`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`205395Orig1s000
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`

`

`FDA CDER EES
`
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Application:
`
`0
`
`do:
`
`Priority
`
`Stamp Date:
`
`PDUFA Die:
`
`Action Goal:
`
`NDA 2053951000
`
`530
`
`4Y
`
`31 MAR-2014
`
`31 JAN 2015
`
`Sponsor:
`
`JANSSEN PRODS
`
`1125 TRENTON HARBCXJRTON RD
`
`TITUSVILLE. NJ 08560
`
`DARUNAVIRICOBICISTAT
`
`Galleria Name:
`
`District Goal:
`
`02-DEC 2014
`
`Product Hunter; Dosage Form; Ingrodont; Strengths
`
`FDA Com
`
`R. XU
`
`F. UU
`
`E. PFEILER
`
`A. CUFF
`
`N. MANI
`
`S. MILLER
`
`Faciity Reviewer
`
`Prod Qua! Reviewer
`
`Micro Reviewer
`
`Product Quality PM
`
`Regulatory Project Mgr
`
`Team Leader
`
`001 ; TABLET llMgI’HDJCOMP. RELEASE), FILM COATED;
`DARUNAVIR;
`001; TABIET
`DJCOMP. RELEASE). FILM COATED;
`COBICISTAT; 150MG
`
`(HF-22)
`
`(HF 01)
`
`(HFD-530)
`
`301 7%61 87
`
`3017*1409
`
`3017900042
`
`3017904061
`
`2404020333
`
`3017$1418
`
`Overall Rocommondflion:
`
`ACCEPTABLE
`
`on 04-SEP 2014
`
`by R. MOORE
`
`0
`
`2404029988
`
`Establishment:
`
`DMF No:
`
`Responsibilities:
`
`PENDING
`
`on 036EP 2014
`
`by EES PROD
`
`ACCEPTABLE
`
`on 20-AUG 2014
`
`by EES PROD
`
`PENDING
`
`PENDING
`
`Ill) (4)
`
`on 23-APR 2014
`
`by EES PROD
`
`on 09-APR 2014
`
`by EES PROD
`
`FEI:
`III) (4)
`
`III) (4)
`
`AADA:
`
`DRUG SUBSTANCE MANLFACTURER
`
`DRUG SUBSTANCE OTHER TESTER
`
`DRUG SUBSTANCE REI£ASE TESTER
`
`INTERMEDIATE MANUFACTURER
`
`Profile:
`
`NON-STERILE API BY CHEMICAL SYNTHESIS
`
`OAI sums:
`
`NONE
`
`Last Milestone:
`
`Milestone one:
`
`Decision:
`
`0C RECOMMENDATION
`
`24-APR-2014
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`January 21, 2015 6:26 PM
`
`FDA Confidonfld - Intern! Dismaon Only
`
`Page 1 o“
`
`Reference ID: 3699643
`
`

`

`FDA CDER EES
`
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Esidalishmont:
`
`CFN:
`
`9615378
`
`FEI: m10278t3
`
`DMF No:
`
`Responsibilities:
`
`GILEAD ALBERTA ULC
`1021 HAYTER RD NW
`
`EDMONTON. ALBERTA. CANADA
`
`DRUG SUBSTANCE MANUFACTURER
`
`DRUG SUBSTANCE PACKAGER
`
`DRUG SUBSTANCE RELEASE TESTER
`
`AADA:
`
`Profile:
`
`NON-STERILE API BY CHEMICAL SYNTHESIS
`
`OAI Stuns:
`
`NONE
`
`Last Milestone:
`
`Milestone om:
`
`Decision:
`
`0C RECOMMENDATION
`
`1 1 APR 201 4
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`Establishmnt:
`
`CFN:
`
`2952384
`
`FEI:
`
`1000523075
`
`GILEAD SCIENCES, INC.
`
`DMF No:
`
`Responsibilities:
`
`FOSTER CITY, , UNITED STATES 944041147
`
`AADA:
`
`DRUG SUBSTANCE RELEASE TESTER
`
`DRUG SUBSTANCE STABILITY TESTER
`
`Profile:
`
`CONTROL TESTING LABORATORY
`
`OAI Status:
`
`NONE
`
`Last Milestone:
`
`Milestone Date:
`
`Decision:
`
`0C RECOMMENDATION
`
`04 SEP 2014
`
`ACCEPTABIE
`
`DISTRICT RECOMMENDATION
`
`Esulilishmont:
`
`CFN:
`
`2650104
`
`FEI:
`
`(”02942061
`
`DMF No:
`
`Responsibilities:
`
`Profile:
`
`Last Milestone:
`
`Milestone DUI:
`
`Decision:
`
`JANSSEN ORTHO L.L.C.
`
`GURABO. , UNITED STATES (D778
`
`FINISHED DOSAGE LABELER
`
`FINISHED DOSAGE MANUFACTURER
`
`FINISHED DOSAGE PACKAGER
`
`FINISHED DOSAGE RELEASE TESTER
`
`TABLETS, PROMPT RELEASE
`
`0C RECOMMENDATION
`
`22-APR 2014
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`OAI Status:
`
`NONE
`
`January 21, 2015 6:26 PM
`
`FDA Confidential - Intomd Distrlbution Only
`
`PageZof4
`
`Reference ID: 3699643
`
`

`

`FDA CDER EES
`
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Establishment:
`
`CFN:
`
`9310034
`
`FEI:
`
`3002007337
`
`IMF No:
`
`Responsibilities:
`
`.iANSSEN PHARMACEUTICA N.v.
`JANSSEN PHARMACEnCALAAN 3
`
`GEEL, . BELGIUM
`
`INTERMEDIATE MANUFACTURER
`INTERMEDIATE RELEASE TESTER
`
`MM:
`
`Ploflle:
`
`NONSTERILE API BY CHEMICAL SYNTHESIS
`
`OAI Status:
`
`NONE
`
`L,“ “.hsm:
`
`Milestone Date:
`
`Decision:
`
`OC RECOMMENDATION
`
`11 APR 2014
`
`ACCEPTABLE
`
`Reason:
`BASED ON PROFILE
`
`
`Establishment
`
`CFN:
`
`00110II V
`
`I
`
`h
`
`FEI:
`
`3002007301
`
`DMF No:
`
`Responsibilities:
`
`.iANSSEN PHARMACEUTICAL LTD.
`Ul'TLE ISLAND
`
`CORK. , IRELAND
`
`DRUG SUBSTANCE MANUFACTURER
`DRUG SUBSTANCE OTHER TESTER
`
`DRUG SUBSTANCE RELEASE TESTER
`
`AADA:
`
`Pr "~:
`
`NON-STERILE API BY CHEMICAL SYNTHESIS
`
`OAI Status:
`
`NONE
`
`u.m mum;
`
`Milestone Dan:
`
`Decision:
`
`Reason:
`
`oc RECOMMENDATION
`
`10 JUN-2014
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`ESTEISIIIMM:
`
`CFN:
`
`2242843
`
`FEI:
`
`2242843
`
`_ '
`
`.iANSSEN PHARMACEUTICALS. INc.
`
`DMF No:
`
`. , UNITED STATES
`
`MDA:
`
`Responsibilities:
`
`FINISHED DOSAGE STABI LITY TESTER
`
`Pmlile:
`
`CONTROL TESTING LABORATORY
`
`OAI Stuns:
`
`NONE
`
`Last Mlhstono:
`
`Milestone Date:
`
`Decision:
`
`Reason:
`
`OC RECOMMENDATION
`
`11-APR-2014
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`Janqu 27, 2015 6:26 PM
`
`FDA Confldontid - Inland Distribution Only
`
`Page 3 of4
`
`Reference ID: 3699643
`
`

`

`FDA CDER EES
`
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`
`
`DRUGSUBSTAME STABIJTYTES‘IER
`
`CONTROL TESTNG LAMRATCRY
`
`OAI anus:
`
`OC EMMA‘HW
`
`08 JLl-2014
`
`
`
`DRUG SUBSTANCE RE.EASE TESTER
`
`CONTROL TESTNG LABGiATORY
`
`(X) REWATKN
`
`‘l 1-APR-2014
`
`AOCEPTABIE
`
`BASED ON PRCFLE
`
`
`
`
`mCFN:
`
`DRUG SUBSTANCE MAMJFACTURER
`
`DRUGSUBSTANCE PACKAGER
`
`MUGSUBS'I’ANCE RELEASE‘IESTER
`
`NON-STERlLEAPI BYCl-EMICALSYNTHESIS
`
`Ml SW8:
`
`NOIE
`
`OC REWATIGJ
`
`11-APR-2014
`
`ACCEPTABLE
`
`BASED ON PROFLE
`
`HF Io:
`
`Rupensblles:
`Ploilln:
`
`Last Ilm:
`
`llm Dab:
`
`E—mblbllnmfi
`
`DHF lo:
`
`mum-s:
`
`but NW
`
`Mm Dab:
`
`Dodslon
`
`Jam-y 21,2015 6:8 PM
`
`HJA Confidmllll - kit-ml Dlsfllblllul Olly
`
`M40“
`
`Reference ID: 3699643
`
`

`

`NDA 205395-0rigl-New/NDA(1): Overall Manufacturing Inspection R...
`
`http://panorama.fda.gov/attask/taskView.cmd?lD=5425c99fl)0cf7b4638...
`
`271
`
`Owen“ Manufacturing Inspectlon Recommendation
`mmmlmwn)
`
`”mm.
`
`Facility Inspection Overall Apfliation Recommendation
`Fadlly mum Ovadl unima-mm
`A”
`
`Fadly Inqnedlm Olaallluilaslhn Reevdualon Due
`Hulls
`
`mmmwawmtwmlmurusmms
`
`“SMNTWD
`
`Reference ID: 3699643
`1 ofl
`
`1/28/2015 5:02 PM
`
`

`

`
`
`NDA 205395
`
`Darunavir/Cobicistat Tablet, 800 mg/150 mg
`
`Janssen Products, LP.
`
`Fuqiang Liu, Ph.D.
`Branch V, ONDQA
`
`For the Division of Anti-Viral Products
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................3
`
`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 Chemistry 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.......................................................... 9
`
`C. Basis for Approvability or Not-Approval Reconmlendation ............................................................ 9
`
`III. Administrative......................................................................................................................... 12
`
`A. Reviewer’s Signature ...................................................................................................................... 12
`
`B. Endorsement Block......................................................................................................................... 12
`
`C. CC Block ........................................................................................................................................ 12
`
`Chemistry Assessment ........................................................................................... 13
`
`I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data ....... 13
`
`S DRUG SUBSTANCE [Name Manufacturer] .............................................................................. 13
`
`P DRUG PRODUCT [Name, Dosage form] .................................................................................... 20
`
`A APPENDICES .............................................................................................................................. 50
`
`R REGIONAL INFORMATION ..................................................................................................... 51
`
`II. Review Of Common Technical Document—Quality (Ctd-Q) Module 1 .................................. 51
`
`A. Labeling & Package Insert ............................................................................................................ 51
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion ................................................... 53
`
`III.
`
`List Of Deficiencies To Be Communicated ....................................................................... 53
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 205395
`
`2. REVIEW #2 01
`
`3. REVIEW DATE: 16—Dec—2014
`
`4. REVIEWER: Fuqiang Liu, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`None
`
`Document Date
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission! 3! Reviewed
`Original NDA
`SDN# 010 Multiple Categories/Subcategories
`SDN# 015 Quality/Quality Information
`SDN# 018 Quality/Response to Information Request
`
`Document Date
`3 1-Mar-2014
`14-Jul-2014
`12-Sept-2014
`17-Oct—2014
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`
`Address
`'
`
`Janssen Products, LP
`
`1125 Trenton-Harboulton Road,
`Titusville, NJ 08560
`
`Representative:
`
`Karen Geny, BSc, Global RA Manager
`
`Telephone:
`
`416-382-48 19
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`Page 3 of 66
`
`

`

`
`
`Chemistry Review Data Sheet
`
`a) Proprietary Name: Prezcobix
`b) Non-Proprietary Name (USAN): darunavir/cobicistat
`c) Code Name/# (ONDC only): DRV/COBI
`(1) Chem. Type/Submission Priority (ONDC only):
`
`0 Chem. Type: 4
`
`0 Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION: N/A
`
`10. PHARMACOL. CATEGORY: Anti-Viral (Treatment of HIV infection)
`
`11. DOSAGE FORM: Tablet
`
`12. STRENGTH/POTENCY: 800 mg/ 150 mg
`
`13. ROUTE OF ADMINISTRATION: Oral
`
`14. Rx/OTC DISPENSED:
`
`x Rx
`
`OTC
`
`:
`15. SPOTS SPECIAL PRODUCTS ON-LINE TRACKING SYSTE
`
`SPOTS product — Form Completed
`
`
`x Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`1) Darunavir
`
`®k3$v W
`
`Page 4 of 66
`
`

`

`
`
`Chemistry Review Data Sheet
`
`IUPAC name: [(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-
`l-(phenylmethyl)propyl]-carbamic acid (3R,3aS,6aR)—hexahydrofuro[2,3-b]fiJran-3—yl ester
`monoethanolate.
`
`USAN: Darunavir
`
`Formula: C27H37N307$ ° C2H5OH
`
`Molecular weight: 593.73.
`
`The defined drug substance is danmavir ethanolate.
`
`2) Cobicistat
`
`N’
`J
`
`:
`
`,.
`fiNl
`H
`
`\g
`
`1
`He
`N-V/h“
`> 9]
`
`/"\
`[A
`V V
`_
`- gNio
`/‘\\.H
`L...
`
`s
`[\[NQ
`
`IUPAC name: 1,3—thiazol-5-yhnethyl [(2R,5R)-5-{[(2S)2-[(methyl{[2-(propan-2-yl)-1,3-
`thiazol-4—yl]methyl} carbamoyl)amino]-4—(morpholin—4yl)butanoyl]amino} -1 ,6-
`diphenylhexan—Z-yl]carbamate.
`
`USAN: Cobicistat
`
`Formula: C4oH53N70582
`
`Molecular weight: 776.0
`
`The defined drug substance is cobicistat
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`(M)
`
`REVIEW
`
`COMMENTS
`
`A. Ban 'ee
`
`Reviewed by
`G. Lunn
`
`Reviewed by
`
`Page 5 of 66
`
`

`

`(b) (4)
`
`
`
`Adequate
`
`Mar. 2012
`
`Reviewed by
`G. Holbert
`
`-—-
`
`Adequate
`
`Oct. 2013
`
`Reviewed by
`Y. Chen
`
`-_-
`
`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:
`
`
`
`APPLICATION NUMBER
`
`DESCRIPTION
`
`1 13198
`62477
`21976
`202895
`
`203100
`
`darunavir/cobicistat 1ND
`darunavir tablets 1ND
`darunavir tablets NDA
`darunavir oral sus DCDSiOD NDA
`
`Stribild tablets NDA (FDC .
`includin Cobicistat) b Gilead
`
`b Gilead
`
`NDA
`NDA
`
`NDA
`
`NDA
`
`18. STATUS:
`
`ONDQA:
`CONSULTS/ CMC
`
`RELATED
`
`REVIEWS
`
`RECOMMENDATION
`
`DATE
`
`————
`
`————
`04-Set-2014 Rose Xu, PhD.
`———-m_
`
`————
`
`Page 6 of 66
`
`

`

`
`
`Chemistry Review Data Sheet
`
`OPDRA ——
`Consult sent b A. Cuff
`16 Dec 2014
`
`James Laurenson 16-Jul-2014
`
`En‘ka APfeiler, PhD.
`
`Page 7 of 66
`
`

`

`
`
`Executive Summary Section
`
`The Chemistry Review for NDA 205395
`
`The Executive Summafl
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`NDA 205395 has provided adequate CMC information to assure the identity, strength, purity, and
`quality of the drug product. The Drug Master Files (DMF 25188 and DMF 18825) for the cobicistat on
`silicon dioxide and danmavir ethanolate drug substances supporting this NDA are adequate. The labels
`and labeling are adequate from a CMC perspective, but are pending 0ND team review for finalization.
`The overall recommendation from the Office of Compliance is ACCEPTABLE as of Sept. 4, 2014 for
`the establishment evaluation. The Product Quality Microbiology review from Dr. Pfeiler and the
`Biophannaceutics review from Dr. Hughes both recommend approval. The Environmental Assessment
`data supplied for Darunavir was found to be acceptable by James Laurenson (EA Staff), and a Finding
`of No Significant Impact (FONSI) was issued. From the Quality perspective this NDA is
`recommended for approval.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable
`
`None
`
`11. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`Drug Substances
`
`All cobicistat drug substance information is referenced to Gilead’s Drug Master File G)MF) 25188.
`The drug substance, as defined in DIVIF 25188, is cobicistat on silicon dioxide. Cobicistat is
`(but)
`2'3 adsorption onto silicon dioxide
`"m"
`DMF 25188 was found adequate on July 22, 2014 by Dr. George Lunn. No new
`information has been submitted since then, thus DMF 25188 remains adequate. NDA 205395 sources
`cobicistat on silicon dioxide drug substance manufactured at the Yuhan, Korea and Gilead Alberta
`Sltes.
`
`All danmavir drug substance information is referenced to Janssen’s DMF 18825. The drug substance,
`as defmed in DMF 18825, is danmavir ethanolate
`(m4) DMF 18825 was found adequate on May 8,
`2014 by Dr. Anamitro Banerjee. No new information has been submitted since then, thus DMF 18825
`remains adequate. NDA 205395 sources danmavir drug substance manufactured at the Cilag AG,
`Switzerland and Janssen Cork, Ireland sites.
`
`Drug Product
`
`Page 8 of 66
`
`

`

`
`
`Executive Summary Section
`
`The drug product is an immediate release, film-coated tablet consisting of a fixed dose combination
`(FDC) of 800 mg equivalent of darunavir
`M“) and 150 mg equivalent of cobicistat
`mar
`The tablets are oval shaped, debossed, and fihn-coated with pink color.
`
`The danmavir/cobicistat tablets contain excipients commonly used in tablet dosage forms: colloidal
`silicon dioxide, crospovidone, hypromellose, silicified microcrystalline cellulose and magnesium
`stearate. The fihn-coats contain iron oxide black, iron oxide red, polyethylene glycol, polyvinyl
`alcohol (partially hydrolyzed), talc and titanium dioxide. The drug product is packaged in a white
`HDPE, 120 mL bottle with
`“M”.
`
`The tablets are manufactured by Janssen Ortho, Gurabo, Puerto Rico using
`
`(hm)
`
`. The
`
`drug product specifications are reasonable and include appearance, identification, assay, degradation
`products, content uniformity, dissolution, etc. There are no specified darlmavir related degradation
`products. The three specified cobicistat related degradation products are all reported in NDA 203100
`and NDA 203094. The proposed specification is adequately justified for the drug product both at
`release and at the proposed shelf life.
`
`Stability data were provided for the three primary stability batches, indicating that the drug product is
`stable for 18 months when stored in the proposed commercial container closure system at
`M4)
`N0 degradation of danmavir above the level of (”(0% is observed throughout
`the stability studies. The three specified cobicistat degradation products remained at below M“’%, far
`below the specification criteria. Dissolution over shelf life was found acceptable by the
`biopharmaceutics reviewer. Please refer to the biopharmaceutics review for details.
`
`A shelf life of 24 months is granted for all climatic zones for drug product packaged in the proposed
`commercial container closure system.
`
`B. Description of How the Drug Product is Intended to be Used
`
`The darimavir/cobicistat 800 mg/150 mg tablet is a two drug fixed dose combination (FDC) of
`
`darunavir, 3 HIV-1 protease inhibitor and cobicistat, a CYP3A inhibitor for the treatment of HIV—1
`
`infection in adult patients. The recommended dose is one tablet taken orally, once daily, with food.
`
`The darimavir/cobicistat 800 mg/150 mg tablets are packaged in 120 mL, white, high density
`polyethylene (HDPE) bottles. Each bottle contains 30 tablets and is capped
`(mm
`A shelf life of 24 months is granted for all climatic
`
`zones for drug product packaged in the proposed commercial container closure system.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`Information provided for NDA 205395 regarding drug product manufacturing, raw materials controls
`and specifications, analytical methods, and drug product stability is adequate to support the quality of
`
`Page 9 of 66
`
`

`

`
`
`Executive Summary Section
`
`the drug product through its shelf-life of 24 months. The DIVIFs for the danmavir and cobicistat drug
`substances are adequate. The labels and package insert are adequate from a CMC—perspective although
`the labels and labeling are pending final 0ND team review.
`
`The overall reconnnendation from the Office of Compliance is “ACCEPTABLE” as of September 4,
`2014 for the establishment evaluation. Therefore, from the CMC perspective, this NDA is
`recommended for approval.
`
`D. Lifecycle Knowledge Management
`
`a) Drug Product — Initial Risk Identification:
`
`Although damnavir is
`highly stable. cobicistat
`is considered
`
`moderately stable thus
`O=3.
`
`RPN=18 is assigned for
`stability (D=3) and
`RPN=6 is for release
`
`Although darunavir is
`crystalline. cobicistat is
`amorphous thus O=4
`
`Formulation
`Container closure
`Raw materials
`Process
`parameters
`Scale/equipments
`Site
`
`Formulation
`Raw materials
`Process
`parameters
`Scale/equipments
`Site
`
`See Physical
`stability
`
`Physical stability
`(solid state)
`
`RPN Values: Low Risk (1-25): Moderate Risk (26-60): High Risk (61-125)
`
`b) Drug Product - Final Risk Assessment
`
`
`
`
`Assay. stability
`
`Physical stability
`(solid state)
`
`Formulation
`Container closure
`Raw materials
`
`Process
`parameters
`Scale/equipments
`Site
`
`Formulation
`gw matenals
`. aggiiisesters
`
`Acceptable
`
`Acceptable
`
`Both drug substances are
`used in other approved
`drugs and covered by
`
`Page 10 of 66
`
`

`

`Review
`
`adequate DMFs. where
`solid state is well
`controlled.
`
`Keep monitoring
`
`Acceptable
`See Dr.
`Pfeiler‘s
`Review
`
`Acceptable
`See Dr.
`
`Hughes’
`
`Sca - equipments
`Site
`
`See Ph sicalstabili
`
`Microbial limits
`
`See Physical stability
`
`See Physical stability
`
`Risk ranking applies to product attn'bute/CQA
`
`Page 11 of 66
`
`

`

`
`
`Executive Summary Section
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`F u q i a n 9 Li u —S ou=FDA, ou=People, cn=Fuqiang Liu -S,
`
`0.9.2342.19200300.100.1.1=20007781 14
`
`Digitally signed by Fuqiang Liu —S
`DN: c=US, o=U.S. Government, ou=HHS,
`
`Fuqiang Liu, Ph.D.
`CMC Reviewer
`
`B. Endorsement Block
`
`Date: 2014.12.16 16:19:02 -05'00'
`
`Digitally signed by Stephen Miller —A
`
`Ste p h e n M i I I e r —A ou=FDA, ou=People, cn=Stephen Miller -A,
`
`0.9.2342.19200300.100.1.12130008701 3
`
`DN: c=US, o=U.S. Government, ou=HHS,
`
`“I concur, this NDA is recommended for approval from the CMC perspective.”
`Stephen Miller, Ph.D.
`CMC-Lead
`
`Date: 2014.12.16 16:37:18 -05'00'
`
`Suffisiigmflfs
`Ra pti D.
`(191342.192003oo.loo.1 .l=1300220251.
`M a d u rawe —A cn=Rapti D. Madman—A
`Date: 2014.111617:16:13 -0$'00'
`
`Rapti Madurawe, Ph.D.
`Branch Chief
`
`C. CC Block
`
`54 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`Page 12 of 66
`
`

`

`“Hm—m"
`
`hm}
`
`has-named
`
`Initial Manufacturing (CGMP/Facilities)
`Assessment (IMA) and Filing Review for Pre-
`Marketing Applications (Original)
`
`<25?!"
`
`Review Cover Sheet
`
`Application Detail
`Filing Checklist
`Manufacturing Summary
`Overall Conclusions and Recommendations
`
`I. Review Cover Sheet
`
`1. OMPQ Reviewer: Rose Xu
`
`2. NDA/BLA Number: NDA 205395
`
`Submission Date:
`
`3/31/2014
`
`21St C. Review Goal Date:
`
`PDUFA Goal Date:
`
`1/31/2015
`
`3. PRODUCT PROPERTIES:
`
`Darunavn/Cob1c1stat 800 mg/150 mg
`
`.
`
`.
`
`Established or Non-Proprietary
`Name (USAN) and strength:
`
`.
`
`4. SUBMISSION PROPERTIES:
`
`Applicant Name:
`
`Janssen Products, LP Responsible Organization
`
`Reference ID: 3503368
`
`Page 1 of 12
`
`

`

`OMPQ Initial Manufacturing (CGMP/Facilities) Assessment and Filing Review
`For Pre-Marking Applications
`
`II. Application Detail
`
`1.
`
`INDICATION: Treatment of HIV-1 infection
`
`2. ROUTE OF ADMINISTRATION: Oral
`
`3. STRENGTH/POTENCY: 800 mg/ 150 mg
`
`4. Rx/OTC DISPENSED:
`
`IERX
`
`DOTC
`
`5. ELECTRONIC SUBMISSION (yes/no)? Yes
`
`6. PRIORITY CONSIDERATIONS: N/A
`
`Yes
`
`Unk
`
`NME/PDUFAV
`
`Breakthrough Therapy
`' Designation
`
`3-
`
`0WD“
`
`
`
`-
`-
`DeSIgnatlon
`ll—---—
`
`.-
`
`X
`
`I MedicallyNecessary I..—5.
`
`.
`.
`Determination
`
`X
`
`Potential Shortage
`Issues [either alleviating
`or non—approval may
`cause a shorta - e
`
`X
`
`Rollin Submission ---—
`Drug/device
`combination product
`with consult
`
`X
`
`fl—--
`Other (e.g., expedited
`X
`for an unlisted reason)
`
`Reference ID: 3503368
`
`Page 2 of 12
`
`

`

`OMPQ Initial Manufacturing (CGMP/Facilities) Assessment and Filing Review
`For Pre-Marking Applications
`
`III. FILING CHECKLIST
`
`The following parameters are necessary in order to initiate a fill] review (i.e.. the application is complete
`enough to start review but may have deficiencies). On initial review of the NDA application:
`
`A. COMPLETENESS 0F FACILITY INFORMATION
`
`__
`Is a single comprehensive list
`of all involved facilities
`available in one location in the
`
`X
`
`application?
`Is all site information complete
`(e. g., contact information,
`responsibilities, address)?
`
`.
`
`
`
`13.
`
`14.
`
`'
`
`For testing labs, is complete
`information provided
`regarding which specific test is
`performed at each facility and
`what sta e of manufacturin ?
`
`Do all sites indicate they are
`ready to be inspected (on
`356h)?
`
`Additional notes (non-filing
`issue)
`1. Are all sites registered
`or have FEI #?
`
`2. Do cements in EES
`indicate a request to
`participate on
`inspecti0n(s)?
`Is this first application
`b the a olicant?
`
`.
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`*If any information regarding the facilities is missing/omitted, communicate to OPS/ONDQA
`regarding missing information and copy EESQ. Notify OMPQ management if problems are
`not resolved within 3 days and it can be a potential filing issue.
`
`Reference ID: 3503368
`
`Page 3 of 12
`
`

`

`OMPQ Initial Manufacturing (CGMP/Facilities) Assessment and Filing Review
`For Pre-Marking Applications
`
`B. DRUG SUBSTANCE IS / DRUG PRODUCT IP
`
`__
`Have any Comparability
`X
`Protocols been re nested?
`
`IMA CONCLUSION
`
`
`
`-Does this application fit one ofthe
`
`Palametel
`
`EES Product S ecific Cate- ories?
`
`Have EERs been cross referenced
`
`against the 356h and product
`specific profile for accuracy and
`completion?
`Have all EERs been updated with
`final PAI reconnnendation?
`
`X
`
`X
`
`From a CGMP/facilities
`
`perspcctivc, is the application
`fileablc?
`
`Ifthe NDA18 not fileable from a
`
`product quality perspective state the
`reasons and provide filing comments
`
`t—obe sent to the A licant.
`
`Reference ID: 3503368
`
`Page 4 of 12
`
`

`

`OMPQ Initial Manufacturing (CGMP/Facilities) Assessment and Filing Review
`For Pre-Marking Applications
`
`IV. Manufacturing Summary:
`Critical Issues and Complexities
`
`Does the submission contain any of the following elements?
`Nanotechnology
`RTRT Proposal
`PAT
`|:l
`D
`D
`
`Drug/Device Combo
`D
`
`PET
`|:l
`
`Design Space
`D
`
`Continuous Mfg Naturally derived API
`D
`D
`
`Other (explain):
`
`Manufacturing Highlights
`1. Drug Substance
`
`__
`Is manufactluing process
`considered complex (e.g.,
`unusual unit operations,
`innovative manufacturing
`technology, unusual control
`
`
`
`X
`
`

`

`OMPQ Initial Manufacturing (CGMP/Facilities) Assessment and Filing Review
`For Pre-Marking Applications
`
`2. Drug Product
`
`Is manufacturing process
`considered complex (e.g.,
`unusual unit operations,
`innovative unnufaetun'ng
`
`technology, unusual control
`
`
`
`
`3. Facility-Related Risks or Complexities (e.g., number of foreign sites, large
`number of sites involved, etc.)
`None
`
`
`
`

`

`OMPQ Initial Manufacturing (CGMP/Facilities) Assessment and Filing Review
`For Pre-Marking Applications
`
`
`
`Page 7 of 12
`
`Reference ID: 3503368
`
`(b) (4)
`
`

`

`OMPQ Initial Manufactun'ng (CGMP/Facilities) Assessment and Filing Review
`For Pre-Marking Applications
`
`damnvlrlcobldsm
`ill-16mm Tablet
`
`3.23.3.3We.MW Proton and Process Coir-ls
`flowchart
`
`
`
`

`

`OMPQ Initial Manufacturing (CGIvIP/Facilities) Assessment and Filing Review
`For Pre-Marking Applications
`
`Manufacturing Facilities Chart (generated from 602A DARRTS report and OMPQ macro):
`
`Note: See Coki Chart
`
`For each EER, indicate PAI recommendation on the Manufacturing Facilities Chart above (e.g., PS, GMP, 10 Day, AC based on file
`review .
`
`Establishment Name
`
`Responsibilities
`
`Most Recent
`
`Inspection
`
`Comments
`
`0C
`Recommendation
`
`Inspection History
`Date: Covered
`processes -
`Classification
`
`CSN-
`
`Date: Oct 2012
`
`10/25/2012 — NAI
`
`Acceptable
`until Oct
`20 l 5
`
`CSN-
`
`Acceptable
`until Feb
`20 l 7
`
`CSN-
`
`Acceptable
`until Sept
`20 1 6
`
`CSN-
`
`Acceptable
`as of April
`20 l 3
`
`Coverage:
`-CGMP (AC)
`- PAI (AC)
`
`8/5/2011 —
`NVAI
`
`Date: Feb
`20 14
`
`Coverage:
`-CGMP (VAI)
`- PAI (AC)
`
`Date: Sept
`20 l 3
`
`9/12/2013 —NAI
`
`10/18/2012—VAI
`
`Coverage:
`- CGMP (NAI)
`- PAI (AC)
`Date: April
`2009
`
`Coverage:
`- CGNIP
`
`Acceptable
`based on NAI
`classification
`
`Acceptable
`
`Acceptable
`based on
`firm’s
`
`responses
`
`Acceptable
`
`Acceptable
`based on NAI
`classification
`
`assigned
`igppection to
`(4)
`
`Acceptable
`
`Gilead Alberta ULC
`
`1021 Hayter Rd NW
`Edmonton. Canada
`
`3001027806
`
`DS manufacture
`
`packaging
`release testing
`
`(5)“)
`
`Cilag AG
`Hochstrasse 201
`Schflhausen.
`Switzerland
`
`3002806695
`
`Janssen Pharmaceutica
`
`Janssen
`Pharmaceticalaan 3
`
`Geel. Belgium
`
`Janssen
`Pharmaceutical. Ltd.
`Little Island
`Cork. Ireland
`
`3002807337
`
`3002807361
`
`testin~ release and
`
`

`

`OMPQ Initial Manufacturing (CGMP/Facilifies) Assessment and Filing Review
`For Pre-Marking Applications
`
`
`
`Janssen Orlho L.L.C.
`Carr # 933 Km
`Ward
`munch-co.
`00778, United States
`
`12/12/2013 —NAI
`
`11/16/2012 -NAI
`
`2/22/2013 —VAI- 483
`issued on firm’s
`
`was
`adverse drug events
`reporting system,
`$53?”
`3““
`6/13/201 1 -VAI
`
`Titusville, New Jersey,
`08560-1503, United
`
`3002942061
`
`.
`
`2
`
`:
`
`

`

`OMPQ Initial Manufacturing (CGMP/Facilities) Assessment and Filing Review
`For Pre-Marking Applications
`
`Gilead Sciences, Inc.
`
`
`333 Lakeside Drive
`
`release testing
`
`
`
`follow up on Coverage:
`
`1000523075
`stability testing
`
`
`
`
`00(4)
`
`assigned
`PENDlNG
`inspection to
`(4)
`
`
`Foster City.
`California. 94404-
`1147. United States
`Johnson & Johnson
`
`Date: Oct
`Limited. Consumer
`
`
`CTL-
`2010
`Global R&D
`
`
`.
`_
`
`
`Operations
`.
`.
`.
`Acceptable
`Coverage.
`
`
`Opp Fire Brigade.
`3007543295
`DS stability testing
`as ofOct
`_ CGIVIP
`
`
`L.B.S..Marg. Muland
`2013
`(NAI)
`
`(West)
`- PAI (AC)
`
`
`
`Mumbai. India
`
`_
`10/15/2010 NAI
`
`assigned
`.
`.
`[gispection to
`“’
`
`PENDING
`
`V. Overall Conclusions and Recommendations
`
`Is the application fileable? (yes/no)
`Yes
`
`At this time, is a KTM warranted for any PAI? A potential KTM (Need input from
`CMC reviewer)
`Are there comments/issues to be included in the 74 day letter, including
`appropriate identification of facilities? No
`
`Comments for 74 Day Letter
`1. N/A
`
`2.
`
`3.
`
`

`

`OMPQ Initial Manufacturing (CGMP/Facilities) Assessment and Filing Review
`For Pre-Marking Applications
`
`REVIEW AND APPROVAL
`(DARRTS)
`
`Reference ID: 3503368
`
`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/
`----------------------------------------------------
`RUO H XU
`05/08/2014
`
`MAHESH R RAMANADHAM
`05/08/2014
`
`Reference ID: 3503368
`
`