`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`203284Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`DEPATMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTARTION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`January 16, 2013
`
`MEMORANDUM
`
`
`
`
`
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`
`
`
`
`
`
`DATE:
`
`TO:
`
`FROM:
`
`
`
`THROUGH:
`
`
`
`SUBJECT:
`
`In review # 1 of NDA 203284 for Ravicti Liquid for oral use, this NDA was not
`recommended for approval from the CMC perspective due to the following reasons:
`
`
`
`
`
`
`
`
`
`
`
`
`NDA 203284 CMC Review # 1
`
`Hamid R. Shafiei, Ph.D., CMC Reviewer
`(ONDQA/Division II/Branch IV)
`
`Moo-Jhong Rhee, Ph.D., Branch Chief
`(ONDQA/Division II/Branch IV)
`
`Final CMC Recommendation
`
`1) CMC related label/labeling issues were not resolved
`2) An overall recommendation of “Acceptable” from the Office of Compliance
`regarding the facilities involved in this NDA was not yet issued
`
`
`The CMC label/labeling issues have been resolved via the amendments dated December
`13, 2012 and December 31, 2012 (see the Attachment -2).
`
`The Office of Compliance has also made an overall recommendation of “Acceptable” for
`the facilities involved in this NDA on January 14, 2013 (see the Attachment-1).
`
`
`Recommendation:
`
`This NDA is now recommended for approval from the ONDQA perspective.
`
`
`
`
`
`Reference ID: 3246294
`
`

`

` Addendum to CMC Review # 1 of NDA 203284
`
`Appendix
`
`
`Attachement-1
`
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`
`
`EES Report
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`Reference ID: 3246294
`
`
`
`Page 2 of 12
`
`

`

`Addendum to CMC Review # l of NBA 203284
`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`Embllalmn‘t
`
`DIF No:
`
`Ruponllblfltbs:
`Esublbhment
`Comment:
`Profile:
`
`DRUG SUBSTANCE OTHER TESTER
`
`CONTROL TESTING LABORATORY
`
`0A1 m: NOE
`
`cm
`
`
`
`"Hahn. Narn-
`SUBMITTED TO DO
`
`SUBIflTI'ED TO DO
`
`ASSIGDED INSPECTION TO B
`
`Illodom Duh m Planned cm Decision
`Reason
`
`
`69" landfill
`
`GP Imam
`
`
`the
`
`INSPECTION PERFORMED
`Mswmumwm)dammmmmmmmmsmmdh
`acoudanceuifluamsasflmmDFFlflOBaMCDER/OCIDIDQHCBZ «WWW
`BummhaPDUFAPreAwuvdhspecfiundflwbbormytnevmlheir
`mmdmmsmmdmmwmmmwm), “trending
`W(M)A)20328Mm. ThsholderofflremAisHyperimTharapwlics lnc. SoulSan
`
`lrspecmnsmdcl’nmeIE-Apprmd Inspech'ons. ;.
`Wsmmdmmmgwmmngmmmmnm—
`Mammqmcsoma
`msaPAl
`
`hwmhmmmdflahbamvsm. FaciflasaEuipmmLaId
`Laborahrysysuns‘ PmfilachssCTHCordeesfivLflaordmwwcoveroddumme
`irrspedion.1heinspocfionfomdlntheekfisofGPBwalesamb
`
`DORECMEMJATION -
`
`ocnecomewmou _
`
`ACCEPTABLE -
`INSPECT'ON
`
`ACCEPTABLE _
`DISTRICT REcomlamAnon
`
`January 1a. 2013 12:44 PM
`
`FDA Confidorltid - Inbrnll Diminiion Only
`
`Pay. 2 on
`
`Reference ID: 3246294
`
`Page 3 of 12
`
`

`

`Addendum to CMC Review # l of NBA 203284
`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`mum:
`
`DMF IIo:
`
`Rumbas-s:
`
`cm: —
`
`FEI:_
`
`
`
`AADA:
`
`DRUG suasrmce WACTURER
`DRUG SUBSTANCE PACKAGER
`DRUG StBSTANCE RELEASE TESTER
`
`WWW PROVIDES FOR MANUFACTURNG, CMC TESTING AND RELEASE, PACKAGING, STABILITY TESTING (GLYCEROI.
`Wt
`PHENYLBUTYMTE. DSM)
`
`Profile:
`
`
`on sun»: NONE
`
`
`NON-STERILEAPIBY CHEMICAL smmssus
`
`EM —.M°n°0# mm mm Ln bl”
`Comment
`SUBMTTEOTOOC
`
`
`
`MW
`SUBMTI'EDTODO
`WILL BE OVER 3 YEARS AT THE 0F PDLFA OTHER FIRMS PENDING INSPECTION
`REQUESTS FOR Tl'IS IDA
`
`ASSIGNED uspecnoN TO IB
`
`mm PERFDHIIED
`
`NSPECTICNWE
`I MW
` OC RECMENDATDI
`
`UNJER REVIEW
`CASE ID
`REVIEW;CSONOTYETASSIGNED
`NOD
`D0 RECMENDATW
`
`ACCEPTARE
`NSPECTION
`
`WARE
`DISTRICT REOOIIMEMJATKN
`
`
`Jl‘lulry 16, 201312fi4 PM
`
`FDA Cotfldmtill - Inbmll Didriluflon On};
`
`Page 3 of!
`
`Reference ID: 3246294
`
`Page 4 of 12
`
`

`

`Addendum to CMC Review # l of NDA 203284
`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`mm:
`
`DMF No:
`
`AADA:
`
`Responsibilities:
`
`DRUG SUBSTANCE STABILITY TESTER
`
`mm useomswmmma—
`Confluent:
`Profit:
`CONTROI. TESTING LABORATORIES “ALSO“ (DRUGS)
`ON m: NONE
`
`Mllealone Nine
`
`Mllastone Dan w W Declalon
`Reason
`
`Creator
`
`REQUEST CANCELLED
`
`
`
`SUWITI'ED T0 00
`
`0C RECOMMENDATION
`
`—
`IRREEVANT FACILITYIPROFILE
`
`ACCEPTABLE
`BASED ON PROFILE
`
`
`
`January 16, 2013 12:44 PM
`
`FDA Confidential - Irmrnal Dlstrlbmlon Only
`
`Page 4 of 8
`
`Reference ID: 3246294
`
`Page 5 of 12
`
`

`

`Addendum to CMC Review # l of NDA 203284
`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`autumn:
`
`DIIF No:
`Responsibilities:
`
`cm: -
`
`
`
`AAnA:
`
`DRUG SUBSTANCE MANUFACTURER
`DRUG SLBSI'ANCE PACKAGER
`
`DRUG SLBSI'ANCE STABILITY TESTER
`
`Comment
`‘
`MIN-MM WMB RELEASE. PACKAGING, STABILITYTESTING—
`m:
`NON-STERILE API BY CHEMICAL SYNTHESIS
`
`
`
`SUBMITTED TO 00
`
`SJBMITI'ED TO DO
`
`
`
`
`
`
`
`
`
`
`ASSIGNED NSPECTION TO B
`
`NSPECTION SCIEMED
`
`NSPEC‘IION PERFORMED
`
`TII'_s irspect'm
`
`t ng-
`t
`wasdscorl’nreditFACTS. CTLalsodoestxxupiytofiisfltnasmdbyitn
`Wheat.
`
`Them‘rmemonmmdm
`tecotnmenddionmtrade: Drug
`
`ddmttesrdtirisumceofaFDAMOne
`Mashemetmduumedefllsptmmry
`
`7 lm
`=
`cmswemsweremvaed TlahlmmrgtealtlnmdanMBwetettnh Istsutlnayofdlnge
`can
`
`
`mmmmtorsmnmmmmmmot .
`
`
`IMDER REVIEW
`080 MT VEI' ASSIGIED
`
`DO RECOMEIDATKN
`
`0C REcmATKN
`
`
`
`ACCEPTABLE
`
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`Jlnlll'y 16. 2013 12:“ PI
`
`FDA Confidtminl Anton-rd DIMbIlIIon Only
`
`Page 5 of B
`
`Reference ID: 3246294
`
`Page 6 of 12
`
`

`

` Addendum to CMC Review # 1 of NDA 203284
`
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`
`Reference ID: 3246294
`
`
`
`Page 7 of 12
`
`

`

`Addendum to CMC Review # l of NDA 203284
`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`Eehbliellnent:
`
`:
`
` DIE No:
`
`FEI:-
`
`Reeponeibilifiee:
`
`FINISHED DOSAGE OTHER TESTER
`
`Est-lawman!
`Comment:
`Profile:
`
`UAseoFonmcnomoemTESTING—
`CONTROL TESTING LABORATORY
`OAI m: NONE
`
`Ilium Nam
`Comment
`SUBMITTED TO GO
`
`“None Date m PlannedM Declslon
`Reeeon
`
`Creator
`
`10-Day LeIIer
`SUBMITTED TO DO
`.IJST A DOLBIE CI-ECK T0 TI-E DO FOR MICRO TESTING
`
`DORECOMEMMTION —
`INSPECTION WAS CLASSIFIED VAI‘
`TI-E FIRM WAS LAST NSPECTED
`EWEDAM) DETERIIN‘ED TO BE
`CORRECTIVE ACTIONS T0 ISSU
`APPRCI’RIATE FIRM HAS APPROPRIATE COMPLIAMZE HISTORY. DISTRICT RECOMhfimS
`APPROVAL OF THIS SITE FOR THIS APPLICATION BASED ON THE PREVIOUS INSPECTION
`RESULTS.
`
`ACCEPTABLE
`BASED m FILE
`
`
`
`
`
`0c RECOMAEMJATION -
`
`ACCEPTABLE
`DISTRICT RECOMNDATION
`
`
`
`Jammy 10, 2013 12:44 Pll
`
`FDA COMM“ - Imam-I Dletllluflon Only
`
`Page 1 of B
`
`Reference ID: 3246294
`
`Page 8 of 12
`
`

`

`Addendum to CMC Review # l of NBA 203284
`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`Establlshmont:
`
`CFN:
`
`FEI;-
`
`
`
`AADA:
`
`DMF No:
`
`WNW:
`
`MUG SUBSTANCE OTHER TESTER
`
`USED FOR MCRGBIOLOGICALTESTING (GLYCEROL PI-BJYLBUTYRATEq--—
`Est-blhmm
`CW -
`Prolle:
`CONTROL
`NG WHEY
`0‘! m: m
`
`Rum“ Tm PmCM m cm
`
`
`Hinton. Dd!
`Ilium Name
`cm
`
`
`SUBMTTEDTOGOGMP_-Inspec1i—on
`
`
`“CRO TESTING OF DRUG SLBSTANCE
`
`
`
`
`SUBMTI'ED TO DO
`
`
`
`
`DORECOIIIENJATION IW momma
`
`ASSIGPED NSPECTION TD IB
`
`INSPECTKN PERFORMED
`
`INSPECTDN PEWORIED
`
`INSPECTICN SCHEDLLED
`
`REPRESENTATIVE COVERAGE OF TESTING FESPONSIBIJIES PROVIDED DURING
`NSFECTKW ENDINGO_. INSPECT“ WAS CLASSFIED NAI
`
`BASED ON FILE
`
`AmEFTABLE
`oc RECMEIDATION *
`DISTRICT REcmmAmN
`
`
`January 1c, 2013 12-4490:
`
`FDAWm . Imml Wonmlly
`
`Page a on
`
`Reference ID: 3246294
`
`Page 9 of 12
`
`

`

` Addendum to CMC Review # 1 of NDA 203284
`
`Attachment-2
`
`1) Final labeling: The applicant has submitted an interim labeling on December
`31 2012 addressing all CMC labeling issues that were documented in CMC
`review #1 of this NDA.
`
`
`
`
`HIGH LIGHTS
` ACCEPTABLE
`
`
`
`
`Dosage Form and Strength: Liquid. Each mL of Ravicti contains 1.1
`grams of glycerol phenylbutyrate.
`
`• 25 mL multidose glass bottle
`
`
` ACCEPTABLE
`FULL PRESCRIBING INFORMATION
`Description: Ravicti (glycerol phenylbutyrate) is a clear, colorless to pale
`yellow liquid, for oral administration. It is insoluble in water and most
`organic solvents, and it is soluble in dimethylsulfoxide (DMSO) and >
`65% acetonitrile.
`Glycerol phenylbutyrate is a nitrogen binding agent. It is a triglyceride
`containing 3 molecules of PBA linked to a glycerol backbone, the
`chemical name of which is benzenebutanoic acid, 1', 1' ' –(1,2,3-
`propanetriyl) ester with a molecular weight of 530.67. It has a molecular
`formula of C33H38O6. The structural formula is:
`
`
`
`
`
`
`
`
`
`
`
`How Supplied: Ravicti (glycerol phenylbutyrate) liquid 1.1 g/mL is
`supplied in multi-use, 25 mL, glass bottles. The bottles are supplied in the
`following configurations:
`
`
`• NDC 76325-100-25: Single 25 mL bottle per Carton
`• NDC 76325-100-04: Four 25 mL bottles per Carton
`
`Store at 20°–25°C (68°–77°F) with excursion permitted to 15°–30°C
`(59°–86°F).
`
`
`
`Page 10 of 12
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3246294
`
`

`

` Addendum to CMC Review # 1 of NDA 203284
`
`
`
`
`
`Reference ID: 3246294
`
`
`
`
`
`
`2) Final immediate container/carton label
`The applicant has provided a labeling amendment on December 31, 2012 that
`provides the immediate container as well carton labels Ravicti (glycerol
`phenylbutyrate) Liquid for oral use.
`
`
`The figure below is the immediate container and carton labels,
`respectively for Ravicti packaged in 25-mL glass bottles.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`ACCEPTABLE
`
`
`
`
`
`Page 11 of 12
`
`

`

`Addendum to CMC Review # 1 of NDA 203284
`
`ACCEPTABLE
`
`1|" N 50131511 1mm
`(alum!!! INN“)
`.. |.|. DIAV 5
`
`IX MSW-ZS
`
`h C!
`
`NIX IBIS-IWZS
`
`I! III
`
`Manley. [am mlomvm (mans
`
`Stovea MIST (GE'Jm
`emmm to
`IS'-30'( (S‘Hfil
`
`Wk
`tum-L
`unmmzsm
`mam-ah.
`mmm ac
`(mu-anthem
`mmmum
`
`O
`”WEN?”
`
`RAVI CT I"
`(glvwol mmwbltvrale)
`qud
`1.] grams per ml
`
`Fowlal UseOnN
`
`mmmem
`kmmmtooaiem
`
`RAVICT I"
`(am nmmm)
`Limit!
`1.] glams per ml
`
`Ll qmnsot mm
`name muddle:
`1.02 msofnhmmae.
`mmdmmolm
`
`mmomme m
`a measwn date
`awme fl! me
`We!“ (IR
`
`F0! Oral USE 0an
`
`mmommm
`Miami mm mm
`
`Reference ID: 3246294
`
`Page 12 of 12
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`HAMID R SHAFIEI
`01/16/2013
`
`MOO JHONG RHEE
`01/16/2013
`Chief, Branch IV
`
`Reference ID: 3246294
`
`

`

`
`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`
`METHODS VALIDATION REPORT SUMMARY
`
`TO:
`
`
`
`
`Hamid R. Shafiei, Ph.D., CMC Reviewer
`Office of New Drug Quality Assessment (ONDQA)
`E-mail Address: hamid.shafiei@fda.hhs.gov
`Phone: (301)-796-2326
`Fax:
`(301)-796-9745
`
`FROM: FDA
`
`Division of Pharmaceutical Analysis
`Michael Trehy, MVP Coordinator
`Suite 1002
`1114 Market Street
`St. Louis, MO 63101
`Phone: (314) 539-3815
`
`
`
`
`Through: Benjamin J. Westenberger, Deputy Director
` Phone: (314) 539-3869
`
`SUBJECT: Methods Validation Report Summary
`
`
`
`Application Number: 203-284
`
`
`
`
`Name of Product: Ravicti (glycerol phenylbutyrate)
`Applicant: Ucyclyd Pharma, Inc.
`Applicant’s Contact Person: Klara Dickinson, Sr. VP Regulatory Affairs
`Address: 7720 N. Dobson Road, Scottsdale, AZ 85256
`
`Telephone: (480) 291-5953
`
`
`
`
`
`Fax: (480) 302-6333
`
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`Page 1 of 3
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`
`
`Version: 7/13/2011
`
`
`
`
`
`
`
`Date Methods Validation Consult Request Form Received by DPA: 4/27/12
`Date Methods Validation Package Received by DPA: 4/27/12
`
`Date Samples Received by DPA: 5/16/12
`Date Analytical Completed by DPA: 8/9/12
`
`Laboratory Classification: 1. Methods are acceptable for control and regulatory purposes.
`
`2. Methods are acceptable with modifications (as stated in accompanying report).
`
`3. Methods are unacceptable for regulatory purposes.
`
`
`
`Comments:
`See attached memo
`
`
`
`
`
`
`
`DPATR-FY12-104
`
`
`Reference ID: 3172534
`
`
`

`

`a
`r
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`Food and Dru Administration
`
`Center for Drug Evaluation and Research
`Division of Pharmaceutical Analysis
`St. Louis, MO 63101
`Tel. (314) 539-3866
`
`Date:
`
`To:
`
`July 30, 2012
`
`Hamid R. Shafiei, Ph.D., CMC Reviewer
`Marie Kowblanski, Ph.D., CMC Lead
`
`Through:
`
`B. J. Westenberger, Deputy Director, Division of Pharmaceutical Analysis
`
`From:
`
`Jamie D. Dunn, Chemist
`
`Subject:
`
`Methods Validation for NDA 203284
`Ravicti (Glycerol Phenylbutyrate) Oral Liquid
`Hyperion Therapeutics, Inc.
`
`The following methods were evaluated and are acceptable for quality control and regulatory purposes:
`
`1. LAG-0179 revision 2 “HPLC Assay for— in Glycerol Phenylbutyrate and HPN-lOO (glycerol
`phenylbutyrate) Oral Liqui ”
`2. LAG-0174 revision 3 “HPLC Assay for the Determination of- Impurities in Glycerol Phenylbutyrate (GPB)
`and HPN-lOO (glycerol phenylbutyrate)”
`
`The Division of Pharmaceutical Analysis (DPA) has the following comments pertaining to these methods.
`
`1. LA6-0179 revision 2 “HPLC Assay for— in Glycerol Phenylbutyrate and HPN-100
`(glycerol phenylbutyrate) Oral Liquid”
`
`
`
`2. LA6~0174 revision 3 “HPLC Assay for the Determination of- Impurities in Glycerol Phenylbutyrate (GPB)
`and HPN-100 (glycerol phenylbutyrate)”
`
`0
`
`Typographical error in the Title on pages 1-15 needs to be corrected. Change phenlybutyrate to
`phenylbutyrate on all pages.
`
`
`
`DPATR-FY12-104
`
`Page 2 of3
`
`Version: 7/13/2011
`
`Reference ID: 3172534
`
`

`

`Summary of Results
`
`NDA 203284
`
`1. LA6-0179 revision 2 “HPLC Assay for— in Glycerol Phenylbutyrate and I-IPN-loo
`(glycerol phenylbutymme) Oral Liquid”
`
`
`
`2. LA6-0174 revision 3 “HPLC Assay for the Detenninalion of- Impun'fiee in Glyeexol Phenylbmyme (GPB)
`and HPN—lOO (glycerol phmylbutyrate)”
`
` m_l
`
`DPATR-FY12-104
`
`Page 3 of3
`
`Vasim: 7/130011
`
`Reference ID: 3172534
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MICHAEL L TREHY
`08/09/2012
`
`BENJAMIN J WESTENBERGER
`08/10/2012
`
`Reference ID: 3172534
`
`

`

`
`
`NDA 203284
`
`Ravicti
`
`(glycerol phenylbutyrate)
`25mL
`
`Ucyclyd Pharma, Inc.
`
`Hamid R. Shafiei, Ph.D.
`
`Review Chemist
`
`Office of New Drug Quality Assessment
`Division of New Drug Quality Assessment II
`Branch IV
`
`For the Division of Gastroenterology and Inborn Errors Products
`
`CMC REVIEW
`
`Reference ID: 3216105
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`CMC Review Data Sheet .........................................................................................4
`
`The Executive Summary .........................................................................................8
`
`1. Recommendations ....................................................................................................................... 8
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 8
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments Agreements, and/or Risk
`Management Steps, if Approvable ................................................................................................... 8
`
`II. Summary of CMC Assessments ................................................................................................. 8
`
`A. Description of the Drug Product(s) and Drug Substance(s) ............................................................. 8
`
`B. Description of How the Drug Product is Intended to be Used........................................................ 10
`
`C. Basis for Approvability or Not-Approval Recommendation ......................................................... 10
`
`III. Administrative......................................................................................................................... 11
`
`CMC Assessment.................................................................................................... 12
`
`I. Review Of Common Technical Document—Quality (Ctd—Q) Module 3.2: Body Of Data ....... 12
`
`S DRUG SUBSTANCE .................................................................................................................... 12
`8.1
`General Information ........................................................................................................................ 12
`S.2
`Manufacture .................................................................................................................................... 13
`8.3
`Characterization .............................................................................................................................. 32
`
`8.4
`8.5
`
`8.6
`SJ
`
`Control of Drug Substance .............................................................................................................. 40
`Reference Standards or Materials ................................................................................................... 56
`
`Container Closure System............................................................................................................... 57
`Stability ........................................................................................................................................... 59
`
`P DRUG PRODUCT ........................................................................................................................ 65
`
`Pl
`P.2
`P3
`
`PA
`RS
`R6
`
`R7
`RS
`
`Description and Composition of the Drug Product ......................................................................... 65
`Pharmaceutical Development.......................................................................................................... 65
`Manufacture .................................................................................................................................... 70
`
`Control of Excipients ...................................................................................................................... 74
`Control of Drug Product ................................................................................................................. 75
`Reference Standards or Materials ................................................................................................... 78
`
`Container Closure System............................................................................................................... 78
`Stability ........................................................................................................................................... 79
`
`A APPENDICES .............................................................................................................................. 83
`
`Al
`A2
`A3
`
`Facilities and Equipment (biotech only) ......................................................................................... 84
`Adventitious Agents Safety Evaluation .......................................................................................... 84
`Novel Excipients ............................................................................................................................. 84
`
`R REGIONAL INFORMATION ..................................................................................................... 84
`
`CMC Review #1
`
`Page 2 of 102
`
`Reference ID: 3216105
`
`

`

`'nfl‘x
`
`CMC REVIEW OF NDA 203284
`
`:2:
`
`R1
`
`Executed Batch Records ...................................................................................................................... 84
`
`R2 Comparability Protocols ...................................................................................................................... 84
`R3 Methods Validation Package ............................................................................................................... 84
`
`II. Review Of Common Technical Document—Quality (Ctd—Q) Module 1 .................................. 85
`
`A. Labeling & Package Insert ............................................................................................................. 85
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion .................................................. 92
`
`III. List Of Deficiencies ................................................................................................................. 92
`
`IV. Attachments ............................................................................................... 94
`
`CMC Review #1
`
`Page 3 of 102
`
`Reference ID: 3216105
`
`

`

`
`
`CMC Review Data Sheet
`
`CMC Review Data Sheet
`
`1. NDA 203284
`
`2. REVIEW #: 1
`
`3. REVIEW DATE: 15-July-2012
`
`4. REVIEWER: Hamid R. Shafiei, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission! 3) Reviewed
`Original Submission
`Correspondence (C)
`Amendment (BC)
`Amendment (BC)
`
`Document Date
`
`12/23/2011
`07/02/2012
`N/A
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`Address:
`
`Representative:
`Telephone:
`
`Hyperion Therapeutics
`60] Gateway Blvd, Suite 200
`South San Francisco, CA 94080
`Karla A Dickinson
`(650) 745—7820
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: Ravicti
`b) Non-Proprietary Name: Glycerol Phenylbutyrate
`c) Code Name/# (ONDQA only): N/A
`d) Chem. Type/Submission Priority (ONDQA only):
`
`0 Chem. Type: 2
`
`0 Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)(2)
`
`10. PHARMACOL. CATEGORY: Adjunctive Therapy for Chronic Management
`of Urea Cycle Disorder in Patients 3 6 years of age
`
`CMC Review #1
`
`Page 4 of 102
`
`Reference ID: 3216105
`
`

`

`
`
`CMC Review Data Sheet
`
`11. DOSAGE FORM:
`
`Liquid for Oral Administration
`
`"’"" Active Ingredient
`12. STRENGTH/POTENCY: 25mL of
`(glycerol phenylbutyrate)
`
`l3. ROUTE OF ADMINISTRATION: Oral
`
`l4. Rx/OTC DISPENSED:
`
`‘1 Rx
`
`OTC
`
`15. SPOTS SPECIAL PRODUCTS ON—LINE TRACKING SYSTEM :
`
`SPOTS product — Form Completed
`
`‘1 Not a SPOTS product
`
`1. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`{Q0
`OWOi/O O
`
`O
`
`USAN and INN: Glycerol Phenylbutyrate
`IUPAC: Propane-1 ,2,3—t1yl tris(4-phenylbutanoate)
`Empirical formula:
`C33H3806
`Molecular Mass:
`530.67
`
`CAS Number:
`
`61 1 168-24-2
`
`CMC Review #1
`
`Page 5 of 102
`
`Reference ID: 3216105
`
`

`

`
`
`CMC Review Data Sheet
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`DATE
`REVIEW COMMENTS
`COMPLETED
`
`
`
`----
`
`lAction codes for DMF Table:
`l — DMF Reviewed.
`
`Other codes indicate why the DMF was not reviewed, as follows:
`2 —Type 1 DMF
`3 — Reviewed previously and no revision since last review
`4 — Sufficient information in application
`5 — Authority to reference not granted
`6 — DMF not available
`
`7 — Other (explain under "Comments")
`
`2 Adequate. Inadequate. or N/A (There is enough data in the application, therefore the DMF did
`not need to be reviewed)
`
`B. Other Documents:
`
`DOCUMENT
`
`APPLICATION NUMBER
`
`DESCRIPTION
`
`N/A — N/A —
`
`-EE-
`
`CMC Review #1
`
`Page 6 of 102
`
`Reference ID: 3216105
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`

`

`
`
`CMC Review Data Sheet
`
`18. STATUS:
`
`ONDC:
`CONSULTS/ CMC
`
`
`
`————
`—-_——
`————
`_———
`_———
`Methods Validation
`N/A, according to the
`current ONDQA olic
`DMETS ———
`EA
`Categorical exclusion (see
`review
`
`Microbiolo ———
`
`CMC Review #1
`
`Page 7 of 102
`
`Reference ID: 3216105
`
`

`

`
`
`Executive Summary Section
`
`The CMC Review for NDA 203-284
`
`The Executive Summam
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`The applicant of this NDA has provided sufficient information to assure identity,
`strength, purity, and quality of the drug product, Ravicti liquid for oral administration.
`
`However, the Office of Compliance has not made an overall “Acceptable”
`recommendation regarding the facilities involved in this NDA.
`
`Also label/labeling issues identified have not been satisfactorily resolved.
`
`Therefore, from the ONDQA perspective, this NDA is not recommended for approval
`in its present form, per 21 CFR 314.125(b)(6) & (13).
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable
`
`Not applicable.
`
`II. Summary of CMC Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`(1) Drug Substance
`
`The Drug substance, glycerol phenylbutyrate is intended for the treatment
`of patients 6 years of age or older with urine cycle disorder and is a prodrug
`consisting of three phenylbutyrate linked together by glycerol. The
`mechanism of action for this drug is that if swallowed it is expected to
`break down to phenylbutyrate in the gut. Phenylbutyrate is converted to
`phenyl acetate in the body. Phenyl acetate reacts with the amino acid
`glutamine, a nitrogen containing amino acid and forms a substance that can
`be removed from the body by kidneys. Removal of the nitrogen containing
`glutamine from the body leads to the reduction in the production of
`ammonia.
`
`CMC Review #1
`
`Page 8 of 102
`
`Reference ID: 3216105
`
`

`

`F .AFI‘
`
`CMC REVIEW OF NDA 203284
`
`Executive Summary Section
`
`phat-h
`
`‘
`
`The drug substance, glycerol phenylbutyrate is a colorless to pale yellow liquid
`with a molecular formula of C33H3306, a molecular mass of 530.67g/mole, and a
`density of 1.1g/mL. This drug substance is soluble in dimethylsulfoxide and >
`65% acetonitrile-water, freely soluble in toluene and acetone, sparingly soluble in
`isopropyl alcohol, and insoluble in water. Glycerol phenylbutyrate decomposes at
`160°C, and therefore, boiling point for this drug substance could not be
`determined. Furthermore, due to lack of any ionizable moiety in this molecular
`entity, the pH of this API could not be determined.
`
`Glycerol phenylbu
`manufacturers,
`
`ate is manufactured and supplied by two different
`
`
`
`
`ve propose and
`Bo API man acturers
`
`
`utilized adequate in-process testing procedures for controlling the manufacturing
`steps identified as critical. The API manufacturing information rovidedm this
`illustrates that dru substance manufactured
`
`
`
`The proposed API release and stability specification includes testing and
`acceptance criteria for appearance, identification, assay, related substances
`(related impurities), water content, residue on ignition, heavy metals, and residual
`solvents. The proposed specification is deemed adequate to assure the identity,
`strength, purity, and quality of the API, glycerol phenylbutyrate. Furthermore, the
`drug substance manufacturers have provided sufficient release and stability data
`to support the proposed API re-test period.
`
`(2) Drug Product
`
`The dru
`
`roduct Ravicti is
`
`
`
`Although the photostability data provided indicates that this drug
`
`CMC Review #1
`
`Reference ID: 3216105
`
`Page 9 of 102
`
`

`

`
`
`Executive Summary Section
`
`product may not be sensitive to light, nevertheless, the outer cartons provide
`adequate protection from exposure to light.
`
`The in-process testing of the drug product entails
`
`01(4)
`
`The proposed drug product release and stability specification includes testing and
`acceptance criteria for appearance, identity, assay, related substances (related
`impurities), and
`(m4)
`is omitted from the drug product release and stability testing since
`these impurities are controlled during the testing and release of the drug substance.
`The proposed drug product specification is deemed adequate to assure the identity,
`strength, purity, and quality of the drug product, Ravicti.
`
`Based on the 6-month accelerated, 24-month long-term real-time stability data and
`statistical treatment of the stability data, an expiration dating period of 36 months is
`proposed. The proposed expiration dating period is considered acceptable.
`
`B. Description of How the Drug Product is Intended to be Used
`
`The drug product Ravicti is
`
`M“)
`
`This drug product is
`intended for oral use in the treatment of patients with the rare disease of urine cycle
`disorder. Based on very small population of patients diagnosed with this disorder, this
`drug product has been given an orphan drug status.
`
`C. Basis for Not-Approval Recommendation
`
`21 CFR314.125 (b)(13)
`
`0 The final “Acceptable” recommendation from the Office of Compliance is still
`“Pending”.
`
`21 CFR 314.125 (b)(6)
`0 Label/labeling issues has not been resolved.
`
`CMC Review #1
`
`Page 10 of 102
`
`Reference ID: 3216105
`
`

`

`F .AF“
`.‘
`
`CMC REVIEW OF NDA 203284
`
`Executive Summary Section
`
`F ”Ml"
`.‘
`
`III. Administrative
`
`A. Reviewer’s Signature:
`
`(See appended electronic signature page)
`
`Hamid R. Shafiei, Ph.D.
`
`B. Endorsement Block:
`
`(See appended electronic signature page)
`
`Moo-Jhong Rhee, Ph.D., Branch Chief, Branch IV, DNDQA II/ONDQA
`
`C. CC Block: entered electronically in DFS
`
`
`
`CMC Review #1
`
`Page 1 1 of 102
`
`Reference ID: 3216105
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`HAMID R SHAFIEI
`11/13/2012
`
`MOO JHONG RHEE
`11/13/2012
`Chief, Branch IV
`
`Reference ID: 3216105
`
`

`

`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`
`METHODS VALIDATION CONSULT REQUEST FORM
`
`FDA
`Division of Pharmaceutical Analysis
`Attn: Benjamin (Nick) Westenberger
`Suite 1002
`1114 Market Street
`St. Louis, MO 63101
`
`
`TO:
`
`
`
`
`
`FROM: Hamid R. Shafiei, Ph.D., CMC Reviewer
`Marie Kowblanski, Ph.D., CMC Lead
`Office of New Drug Quality Assessment (ONDQA)
`E-mail Address: hamid.shafiei@fda.hhs.gov
`Phone: (301)-796-2326
`Fax.:
`(301)-796-9745
`
`
` Through: Moo Jhong Rhee, Ph.D., Branch Chief, Branch IV, Division II
`
`Phone: (301)-796-1440
`
`
`
`
`SUBJECT: Methods Validation Request
`
`
` and
`
`Jeannie David, ONDQA Methods Validation Project Manager
`Phone: 301-796-4247
`
`Application Number: NDA 203-284
`
`
`
`
`Name of Product: Ravicti (gylcerol phenylbutyrate), Liquid Drug Substance
`Applicant: Ucyclyd Pharma, Inc.
`Applicant’s Contact Person: Klara Dickinson, Sr. VP Regulatory Affairs
`Address: 7720 N. Dobson Road, Scottsdale, AZ 85256
`
`Telephone: 480-291-5953
`
`
`
`
`
`Fax: 480-302-6333
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Submission Classification/Chemical Class: 0
`
`
`Special Handling Required: No
`DEA Class: N/A
`
`Format of Methods Validation Package (MVP)
` Paper
` Electronic
` Mixed
`
`
`
`
`
`
`
`
`Date NDA Received by CDER: 12/23/2012
`
`
`Date of Amendment(s) containing the MVP: 12/23/2012
`DATE of Request: March 30, 2012
`
`
`
`Requested Completion Date: 8/1/2012
`
`
`
`PDUFA User Fee Goal Date: 10/23/2012
`
`
`
`We request suitability evaluation of the proposed manufacturing controls/analytical methods as described in the subject application. Please submit a
`letter to the applicant requesting the samples identified in the attached Methods Validation Request. Upon receipt of the samples, perform the tests
`indicated in Item 3 of the attached Methods Validation Request as described in the NDA. We request your report to be submitted in DARRTS promptly
`upon completion, but no later than 45 days from date of receipt of the required samples, laboratory safety information, equipment, components, etc. We
`request that you notify the ONDQA Methods Validation Requestor and the ONDQA Methods Validation Project Manager of the date that the validation
`process begins. If the requested completion date cannot be met, please promptly notify the ONDQA Methods Validation Requestor and the ONDQA
`Methods Validation Project Manager.
`Upon completion of the requested evalua