinol, isthedrugsubstaneeof'
`II
`memugpodeoflymmTableb.MifipdsmisasyMeficstaoidbebngingwmech$of
`I
`I
`oornpoundslmedicationsknownasantipiogestationalsteroids. Itisaprogeeteroneandoortisolantagonist,andexerts
`I
`its physiological actimbybloclnng the activity of progesterone and glucocorticoid (GR-II) receptors. Mifepi'istone,
`I
`I
`fonnerlyknmnasRU4869(codenamegivenbyRinissel-Uciat), istlieactiveingiedieiitofthewidelyusedand
`I
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`approvedoraltabletsformedicalabortionhflfisappfimfiomniefipfistoneisproposedmreduceflieefiectsof
`I
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`
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`
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`
`this application (letter
`o authorinition (IDA)dated 11Mar2011) 'l‘liedrugsubstancews) is
`
`forCoreept
`Details.ofthe
`andmanufiictuiingpmcessfor
`'oniniderDMF
`eare
`. Itsstmctureandphysicochemical
`
`properties, welldesciihedinDMF
`,arewellknowninthe
`'
`teratiire. TheaqiieoussoliibilityispH
`
`
`dependent, with a sharp decline in so betweeanl..5.—20 AtpHvalnesabover, thesolubilityof
`niifeiiiisttiiieislelsthanOHSmg/mL AcoordingtotheBiphaiinaoeuticsClassificationSystemmCS), niifepristoneis
`aclassZoompoundmighpeimeabilityJowsolubility).
`
`employed for the maimfiicture of Korlyin‘" (niifepi'istone) Tablets has an appeaiance of a
`
`powder(miaD.1heDScompfieswflhmdePI£basedidufitytests,spedficopficfl
`
`w/wcontentRegardingpuiity, estimatedbyHPDC theconteiit
`
`
`
`NDA 202-107 CMC Review it 2 Page 6 of 14
`
`Reference ID: 3072819
`
`myslioiildlielboqu—h'iw
`
`Mdhewntmhflainm
`Wfiirednuhdllyuwellu
`
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`oDe-ufliehmnbwmtsxes.
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`hyphysicodiemicafleg, partickliu
`mm, morphiefi-m)
`“biologic-Imus“
`
`pafiimanoeailllorhgllodndqnality
`Thetypelidahlof'uneswillnry
`
`medium
`
`II
`
`I
`l
`I
`
`

`

`”M — "M
`I
`CHEMISTRY REVIEW
`
`I
`
`Executive Summary Section
`
`and
`
`seomdarypachging
`
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`
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`
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`datedz7-Dec-2on(de1ailsrefenedtoDMF-mCReviewslmdemdos—Oct-zou
`and 29-Dec-20] 1 methamJ
`
`Drug Product Kodym'n‘ (mifepiflune) Tablet
`
`Kuiym"(Mflqliskm)Tabldsmimmfimrduxhbletcmmiflng3wmgoffiexfiwW
`mifeplistm.Ktrlym“Tabletsuelightyellowtoydlw,ovaLfihnooatedtabletsdebossedwifll"OORCEl’l‘on
`onesideand'300"uflleother.
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`
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`m,mmm,mmmmmy,mmmmmm_mg
`mummmmmmamummmm-mmm
`mmmmmmm-
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`
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`Whepimypchgngomfignfim(2&mammmm)mwmhmepoductNo
`
`protechonnsreqmed.
`
`NDA202-107 CMCReview#2 M70114
`
`Reference ID: 3072819
`
`

`

`aim-n
`
`bum)
`
`CHEMISTRY REVIEW
`
`Executive Summary Section
`
`FM?"
`
`we”:
`
`
`
`degmhhonpmductandaspeuficahmfmfimflledmgpmdlmtlsnotreqlmed
`
`Basedmfieovmflasessmfloffiemfltfinmflfimeandmlmatedcmdifimsfmflnflmmfl
`
`shbflfiystldiesfmfllepimrysmbifitybamhesmdfmmemppmfiveshbifitybam,aswellasfllephotostability
`shidy,ashelflifeof2yearsisproposedforKorlym"Tablets.
`
`[Dhagmemwwofthedmgptodmmfimammforaflifimflmfomafimmsmdmmemmer
`of DMF
`_ Afier Ammdment dated 27—Dec—2011, the infonnation
`‘
`' %
`was defined aocep13ble(ddails refund to DMF
`CMC Renew l,
`05-
`Jan-2012 _
`
`B. [Descriptionofllow thenmgrroauctislmndedtobevsei
`
`Comment [mum]:
`
`MMWWWTabmwmwmmexfivecmmmqunismqmacfiwwfiml Mkmfih of
`teceptotblockel',isindicatedtotreatflleclinicalandmetabolic efl'eclsofhypelcorfisolisminpafianswifll mwks.
`II”:
`I m
`mdogmsfixshmg’ssymme.1hehlgpmmubhmdmbeusdmfly$a§nglemflydom.Bamdm mmmm)
`assessmentofclinicaltesponseandtolelability,filestatfingdoseof300mgonoedaily,nuybeinueasedt0600mg
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`some
`'
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`
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`
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`
`C. [Basis for Appmvability or Not—Appmval Recommendatioli ___________________________
`
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`mbstance(DS)anddmgpmduct(DP).DSandDPmamrfichnedandpackagedinaccordaneewiththepmoedmes
`MmmndafimsgivmmflmofiginflmhmmdpufimDMFsanmdnmSwmsmngww
`'
`'
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`_
`oomphamemfllmrpuoposedspeufimhmgmamfllmthtymrwglunshelfhfe
`
`‘
`
`NDA 202-107 CMC Review it 2 Page 8 of 14
`
`Reference ID: 3072819
`
`

`

`XavierYsem,PhD
`Chemist,0NDQA/DNDQAI]I/anchvn
`
`
`
`Date: 17—Jan-2012
`
`B. [Endorsement 1;th_______________________________________________________
`
`AliAl—Hakim, pm)
`
`BnnchChiefiONDQAl DNDQAIlI/BtanchVII
`
`Date: 17-Jan-2012
`
`
`
`
`c. Iccnml __________________________________________________________\
`J.- M Weber
`Project Manager, 0ND] ODEIIIDMEP
`
`\“
`
`NDAZOZ-IO'I CMCRcvicwiIZ 155:9 of“
`
`Reference ID: 3072819
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`XAVIER J YSERN
`01/17/2012
`All CMC pending issues have been satisfactorily resolved
`
`SUONG T TRAN
`01/17/2012
`For Ali Al Hakim, Branch Chief
`
`Reference ID: 3072819
`
`

`

`
`
`NDA 202-107
`
`KorlymTM (Mifepristone) Tablets
`
`Corcept Therapeutics
`
`Xavier Ysern, PhD
`
`ONDQA/ DNDQA III/ Branch VII
`
`(Clinical Review Division: DMEP)
`
`NDA 202—107 CMC Review # l Page 1 of 74
`
`Reference ID: 3071433
`
`

`

`Colnmentlflotel]:
`
`fiflowmgsecfimupniududiown
`hue Reviewuashonldfielfieeto
`
`eiflH'thyuAlfl-Shifii-U
`
`heatinguneededuaingmdoufline
`convutim
`TomniuflyhaveMSWotdnpdm
`fieTableofConlentsv-flhflieconect
`paginafiomflickonceanywhueinlhe
`Tableot‘CoanIeTahleot'Conluns
`Maintaining-Mingus
`
`
`
`rl'able of ContentsL ___________________________
`
`Table of Contents.........................................................................................................................................................2
`
`Chemistry Review Data Sheet ....................................................................................................................................3
`
`The Executive Summary .............................................................................................................................................6
`
`I. Recommendations __________________________________________________________________________________________________________________________________________________ 6
`
`A. Recommendation and Conclusion on Approvabilily.......................................................................................6
`
`B. Recounnendati-onPhase4 (Post—Marketing) Commitments,Agi'eements, and/orRiskManagement
`Steps, ifApprovable ........................................................................................................................................6
`
`IL Summary ofChemisuy Assessment ..................................................................................................................... 6
`
`A. Description ofthe Drug Pmduct(s) and Drug Substance(s)..............................................................................6
`
`B. DesuiptionofHowtheDmngductisIntendedtobeUsed..........................................................................7
`
`C. Basis for Approvabilily or Not-Approval Recommendation ............................................................................8
`
`111 Administiative ........................................................................................................................................................9
`
`A. Reviewer’s Signature........................................................................................................................................9
`B. Endorsement Block ...........................................................................................................................................9
`
`C. CC Block ..........................................................................................................................................................9
`
`Chemistry Assessment
`
`I. Review OfCommon Technical Document—Quality (Ctd—Q) Module 3.2: Body OfData
`
`S
`
`DRUG SUBSTANCE [Mifepristone’
`
`3. i 334.
`p DRUG PRODUCT [Korlymn‘ (mifepn'stone) Tablets] ...............................................................................26
`A APPENDICES..............................................................................................................................................69
`
`R REGIONAL INFORMATION_____________________________________________________________________________________________________________________69
`
`IL Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ............................................................... 70
`
`A. Labeling & Package Insert.............................................................................................................................70
`
`B. EnvironmlalAssesmnentOtClaimOfCategoricalExchlsion....................................................................70
`
`III. ListOfDeficienciesToBeComunmicated None
`
`NDA 202—107 CMC Review it 1 Page 2 of 74
`
`Reference ID: 3071433
`
`

`

`FDA?“
`
`m
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`F'AFI"
`
`w
`
`1. NBA:
`
`201-107
`
`
`
`MIMI]:
`kZIIemBIryReviewData SheelL _______________________ mummy...“ on,
`fiiu-inlnoldwilllieillreh“
`Hue-emudo-um,
`ummumumu
`.m-‘NIA'Iifi-Iqhflinm
`
`2' “VIEW’Ii ——————1———————————————————————————————————————————————————— -\
`bwhyhm'floflllcfiuism
`mamma- 'l‘lnislzview
`Dame-megawatt:
`10-Jan-2012
`”mama-ups:
`
`
`
`Comment [Home]:
`Add Ihe review number for Ibis
`review. AI reviews {or an AINDA
`
`should be numbered sequentialy
`
`6. SUBMISSIONS) BEING REVIEWED:I
`
`5) Reviewed
`
`SM"'
`Original
`Amem‘hmnt (Proptidaty name)
`Amendmtaabelmg/Packagelnsatmcmamm)
`
`
`
`
`\
`
`
`
`
`Document Date
`15-Apr-2011
`19-Apr-20] 1
`25-Apr-2011
`
`‘\
`
`\\
`
`\
`
`7. NAME & ADDRESS OF APPLICANTL
`
`Name: Comept Therapeutics
`Address:
`149 Commonwealth D11, Marlo Park, CA 94025
`Representafive: Luana Shiger
`Telephone:
`650 678 7230 (email: lstaiger@corcep.u-)
`
`8.IDRUG monvcr NAME/CODEITYPEzL _______________________________________ J"
`
`‘ \
`
`
`
`
`
`
`
`
`
`
`a)
`b)
`
`
`
` Comment [“14]:
`
`FuONDCnsemly medias“?
`
`
`
`10- MACOL- CATEGORYI. _ _ _ _ Wemggxom_mm _____________ \ \ \ (“W“MY) m
`redueetheefi'ects fhypercorfisolism'
`'
`tswifllmdoguwus \
`Coll-merit [Hotels]:
`
`
`
`gLn‘ng‘s SyndromeJo
`Inpahen
`\\
`Thesecion staid include:
`m
`Confluent [Hotels]:
`Refit Io FDA Form 356i: cravinble
`
`
`refereneee
`
`\
`
`NDA 202-107 CMC Review it 1 Page 3 0174
`
`Reference ID: 3071433
`
`Nun-l ____________________ISoslylpf'icnyienmuaklse ____________ J"
`011--Proptiehry Name (USAN){ _____________W____________________________
`Name/H ________________________-; _______________________________
`d)Chern
`SubnnssionPrimily(0NDConly):
`_T_w¢-_ __ ______________11m 5: :stfelznsllayeq ................
`on PrimityE _____________________________________________ _\\ x \
`
`\\
`
`‘
`
`
`
`
`

`

`
`
`Chemistry Review Data Sheet
`
`12.
`
`GTE/POTEN
`
`300
`
`
`11.b08AG1-:1-‘om¢ ____________ 12111131 __________________________________________ mlmm:
`Rafa b the ODE! Dal: Md:
`Manual (Genelal itiulMPPist
`CYE ----------n-Ig‘ ---------------------------- -\‘ Wmmhwlmfnwnm).
`mm
`
`
`as needed or.
`naval doom fonns
`
`
`13. hour]: 0F Annmnsmnmi _ 95a! _______________________________________ X
`... .1mm"W
`\\
`".
`Coll-lilies. ForW, lyopllizod
`\ www.ma
`14 chmsmt _________ 3g ________________________________________ .
`
`
`
`16. kZHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA, MOLECULAR
`wucmt ________________________
`
`Mfeplistone
`RmmelUclafcomnynamezRUm
`Fonmla:ngI-135NO7
`
`Mw: 429.60 g/mol
`
`CAS #2 84371-65—3
`
`Comment [Note19]:
`
`
`
`(mlmwniggwfiozaw
`N
`due Wading] ll
`"10/
`fiffllfi.“
`
`mfifl'm
`
`WWI. _
`mum-war
`
`“Iopohnqjul'l. hem
`
`
`llB—[pMylmfimM}l7fl-hy¢oxy—l7(l1xopynybesha4,9—dim-m ammo name)
`im$$_fi.mfl“
`
`
`
`
`
`17. REIATEINSUPPORTINGW ______________________________________
`
`A. DMFs:
`
`IA)A|
`-BEZig'Z-
`“"5
`“‘3
`ItemRefaenced
`Holda-
`mmleted 1‘1
`I
`——— ‘
`1 W m
`|
`
`4
`
`Adequate
`
`'flstpage.ifpoasi1|e.soasb
`
`
`«nila'n lasagna-medians. If
`|!\
`05-Jan-2012 03-m-'fl|eslmd1leisla9eflhana
`
`
`
` lAciioncodes fotDMF Table:
`l—DMFReviewetl
`Imuommammam
`
`
`
`
`0|hercodesindimtewhyfl1eDMFwasnotmviewed,asfollows:
`2—TypelDMF
`3—Reviewedplevimslyandmrevision-elnstmview
`4-Suflicientinfonmfioninapplimfion
`S—Aufllmilytotefiemnoematganted
`6—DMl-‘notavailable
`7—Other(explainulder"Cmmnmts")
`
`’mmmmmN/Aamkmmmmmmmmmmmmmmm
`reviewed)
`
`WellieDMFdidmtneedbbe
`mauled)
`
`
`
`NDAZOZ-IO'I CHOW!” 155940174
`
`Reference ID: 3071433
`
`

`

` CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`APPLICATION #
`
`DESCRIPTION
`
`CONSULTS/ CMC
`RECOMMENDATION -w
`RELATED mmvs
`————
`
`_———
`
`Comment [Note26]:
`
`The daleoflesponse and
`recommendalim should be holed.
`‘l'helypesofoonsdlsonelaled
`reviewslhatslnddbenoledareas
`
`nw”aecble
`
`21—Oct—2011 CarolHoW RPh
`
`follows:
`
`DMEPA
`Methods Validation
`Revalidalion by Agency laboratories is
`
`not recommended
`EA
`Ace e table
`Part ofthis review
`
`Tiadename‘
`
`.
`
`—'_———
`DMEPA: Division of Medication Error Prevention and Risk Managemmt.
`
`NDA 202—107 CMC Review it 1 Page 5 of74
`
`Reference ID: 3071433
`
`

`

`Oo-une-tfllotem:
`
`I
`
`WWW-him
`Eli
`.
`l'
`.
`.l
`'I
`l'l'onndlnneikofalmltiph
`
`2 TopwideahHWO-Z pap)
`ofhwmofq-Iityoftl:
`Mum-dingy?”
`
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`
`Comment [Noun]:
`
`Yondionldflwhdhuywr
`WBWW
`ornotapprovablefiomadiaiiistry
`mmpaspeetive.
`
`\
`
`Comment [Noun]:
`
`I
`
`aim-n
`
`W
`
`MS!
`
`1. Recommendations
`
`CHEMISTRY REVIEW
`
`Executive Summary Section
`
`The Chemistry Review for NBA 202-107
`
`FM?"
`
`Exam)
`
`A. kemmmendaflon and Conclusion on ApprovaliilflyL
`
`From CMCpointofviewthisapplicationisreconunendedforAPPROVAL. 'l‘liereconiinendationfiomthe
`OffieeisCompfimeefmflnacceptabifityofthennmrfaeunmgsitesissfinpmding.
`
`Basedontliestabilitydatambmitted,anupiiyof24monthsfmdiugproductpackagedinHDPEbotfles
`mmmderfliereoommendedstoragecondifionsfitmeatzs C(77 F);excui'sionsperniittedtn
`F) [see USP Controlled Room Temperature]. Piotect fiommoisture.
`
`B. Recommendation on Phase 4 (Post—Marketing) Commitments, Agreements, and/or Risk
`Management Steps, it' Approvable
`
`None.
`
`Drug Substance Mifepristone
`
`
`W ' MW“ WW
`
`hassubmittedDMI-‘#
`for-(nufepiistone
`DMl-‘may
`thisapplication(lettei'o authorinition (IDA)dated 11Mai'2011) 'l‘liedi'ugsubstancews) is
`
`Details.ofthe
`andmanufiictmingpmcessfor
`
`underDMF
`. Itsstiiictureandphysicochemical
`,arewellknowninthe
`teiatiire. TheaqiieoussoliibilityispH
`
`‘ betweean 15—20 AtpHvahmabover, thesolubilityof
`
`mifepi'istoneislusthaan ing/mL.Accordingtothe BipliaiinaoeuticsClassificationSystemmCS), niifepristoneis
`aclassZoornpoundmighpeimeabilityJowsolubility).
`
`for the maimfiicture of Korlyin‘" (niifepi'istone) Tablets has an appeaiance of a
`
`
`'
`'
`l
`
`
`rotation
`_
`Point u w.
`
`
`#(visual). TheDScomplieswithIRandIrIPchasedidufityMSpecificqitical
`
`
`w/wcontentRegardingpuiity, estimatedbyHPDC theoonteiit
`ofniifepiiostoneisnotmoi'ethaanl‘
`
`NDA 202-107 CMC Review it 1 Page 6 0174
`
`Reference ID: 3071433
`
` I
`
`Thismyisiiihirledbpullw
`muwumm
`dilingtlndunistryrwha) This
`mmubothuor'flifimb
`tliereview-idashndvaloudocmt
`
`myalionldhelbolbil-h'no
`
`Mdhewntmhflainm
`Wfiirednuhdllyuwellu
`
`oDeIuiIieflndngpoM(nune(s),
`Mammdosapmm
`Mudhowitispdlged)
`commands-Ms)“,
`USAN, mane) Idmtifyanddauibe
`hyphysioodiemicafleg, putickliu
`mm, morphiefi-m)
`andliiologiulpropatiatliatean
`
`pafiimanoeailllolhgllodnctqnality
`Thetypelidahlof'unes'illvuy
`
`medium
`
`II
`
`I
`l
`I
`
`11. bummryot’ChemistryAssessmentsL ___________________________________________\
`\
`A. [Description oftlie Drug Pmducus) anaDmgSnbsuncqsi ___________________________ \_‘
`I
`I
`I
`I
`I
`I
`Mfepri'stone, cliemicalnaine llB—[p—(Dimetliylamino)plienyl]—17B-liydroxy—17-(1-propynyl)estia—4,9—dien-
`3-one (IUPAC nann), niolecflarfomnila%;fi0-, andnioleuilai'weiglit429.60glinol, isthedi'ugsubstaneeof'
`|II
`theihugpmductKoi'lymmTableIs. Mfepiistoneisasyntheticsteroidbelongingtoflieclassof
`I
`I
`oornpomidslmedicationsknownasantiprogestationalsteroids. Bisaprogeetamemdwrfisolantagonistandexerls
`I
`its physiological actimbyblocliing the activity of progesterone and glucocorticoid (GR-II) receptors. Mifepi'istone,
`I
`I
`fonnerlyknmnasRU4869(oodenamegivenbyRinissel-Uciat), istlieactiveingiedieiitofthewidelyusedand
`I
`I
`approvedoraltabletsformedicalabortionhflfisappfimfiomniefipfistoneisproposedmreduceflieefiectsof
`I
`hypeiemtisolisminpatientswifliemlogenmsCushing’LSyndmme
`I
`I
`I
`I
`I
`
`

`

`”M — ”M
`V
`CHEMISTRY REVIEW
`
`u
`
`Executive Summary Section
`
`
`
`0verttue24monflusoffliestabilitycoupldedtodate, nosignificantcliangestoappenianee,assay,
`iinpirities,particlesize, mnfisfirecmtmtwaeseaudurhgstmageateifliatheaecdaatedmmomtenpaanre
`stoiageconditions.
`mifepristonewliicliisintendedfiircomnmcial
`tabletproductionwillbe
`.Noadditiirnlstabilitystuxlieswillbecmiiictedon
`mifqristom.
`
`DMF
`
`fliereviewoforiginalDMF-, arequestfiiradditionalinfonnationwassendbflieflolderof
`AflAgmcyrecpesteremsweredsafisfictorybyflieHoldaofflieDMFmflieir
`dated27---Dec2011(detailsrefenedtoDMF-(deReviewslandeated06-Oct2011
`and29-Dec—2011 roqiectivu-Jy).]
`
`Drug Product Kodym'n‘ (mifepiflone) Tablet
`
`W"(Mflqaiskm)Tabldsmimm&ahrduxmbletcmmimng3wmgoffiexfiwumonmt
`mifepristone. KmlymflTabletsareligtityellowtoydlow, mLfihncoatedtabletsdebossedwifli'DORCEl’l‘on
`onesideand'300"ua.flieotlier
`
`-childresistantclosure,ora280-countbotflewifli
`
` 'l‘liecoatedtabletsaiepackagedintooneoftwopackaging
`ISM) up ‘ ""
`
`Dnigpodnctspecifieatimsincliideappearanee(visuialaaminalion), idmfificafionGIPIQJssay
`(HPLC), impritiesaIPIJC), dissohitiorgcontaitunifonnity,watercontentandnraobiallimits_ Regarding
`mummmmmmfiamummmm-mmm
`thetotalimpiritycontentnottoexceed-
`Imbakdhfiesdflsimm9mflbsofdahmfieprmnryshhfitybambesswdluupm24nmfis
`long—tmndataavailableonsupportivebatclies. Onlyoccasionaluruidentifiedirrpir'itiesweienotedduringall
`WMNmofflmwereporbdmkvdshghammepwmflampmeufiaimof<
`-
`
`mmugpodwthsbemshwnwbedabkwfiglndewosrcmeypmkagingand,
`mammmmmaemmmmmmwmmmmm
`mdmypadagingkmquuedfmfiglrpmcfionmmmmmmhbehgmhfimfight
`protectionisrequired
`
`NDA202-IO'I CMCRevieIn‘H Pige7of74
`
`Reference ID: 3071433
`
`

`

`aim-n
`
`w
`
`CHEMISTRY REVIEW
`
`Executive Summary Section
`
`FM?"
`
`Exam)
`
`
`
`degmhhonpmductandaspeuficahmfmfimflledmgpmdmisnotreqlmed
`
`Basedmfieovmflassessmfloffiemfltfinmflfimeandmlmabdcmdifimsfmflnflmmfl
`
`shbflfiystldiesfmfllepimqsmbifitybamhesmdfmmemppmfiveshbifitybam,aswellasfllephotoslalility
`sh!dy,ashelflifeof2yeatsispmposedfor- Tablets.
`
`[Dhagmemwmofthedmgmmsecfimammforafiifimflmfomafimwmsmdmmemmer
`of DMF
`. Afier Ammdment dated 27-Dec-2011, the information
`'
`'
`the
`wasdeanedaocemble (details Iefenedto DMF
`CMC Review 1,
`
`05-
`
`Jan-2012.
`
`B. heuripfionofflow thenmgproauctislmndedtobevsei
`
`Comment [Roman]:
`
`Tablemwhichcontainsflleacfivecmnponmtnfifepdsumefinacfivecmfisol mumfih
`Thedmgl’roduct,
`to treat the clinical and metabolic efi'eds of hypelcorfisolism in palienls wifll mzfi‘m“(““5
`receptor blocker, is '
`'
`mdogmsfixshhg’ssym.1hehlgpmmubhmdmbeusdmfly$a§nglemflydom.Bamdm mmmm)
`assessmentofclinicaltesponseandtolelability,fliestatfingdoseof300mgonoedaily,nuybeinueasedt0600mg mum-Imam
`oncedaily.Fmfllflesedafimin300—mginumnmtsmamof1200mgomedaflymybeappmpiatein wwmum“!
`some
`'
`,wifihamsedmonitmhgfmfiskfidmsasmdatedwflhmedmgaeepafimtpachgehsm).
`fishmfldalwaysbemkenwifllam
`
`Imhdeuydskmguulsnpshm
`
`snhmflh‘ELmM
`Humhmwdnae
`“jammy"m‘ Indium I
`_
`_ of”
`_ _bh
`uflyuflqulityofflnhgplohd
`
`C. [Basis for Appmvability or Not—Apprnval Recommendatioli ___________________________
`
`Adeqflehfmafimlnsbemshnitbdbaflmasafisfidoqewhafimoffieqmlflyofbofidmg
`mbstance(DS)anddmglroduct(DP).DSandDPmamrfilcmredandpackagedinaccordanoewflhthepmoedmes
`MmmndafimsgivmmflmmiginflmhmawpufianWsammswmmjudgww
`'
`'
`'
`'
`'
`‘
`'
`_
`oomphamemfllmrploposedspeufiaumgmamflleuthtyfinwghmnshelfhfe
`
`‘
`
`NDA 202-107 CMC Review it 1 Page 8 0174
`
`Reference ID: 3071433
`
`

`

`Chanist, 0NDQA/ DNDQA III/ Branch VII
`
`Date: 10-Jan—2012
`
`B. Endorsement mod_______________________________________________________
`
`AliAl—Halcim, pm)
`
`Bnm‘hChief,0NDQA/ DNDQAHI/BnmcthI
`
`Date: 10-Jan-2012
`
`
`
`
`c. ICC and __________________________________________________________\
`JenaM Weber
`Project Manager, OND/ ODEIIIDMEP
`
`“
`
`
`
`mum-107 CMCReview#l 155990174
`
`Reference ID: 3071433
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`XAVIER J YSERN
`01/12/2012
`
`ALI H AL HAKIM
`01/12/2012
`I concur
`
`Reference ID: 3071433
`
`

`

`Initial Quality/CMC Assessment
`ONDQA
`
`Division of Metabolism and Endocrinology Products
`
`
`
`NDA: 202107
`Applicant: Corcept Therapeutics
`Stamp Date: 18-APR-2011
`PDUFA Date: 18-FEB-2012
`
`Proposed Proprietary Name:
`Established Name: Mifepristone
`Immediate release tablet
`Dosage form and strength:
`300 mg
`Route of Administration: Oral administration
`Indications: Treatment of hypercortisolism associated with
`Cushing’s Syndrome
`
`
`CMC Lead: Su (Suong) Tran, ONDQA
`
`ONDQA Fileability: Yes
`
`
`Are there comments for the 74-day letter? Yes.
`• Confirm that the formulations coded “E2” in the Clinical Summary (section 2.7.1) and “C2” in
`the Quality Summary (sec2.3.P.2) are the same and are the final formulation for the
`commercial product.
`• Submit the master batch records for the drug product manufacture per 21 CFR 314.54(a)(1)(i).
`
`
`
`
`Reference ID: 2960198
`
`Page 1 of 15
`
`(b) (4)
`
`

`

`
`CONSULTS/ CMC
`RELATED REVIEWS
`CBER
`CDRH
`EA
`
`Compliance (DMPQ)
`
`Methods Validation
`
`Microbiology
`OBP
`ONDQA Biopharm
`
`OSE
`Pharm/Tox
`
`Initial Quality/CMC Assessment
`ONDQA
`
`
`COMMENT
`
`Not applicable
`Not applicable
`The categorical exclusion claim will be assessed by Primary
`Reviewer.
`EER was sent to Compliance by ONDQA PM (K. Sharma) on 02-
`MAY-2011.
`Validation may be requested of FDA labs after test methods are
`finalized.
`Not applicable. The product is a solid oral dosage form.
`Not applicable
`Review of all dissolution/drug release-related information. (Reviewer:
`M. Hughes)
`Labeling consult request will be sent as part of DMEP’s request.
`Not applicable (Impurities and degradants limits are within ICH
`qualification thresholds for the maximum daily dose.)
`Not applicable
`
`QbD
`
`This is a paper NDA, filed as a 505(b)(2) application, with the listed drug (LD) being Mifeprex
`(mifepristone) Tablets (different applicant). The