`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`205834Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`

`

`
`
`NDA 205-834
`
`Ledipasvir and Sofosbuvir Tablets, 90 mg and 400 mg
`
`Gilead Sciences, Inc.
`
`George Lunn, Ph.D.
`Division of Anti-Viral Products
`
`Reference ID: 3635816
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................4
`
`The Executive Summary .........................................................................................9
`
`1. Recommendations ....................................................................................................................... 9
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 9
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments. Agreements. and/or Risk
`Management Steps. if Approvable ................................................................................................... 9
`
`II. Summary of Chemistry Assessments .........................................................................................9
`
`A. Description of the Drug Product(s) and Drug Substance(s) ............................................................. 9
`
`B. Description of How the Drug Product is Intended to be Used........................................................ 11
`
`C. Basis for Approvability or Not-Approval Recommendation .......................................................... l 1
`
`III. Administrative......................................................................................................................... 11
`
`A. Reviewer’s Signature ...................................................................................................................... 11
`
`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 [Ledipasvin Gilead Sciences] ................................................................... 13
`
`S DRUG SUBSTANCE [SofosbuviL Gilead Sciences] .................................................................. 61
`
`P DRUG PRODUCT [Ledipasvir
`
`(“"01 ............................................................ 69
`
`P DRUG PRODUCT [Ledipasvir and Sofosbuvir Tablets] ............................................................. 88
`
`A APPENDICES ............................................................................................................................ 132
`
`R REGIONAL INFORMATION ................................................................................................... 133
`
`II. Review Of Common Technical Document-Quality (Ctd—Q) Module 1 ................................ 134
`
`A. Labeling & Package Insert .......................................................................................................... 134
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion ................................................. 136
`
`III. List Of Deficiencies To Be Communicated ........................................................................... 136
`
`Reference ID: 3635816
`
`

`

`
`
`Reference ID: 3635816
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 205-834
`
`2. REVIEW #:
`
`1 - Addendum
`
`3. REVIEW DATE:
`
`26—Sep—2014
`
`4. REVIEWER: George Lunn, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`None
`
`Document Date
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission; s) Reviewed
`
`Document Date
`
`Original
`Amendment
`
`Amendment
`
`Amendment
`Amendment
`
`Amendment
`
`Amendment
`
`Amendment
`
`Amendment
`
`10-Feb-2014
`27-Feb-2014
`
`04-Mar-2014
`
`25-Mar-2014
`
`25-Apr-2014
`02-May-2014
`30-Jun-2014
`
`29-Jul-2014
`
`04-Aug-2014
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Reference ID: 3635816
`
`Page 4 of 154
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Name:
`
`Address:
`
`Representative:
`
`Telephone:
`
`Gilead Sciences, Inc.
`
`333 Lakeside Drive
`
`Foster City, CA 94404
`
`650 574 3000
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: NA
`b) Non-Proprietary Name (USAN):
`c) Code Name/#:
`(1) Chem. Type/Submission Priority:
`
`0 Chem. Type:
`
`1,4
`
`0 Submission Priority:
`
`P
`
`Ledipasvir and Sofosbuvir Tablets
`GS-5885 and GS-7977
`
`9. LEGAL BASIS FOR SUBMISSION: Food Drug and Cosmetic Act 505 (b)(1)
`
`10. PHARMACOL. CATEGORY: Anti-Viral (Hepatitis C)
`
`11. DOSAGE FORM:
`
`Tablets
`
`12. STRENGTH/POTENCY: Ledipasvir 90 mg and sofosbuvir 400 mg
`
`13. ROUTE OF ADMINISTRATION:
`
`Oral
`
`14. Rx/OTC DISPENSED:
`
`X Rx
`
`OTC
`
`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`SPOTS product — Form Completed
`
`X Not a SPOTS product
`
`Reference ID: 3635816
`
`Page 5 of 154
`
`

`

`
`
`Chemistly Review Data Sheet
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`('1) (4)
`
`5‘
`OYN O
`O
`N /
`h" H
`O
`0 Wm
`6 H6
`—F
`
`O
`
`/H
`
`:___ CH3
`
`>—O
`
`Sofosbuvir
`
`Molecular foulllla: C22H29FN309P
`
`Molecular weight: 529.45
`
`17. RELATED/ SUPPORTING DOCUMENTS:
`
`A. DMFS:
`
`
`
`ITEM
`REFERENC ED
`
`TYPE
`HOLDER
`
`
`
`
`
`
`
` m
`
`
`
`m
`
`
`HI
`
`
`
`-_-
`---
`
`
`---
`
`
`STATUS2
`
`DATE
`
`REVIEW
`COMPLETED
`
`COMMENTS
`
`
`
`
`
`“——
`
`Reference ID: 3635816
`
`Page 6 of 154
`
`

`

`
`
`
`
`(5) (4)
`
`1H
`
`Chemistry Review Data Sheet
`
`(b) (4)
`
`4
`
`
`
`4
`
`4
`
`4
`
`4 ---
`4 ---
`4 ---
`4 ---
`4 ---
`4 ---
`4 ---
`4 ---
`4 ---
`
`1n—
`
`
`
`III
`
`1]]—
`
`m
`m
`m
`1H
`I“
`m
`m
`m
`m
`
`
`
`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
`
`Reference ID: 3635816
`
`Page 7 of 154
`
`

`

`—_-—EES
`
`Acce . table
`
`9/3/14
`
`Rose Xu
`
`
`
`
`
`Chemistry Review Data Sheet
`
`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: None
`
`18. STATUS:
`
`CONSULTS/ CMC
`
`REVIEWS
`
`
`————
`9/26/14
`————
`Methods Validation
`Pending (report not
`MV request submitted 2/26/14
`required before
`approval)
`NA
`
`Categorical exclusion
`claimed. Claim is
`
`2/25/14
`
`Microbiology
`
`acce u ted.
`
`Acceptable
`
`3/31/14
`
`Steven P. Donald
`
`Reference ID: 3635816
`
`Page 8 of 154
`
`

`

`
`
`Executive Summary Section
`
`The Chemistry Review for NDA 205-834
`
`The Executive Summafl
`
`1. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`This NDA is recommended for approval from the CMC perspective. CMC information in the
`NDA (as amended July 29 and Aug 4, 2014) has been reviewed and found satisfactory, and the
`labeling has adequate CMC information which will be finalized during team review of
`labeling. The Quality Micro reviewer, Steven Donald, indicates that no product quality
`microbiology deficiencies were identified, and recommends approval. The Biophann reviewer,
`Sandra Suarez, has also recommended approval. An Overall Recommendation of Acceptable
`was made in EES (Sept 3, 2014).
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`
`Risk Management Steps, if Approvable
`
`None
`
`II. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`Complete sofosbuvir drug substance information is provided in approved NDA 204-671 and is
`incorporated in this NDA by reference. Sofosbuvir has a retest period of 8 months at 25
`°C/60% RH.
`
`Ledipasvir drug substance is manufactured
`
`M”
`
`The manufacturing process is described at a reasonable level of detail and the controls on the
`critical steps are acceptable. Laboratory studies have established PARS and the NORs are set
`within these limits. The proposed starting materials are acceptable.
`(law)
`
`A reasonable specification that includes tests for appearance, identity,
`assay, impruities, residual solvents, and elemental impurities is provided. The analytical
`methods are described at a satisfactory level of detail and have been validated. Satisfactory
`
`M"
`
`Reference ID: 3635816
`
`Page 9 of 154
`
`

`

`
`
`Executive Summary Section
`
`made at 8facilities on a
`batch analyses are provided for 20 batches of the
`scale. An acceptable justification of the specification is provided. Generally the specification
`is conventional and the acceptance criteria are reasonable. The specifications for appearance and
`cam) are rather broad but acceptable justifications are provided. The impurities are
`toxicologically qualified and the residual solvents limits are in accord with ICH Q3C. Potential
`genotoxic impurities are controlled in an acceptable manner. Because the next step
`M0
`
`(It) (4)
`
`(h) (4)
`
`Stability data of 11p to 24 months at 25°C/60% RH and 6 months at 40°C/75% RH are supplied.
`There are no out of specification results and no obvious trends although the material is light
`sensitive. A retest date of 8 months when stored at 25°C is reasonable.
`
`Ledipasvir
`
`M4) drug substance is
`
`(um)
`
`(I!) (4)
`
`Up to 12 months of satisfactory stability data obtained at 25°C/60% RH, 30°C/65% RH, and
`40°C/75% RH are provided
`(m4) The shelf-life of 24 months at up to 25°C is reasonable.
`
`The drug product consists of orange film-coated tablets that contain 400 mg sofosbuvir and 90
`mg ledipasvir. The tablets are packaged 28 count in HDPE bottles containing 1 g silica gel
`desiccant and a polyester fiber coil. The bottles are closed with induction seals and child—
`resistant closures. An alternate trade dress for tablets for an access program is also described.
`These tablets are
`(no)
`
`Ledipasvir
`
`M0
`
`The excipients are of compendial quality except for the film coats which are made of compendial
`components.
`
`Reference ID: 3635816
`
`Page 10 of 154
`
`

`

`
`
`Executive Summary Section
`
`The drug product specification contains tests for appearance, identity, water, assay, impurities,
`content uniformity, dissolution, and microbial limits
`(m4) A reasonable
`justification is provided. The analytical methods are described in detail and validation reports
`are provided. Satisfactory batch analysis data are provided for 15 batches of tablets.
`
`For the acceptability of the dissolution method see the separate Biopharm review.
`
`The presence of crystalline ledipasvir will be controlled using the dissolution test. Eventually an
`M0 test will be added to the control strategy.
`
`Up to 15 months of satisfactory stability data obtained at 30°C/75% RH are provided for 9
`batches. Batches have been manufactured
`(mo Their stability behavior is no
`different from other batches although the results of an end to end study are not yet available. An
`expiration dating period of 24 months when stored at or below 30°C is reasonable.
`
`An Overall Recommendation of Acceptable has been made in EES.
`B. Description of How the Drug Product is Intended to be Used
`
`Ledipasvir and sofosbuvir tablets are indicated for the treatment of chronic hepatitis C genotype
`linfection in adults.. The recommended dose is one tablet once daily with or without food. Each
`tablet contains 90 mg of ledipasvir and 400 mg of sofosbuvir. The tablets are supplied 28 count
`in 100 mL white HDPE bottles containing 1 g silica gel desiccant and a polyester coil and closed
`with white child-resistant
`om) screw caps and induction—sealed aluminum—faced liners.
`The expiration dating period is 24 months when stored in accordance with the recommended
`storage condition of “Store below 30°C”.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`The chemistry, manufacturing, and controls for ledipasvir and sofosbuvir drug substances have
`been reviewed and found to be satisfactory. The composition, manufacturing process, and
`specifications for the ledipasvir and sofosbuvir tablets are appropriate and the expiration dating
`period of 24 months when stored below 30°C is supported by adequate data. The container-
`closure system and labeling are appropriate. The data presented in the NDA are acceptable.
`
`This NDA is recommended for approval from the CMC perspective. CMC information in the
`NDA has been reviewed and found satisfactory. The labeling has adequate CMC information.
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`Reference ID: 3635816
`
`Page 11 of 154
`
`

`

`
`
`Executive Summary Section
`
`George len, Ph.D.
`
`Review Chemist
`
`B. Endorsement Block
`
`Stephen Miller, Ph.D. CMC-Lead and Acting Division Director
`
`C. CC Block
`
`142 Page(s) has been Withheld in Full as B4 (CCI/TS) immediately following
`fliis page
`
`Reference ID: 3635816
`
`Page 12 of 154
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`GEORGE LUNN
`09/26/2014
`
`STEPHEN MILLER
`09/26/2014
`As Acting Division Director, I concur: this NDA is recommended for approval from the CMC
`perspective.
`
`Reference ID: 3635816
`
`

`

`FDA CDER EES
`
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`f‘wllcatlon:
`
`NDA 205834/000
`
`Sponaoc:
`
`GILEAD SCIENCES INC
`
`4. Coda:
`
`PrIodty:
`
`Stamp Data:
`PDUFA Dab:
`Action Goal:
`Blatflct Goal:
`
`530
`
`14
`
`10-FEB~2014
`10-OCT-2014
`
`10-JUM2014
`
`FDA Contact: G. LUNN
`
`Prod QuaI Reviewer
`
`5. DONALD
`
`A CUFF
`
`L. ONAGA
`S. MILLER
`
`Moro Reviewer
`
`Product Quality PM
`
`Regulaton Profiecl Mgr
`Team Leader
`
`333 LAKESIDE DR
`
`FOSTER CITY, CA 94404
`
`Brand Mama:
`LEDIPASVIRISOFOSBUVIR FIXED DOSE
`Estlb. Name:
`COMB'NA
`Ganarlc Mama:
`LEDIPASVIRISOFOSBUVIR FIXED DOSE
`Product Numbar: oflgm; lngradknt: Stungtha
`001; TABLET; SOFOSBUVIR; 400MG
`001; TABLET; LEDIPASVIR: 90MG
`
`(MED-805)
`
`(HF-01)
`
`(HFD-530)
`
`3017961701
`
`4107795444
`
`3017964061
`
`3017960759
`3017961418
`
`
`
`Overall Rmondauon:
`
`ACCEPTABLE
`
`on 03-SEP-2014
`
`by R. XU
`
`()
`
`3017966181
`
`PENDING
`
`on O3—SEP-2014
`
`by EES_PROD
`
`PENDING
`on 02-MAY-2014
`by EES_PROD
`
`Eatabllahmom:
`CFN:
`(b) (4)
`FEI:
`(5X4)
`
`(5) (4)
`
`DMF No:
`
`RaaponalbIIIIIaa:
`
`DRUG SUBSTANCE MANUFACTURER
`DRUG SUBSTANCE RELEASE TESTER
`
`(II) (4)
`
`MBA:
`
`N 204671
`
`Pfoflla:
`
`NON-STERILE API BY CHEMICAL SYNTHESIS
`
`ON Status:
`
`NONE
`
`“a “unto”;
`
`Illaatona Data:
`
`DacIann:
`
`Reason:
`
`OC RECOMMENDATION
`
`03-SEP-2014
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`
`
`W 3. 2014 1:20 PM
`
`FDA Confldanflal - humal Diafibuflon Only
`
`Paga 1 of 6
`
`

`

`FDA CDER EES
`
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Establishment:
`
`CFN:
`
`(b) (4)
`
`FEI:
`
`(0(4)
`
`(5) (4)
`
`DNF No:
`
`Ruponslbllltics:
`
`DRUG SUBSTANCE MANUFACTURER
`DRUG SUBSTANCE RELEASE TESTER
`
`(I!) (4)
`
`AADA:
`
`N 204671
`
`Profilo:
`
`NON-STERILE API BY CHEMICAL SYNTHESIS
`
`OAI Status:
`
`NONE
`
`Last "Item:
`
`"Heston. Date:
`
`DocISIon:
`
`Roma:
`
`OC RECOMMENDATION
`
`26-MAR-2014
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`
`ESMIIShmInt:
`CFN:
`(II) (4)
`FEI:
`(b) (4)
`
`(b) (4)
`
`DHF No:
`
`Rupomibllitios:
`
`DRUG SUBSTANCE MANUFACTURER
`DRUG SUBSTANCE RELEASE TESTER
`
`AADA:
`
`Profile:
`
`NON-STERILE API BY CHEMICAL SYNTHESIS
`
`OAI Status:
`
`NONE
`
`L33: mum“;
`
`Milostono Data:
`
`DoclsIon:
`
`Reason:
`
`OC RECOMMENDATION
`
`31-MAR-2014
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`
`Estflllahmcnt:
`CFN:
`(It) (4)
`FE]:
`00(4)
`
`00(4)
`
`DUF No:
`
`00(4)
`
`AADA:
`
`N 204671
`
`Rumlbmtks:
`
`DRUG SUBSTANCE RELEASE TESTER
`
`Profile:
`
`CONTROL TESTING LABORATORY
`
`OAI Status:
`
`NONE
`
`L... mum“
`
`Mllutono Om:
`
`DoclsIon:
`
`Reason:
`
`oc RECOMMENDATION
`
`20-MAR-2014
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`
`
`smug: a, 2014 1:23 PM
`
`FDA Confidential - Internal (mutation Only
`
`Fag. 2 ON
`
`

`

`FDA CDER EES
`
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`' ‘sbllshmant:
`
`CFN:
`
`00(4)
`
`PI:
`(b) (4)
`
`(5) (4)
`
`DMF No:
`
`Responslbilltios:
`
`DRUG SUBSTANCE MANUFACTURER
`DRUG SUBSTANCE RELEASE TESTER
`
`DRUG SUBSTANCE STABILITY TESTER
`
`AADA:
`
`Profile:
`
`NON-STERILE API BY CHEMICAL SYNTHESIS
`
`OAI Status:
`
`NONE
`
`u“ "Imam;
`
`Ililestons Date:
`
`Decision:
`
`OC RECOMMENDATION
`
`26-MAR-2014
`
`ACCEPTABLE
`
`Reason:
`DISTRICT RECOMMENDATION
`
`Establishment
`CFN:
`PI:
`MG)
`
`(5) (4)
`
`DMF No:
`
`Responsibilities:
`
`AADA:
`
`FINISHED DOSAGE LABELER
`FINISHED DOSAGE MANUFACTURER
`
`FINISHED DOSAGE PACKAGER
`
`FINISHED DOSAGE RELEASE TESTER
`
`Profile:
`
`TABLETS. PROMPT RELEASE
`
`OAI Statue:
`
`NONE
`
`m Mllestone:
`
`Milestone Date:
`
`DecIeion:
`
`0C RECOMMENDATION
`
`26MAR-2014
`
`ACCEPTABLE
`
`Reason:
`DISTRICT RECOMMENDATION
`
`Establishment:
`CFN:
`2082946
`FEI:
`2082946
`
`GILEAD SCIENCES, INC.
`
`0MP No:
`
`Responsibilmes:
`
`SAN DIMAS. , UNITED STATES 917732957
`
`AADA:
`
`FINISHED DOSAGE LABELER
`FINISHED DOSAGE PACKAGER
`
`Profile:
`
`TABLETS, PROMPT RELEASE
`
`0A! Status:
`
`NONE
`
`Last Mllsstone:
`
`MIIestonn Date:
`
`Decislon:
`
`0C RECOMMENDATION
`
`07-MAR-2014
`
`ACCEPTABLE
`
`BASED ON PROFILE
`Reason:
`
`
`Septsmbet 3. 2014 1:20 PM
`
`FDA Confidential - lntsmsl Distrlbutlon Only
`
`Page 3 of 6
`
`

`

`FDA CDER EES
`
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Establishment:
`
`CFN:
`
`2952384
`
`FEI:
`
`1000523075
`
`GILEAD SCIENCES, INC.
`
`DMF No:
`
`FOSTER CITY. . UNITED STATES 944041147
`
`AADA:
`
`Responsibilities:
`
`FINISHED DOSAGE RELEASE TESTER
`
`Profile:
`
`CONTROL TESTING LABORATORY
`
`OAI Status:
`
`NONE
`
`Last Milestone:
`
`Milestone Date:
`
`Decision:
`
`DO RECOMMENDATION
`
`O3—SEP-2014
`
`ACCEPTABLE
`
`Reason:
`INSPECTION
`
`Establlshrnent:
`CFN:
`(b) (4)
`FE]:
`(b) (4)
`(b)(4)
`
`DMF No:
`
`ResponsIbIIItIes:
`
`Profile:
`
`Last Milestone:
`
`OC RECOMMENDATION
`
`miestone Date:
`
`25-APR-2014
`
`Decision:
`
`ACCEPTABLE
`
`(It) (4)
`
`AADA:
`
`OAI Status:
`
`NONE
`
`Reason:
`DISTRICT RECOMMENDATION
`
`
`Estabiiehment:
`
`CFN:
`
`Fl:
`
`(5X4)
`(5) (4)
`
`DMF No:
`
`ReeponelbIlItIee:
`
`Profile:
`
`Last Mileetone:
`
`OC RECOMMENDATION
`
`Milestone Date:
`
`Decision:
`
`01-AUG-2014
`
`ACCEPTABLE
`
`AADA:
`
`(b) (4)
`
`OAI Statue:
`
`NONE
`
`DISTRICT RECOMMENDATION
`Reason:
`
`
`September 3. 2014 1:28 PM
`
`FDA Confidentiai - Intemel Distribution Only
`
`Page 4 of 6
`
`

`

`FDA CDER EES
`
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`' ‘ibIIShflIOM:
`
`CFN:
`
`00(4)
`
`PEI:
`
`(b) (4)
`00(4)
`
`DHF No:
`
`Ruponslbfllflu:
`FroIIlo:
`
`Lu! Milestone:
`
`Milestone Date:
`
`Decision:
`
`DRUG SUBSTANCE RELEASE TESTER
`CONTROL TESTING LABORATORY
`
`OC RECOMMENDATION
`
`”MAY-2014
`
`ACCEPTABLE
`
`AADA:
`
`N 204671
`
`OAI Status:
`
`NONE
`
`Reason:
`DISTRICT RECOMMENDATION
`
`EIMIINIOM:
`CFN:
`00(4)
`FEI:
`(5)“)
`
`09(4)
`
`DEF No:
`
`Ruponflbmfiot:
`
`FINISHED DOSAGE RELEASE TESTER
`FINISHED DOSAGE STABILITY TESTER
`
`AADA:
`
`Prom:
`
`CONTROL TESTING LABORATORY
`
`OAI Status:
`
`NONE
`
`Last thatono:
`
`0C RECOMMENDATION
`
`“on. Data:
`
`W401"
`
`DOCISIon:
`
`ACCEPTABLE
`
`Rom:
`DISTRICT RECOMMENDATION
`
`EWIIMOM:
`CFN:
`(I!) (4)
`FEI:
`(b) (4)
`(It) (4)
`
`DIP No:
`
`Rospomlbmfla:
`
`MBA:
`
`FINISHED DOSAGE LABELER
`FINISHED DOSAGE MANUFACTURER
`
`FINISHED DOSAGE PACKAGER
`
`FINISHED DOSAGE RELEASE TESTER
`
`FINISHED DOSAGE STABILITY TESTER
`
`Promo:
`
`TABLETS, PROMPT RELEASE
`
`on Status:
`
`NONE
`
`Last Hunt...“
`
`“Into!“ bah:
`
`Decision:
`
`00 RECOMMENDATION
`
`26-MAR-2014
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`Reason:
`
`
`mm 3, 2014 1:2: PM
`
`FDA OWN - lntunal mmson Only
`
`Pago 5 of o
`
`

`

`FDA CDER EES
`
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Establishment:
`
`CHI:
`
`(5)“)
`
`PEI:
`
`09(4)
`(5) (4)
`
`DMF No:
`
`RosponsIhIlltIos:
`
`AADA:
`
`DRUG SUBSTANCE RELEASE TESTER
`DRUG SUBSTANCE STABILITY TESTER
`
`FINISHED DOSAGE RELEASE TESTER
`
`FINISHED DOSAGE STABILITY TESTER
`
`Profile:
`
`CONTROL TESTING LABORATORY
`
`OAI Status:
`
`NONE
`
`Last mustang:
`
`MIIestono Dao:
`
`Dockslon:
`
`Reason:
`
`0C RECOMMENDATION
`
`10-MAR-2014
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`
`Establishmnt:
`CFN:
`FEI:
`(5X4)
`
`(II) (4)
`
`DMF No:
`
`ResponsIbIIIlIes:
`
`DRUG SUBSTANCE MANUFACTURER
`DRUG SUBSTANCE RELEASE TESTER
`
`MBA:
`
`Profile:
`
`NON-STERILE API BY CHEMICAL SYNTHESIS
`
`OAI Status:
`
`NONE
`
`Last ""9330",;
`
`Milostom Date:
`
`DecIlIon:
`
`Reuon:
`
`OC RECOMMENDATION
`
`01-AUG-2014
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`
`
`Sophmw 3. 2014 1:28 PM
`
`FDA Confidential - lnumal Dlstfibuflon Only
`
`Pageants
`
`

`

`
`
`NDA 205-834
`
`Ledipasvir and Sofosbuvir Tablets, 90 mg and 400 mg
`
`Gilead Sciences, Inc.
`
`George Lunn, Ph.D.
`Division of Anti-Viral Products
`
`Reference ID: 3540512
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................4
`
`The Executive Summary .........................................................................................9
`
`1. Recommendations ....................................................................................................................... 9
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 9
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments. Agreements. and/or Risk
`Management Steps. if Approvable ................................................................................................... 9
`
`II. Summary of Chemistry Assessments .........................................................................................9
`
`A. Description of the Drug Product(s) and Drug Substance(s) ............................................................. 9
`
`B. Description of How the Drug Product is Intended to be Used........................................................ 11
`
`C. Basis for Approvability or Not-Approval Recommendation .......................................................... 11
`
`HI. 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 [Ledipasvin Gilead Sciences] ................................................................... 13
`
`S DRUG SUBSTANCE [SofosbuviL Gilead Sciences] .................................................................. 61
`
`P DRUG PRODUCT [Ledipasvir
`
`(“"01 ............................................................ 69
`
`P DRUG PRODUCT [Ledipasvir and Sofosbuvir Tablets] ............................................................. 88
`
`A APPENDICES ............................................................................................................................ 132
`
`R REGIONAL INFORMATION ................................................................................................... 133
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ................................ 134
`
`A. Labeling & Package Insert .......................................................................................................... 134
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion ................................................. 136
`
`III. List Of Deficiencies To Be Communicated ........................................................................... 136
`
`Reference ID: 3540512
`
`

`

`
`
`Reference ID: 3540512
`
`

`

`
`
`Chemistiy Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 205-834
`
`2. REVIEW #:
`
`1
`
`3. REVIEW DATE:
`
`04—Jun—2014
`
`4. REVIEWER: George Lunn, Ph.D.
`
`5. PREVIOUS DOCUIVIENTS:
`
`Previous Documents
`
`None
`
`Document Date
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission; s) Reviewed
`
`Document Date
`
`Original
`Amendment
`
`Amendment
`
`Amendment
`
`Amendment
`
`Amendment
`
`Amendment
`
`10-Feb-2014
`
`27-Feb-20 14
`04-Mar-2014
`
`25-Mar-2014
`
`25-Apr-20 14
`02-May—20 l 4
`30-Jun-2014
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`
`Gilead Sciences, Inc.
`
`Reference ID: 3540512
`
`Page 4 of 138
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Address:
`
`333 Lakeside Drive
`
`Representative:
`
`Telephone:
`
`Foster City, CA 94404
`
`650 574 3000
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: NA
`b) Non-Proprietary Name GISAN):
`0) Code Name/#:
`(1) Chem. Type/Submission Priority:
`
`0 Chem. Type:
`
`1,4
`
`0 Submission Priority:
`
`P
`
`Ledipasvir and Sofosbuvir Tablets
`GS-5885 and GS-7977
`
`9. LEGAL BASIS FOR SUBMISSION: Food Drug and Cosmetic Act 505 0))(1)
`
`10. PHARMACOL. CATEGORY: Anti-Viral (Hepatitis C)
`
`11. DOSAGE FORM:
`
`Tablets
`
`12. STRENGTH/POTENCY: Ledipasvir 90 mg and sofosbuvir 400 mg
`
`13. ROUTE OF ADMINISTRATION:
`
`Oral
`
`14. Rx/OTC DISPENSED:
`
`X Rx
`
`OTC
`
`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`SPOTS product — Form Completed
`
`X Not a SPOTS product
`
`Reference ID: 3540512
`
`Page 5 of 138
`
`

`

`
`
`Chemistly Review Data Sheet
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`0) (4)
`
`>—0
`
`27
`O
`
`\
`
`0
`||
`N “In P—O
`'
`/
`H 0
`
`Y
`N
`
`/
`
`0
`
`.
`
`CH3
`
`Sofosbmir
`
`Molecular ibmlula: C22H29FN309P
`
`Molecular weight: 529.45
`
`17. RELATED/ SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`
`REFERENC ED
`
`
`
`
`
`ITEM
`
`DATE
`
`REVIEW
`COMPLETED
`
`STATUS2
`
`Adequate
`
`
`
`
`
`III
`
`HI
`
`
`III
`
`4
`
`Adequate
`
`—
`
`Reference ID: 3540512
`
`Page 6 of 138
`
`

`

`
`
`Chemistry Review Data Sheet
`
`(b) (4)
`
`
`
`(b) (4)
`
`
`
`III
`
`
`
`HI
`
`
`
`HI
`
`
`
`III
`
`4
`
`4
`
`4
`
`4
`
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`
`
`III
`
`
`
`III
`
`
`
`III
`
`
`
`III
`
`
`
`III
`
`
`HI
`
`
`
`HI
`
`
`
`III
`
`
`
`III
`
`4
`
`4
`
`4
`
`4
`
`4
`
`4
`
`4
`
`4
`
`4
`
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`1Action codes for DMF Table:
`1 — 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 infonnation in application
`
`Reference ID: 3540512
`
`Page 7 of 138
`
`

`

`
`
`Chemistry Review Data Sheet
`
`5 — Authority to reference not granted
`6 — DMF not available
`
`7 — Other (explain under "Comments")
`
`2Adequate. Inadequate. or N/A (There is enough data in the application. therefore the DMF did
`not need to be reviewed)
`
`B. Other Documents: None
`
`18. STATUS:
`
`CONSULTS/ CMC
`
`RELATED
`
`REVIEWS
`
`RECOMMENDATION
`
`DATE
`
`Steven P. Donald
`
`————
`—-_——
`————
`
`————
`Methods Validation _— MV re n uest submitted 2/26/14
`OPDRA ———
`EA
`Categorical exclusion
`2/25/ 14
`G. Lunn
`claimed. Claim is
`
`acce u ted.
`
`3/31/14
`
`Reference ID: 3540512
`
`Page 8 of 138
`
`

`

`
`
`Executive Summary Section
`
`The Chemistry Review for NDA 205-834
`
`The Executive Summam
`
`1. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`This NDA is not recommended for approval from the CMC perspective. CMC information in
`the NDA has been reviewed and found satisfactory, and the labeling has adequate CMC
`information which will be finalized during team review of labeling. The Quality Micro reviewer,
`Steven Donald, indicates that no product quality microbiology deficiencies were identified. The
`Biopharm reviewer, Sanda Suarez, indicates that ONDQA-Biopharmaceutics cannot provide a
`recommendation because of the pending resolution on the Applicant’s agreement to monitor for
`the
`(no) content of the ledipasvir component.
`
`However, this application is not recommended for approval for the following reasons:
`0 An overall recommendation of Acceptable has not been made in EES.
`o The dissolution method and
`W0 testing have not been agreed.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`
`Risk Management Steps, if Approvable
`
`None
`
`II. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`Complete sofosbuvir drug substance information is provided in approved NDA 204-671 and is
`incorporated in this NDA by reference. Sofosbuvir has a retest period of :2; months at 25
`°C/60% RH.
`
`Ledipasvir drug substance is manufactured
`
`(we)
`
`The manufacturing process is described at a reasonable level of detail and the controls on the
`critical steps are acceptable. Laboratory studies have established PARS and the NORs are set
`within these limits. The proposed starting materials are acceptable.
`(low
`
`Reference ID: 3540512
`
`Page 9 of 138
`
`

`

`
`
`Executive Summary Section
`
`A reasonable specification that includes tests for appearance, identity,
`assay, impurities, residual solvents, and elemental impurities is provided. The analytical
`methods are described at a satisfactory level of detail and have been validated. Satisfactory
`batch analyses are provided for 20 batches of the
`W0 made at gifacilities on a
`(wwscale. An acceptable justification of the specification is provided. Generally the specification
`is conventional and the acceptance criteria are reasonable. The specifications for appearance and
`(”mare rather broad but acceptable justifications are provided. The impurities are
`toxicologically qualified and the residual solvents limits are in accord with ICH Q3C . Potential
`genotoxic impurities are controlled in an acceptable manner. Because the next step
`(m4)
`
`W0
`
`('1) (4)
`
`Stability data of up to 24 months at 25°C/60% RH and 6 months at 40°C/75% RH are supplied.
`There are no out of specification results and no obvious trends although the material is light
`sensitive. A retest date ofM0months when stored at 25°C is reasonable.
`
`Ledipasvir
`
`(m4) drug substance is
`
`(IMO
`
`(I!) (4)
`
`Up to 12 months of satisfactory stability data obtained at 25°C/60% RH, 30°C/65% RH, and
`40°C/75% RH are provided
`we The shelf-life of 24 months at up to 25°C is reasonable.
`
`The drug product consists of orange fihn-coated tablets that contain 400 mg sofosbuvir and 90
`mg ledipasvir. The tablets are packaged 28 count in HDPE bottles containing 1 g silica gel
`desiccant and a polyester fiber coil. The bottles are closed with induction seals and child-
`resistant closures. An alternate trade dress for tablets for an access program is also described
`These tablets are
`00(4)
`
`Ledipasvir
`
`(m4)
`
`Reference ID: 3540512
`
`Page 10 of 138
`
`

`

`
`
`Executive Summary Section
`
`The excipients are of compendial quality except for the film coats which are made of compendial
`components.
`
`The drug product specification contains tests for appearance, identity, water, assay, impurities,
`content uniformity, dissolution, and microbial limits
`(mo A reasonable
`justification is provided. The analytical methods are described in detail and validation reports
`are provided. Satisfactory batch analysis data are provided for 15 batches of tablets.
`
`For the acceptability of the dissolution method see the separate Biopharm review. It is
`interesting to note that the dissolution method is
`mm)
`
`The
`ledipasvir
`applicant has developed a
`
`(mo
`(hm) is not determined. Large amounts of
`m“) but the smallest amount that was is tested wasa'm%. The
`"""method which has a limit of detection
`(m4)
`
`Up to 15 months of satisfactory stability data obtained at 30°C/75% RH are provided for 9
`batches. Batches have been manufactured
`(mo Their stability behavior is no
`different from other batches although the results of an end to end study are not yet available. An
`expiration dating period of 24 months when stored at or below 30°C is reasonable.
`
`Currently the Overall Recommendation in EES is Pending.
`
`B. Description of How the Drug Product is Intended to be Used
`
`Ledipasvir and sofosbuvir tablets are indicated for the treatment of chronic hepatitis C genotype
`linfection in adults. The recommended dose is one tablet once daily with or without food. Each
`tablet contains 90 mg of ledipasvir and 400 mg of sofosbuvir. The tablets are supplied 28 count
`in 100 mL white HDPE bottles containing 1 g silica gel desiccant and a polyester coil and closed
`with white child-resistant
`(m4) screw caps and induction-sealed aluminum-faced liners.
`The expiration dating period is 24 months when stored in accordance with the recommended
`storage condition of “Store below 30°C”.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`The chemistry, manufacturing, and controls for ledipasvir and sofosbuvir drug substances have
`been reviewed and found to be satisfactory. The composition, manufacturing process, and
`specifications for the ledipasvir and sofosbuvir tablets are appropriate and the expiration dating
`period of 24 months when stored below 30°C is supported by adequate data. The container-
`closure system and labeling are appropriate. The data presented in the NDA are acceptable.
`
`This NDA is not recommended for approval from the CMC perspective. CMC information in the
`NDA has been reviewed and found satisfactory, with th