CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`210455Orig1s000
`PRODUCT QUALITY REVIEW(S)
`
`
`
`
`
`
`

`

`QUALITY ASSESSNIENT
`
`Recommendation: Approval
`
`NDA 210455
`
`Review #1
`
`Drug Name/Dosage
`
`SYMTUZA (Darunavir, Cobicistat, Eniricitabine, and Tenofovir
`Alafenamide) Tablets
`
`800mg]1 50mg/200mg/10mg (Fixed Dose Conbo)
`
`Route of
`
`Admins tration
`
`Rx/OTC Dispensed
`A
`a Imam
`
`Janssen
`
`us agent, if applicable—
`
`SUBMISSION(S)
`REVIEWED
`
`DOCUMENT
`DATE
`
`DISCIPLINE(S) AFFECTED
`
`“—
`
`
`Stephen Miller
`
`DISCIPLINE
`
`Drug Slbstance
`& Drug Master Files
`' Product & Labelin
`
`I
`
`Quality Review Team
`PRIMARY REVIEWER
`
`SECONDARY REVIEWER
`
`Mohd Slmhjalmn Kabir
`
`Charles Jewell
`
`Andrei Ponta
`
`Bala'ee Shamm ' am
`
`Process & Microbiology
`
`Iwom Weidlich
`
`Facility
`Biolnnmceutics
`
`Daniel DeCiero
`Zhuo'un Joan Zhao
`
`Arwa El Hagrasy
`
`Ying Zhang
`Elsbeth Chikhale
`
`Envionmental Assessment
`
`James Laurenson
`
`Michael (Scott) Furness
`
`Regulatory Bus'ness
`Process Manager
`
`Application Technical Lead
`
`LIE Rivera
`
`Executive Summary
`
`Page 1
`
`

`

`QUALITY ASSESSNIENT
`
`Quality Review Data Sheet
`
`1. RELATED/SUPPORTING DOCUMENTS
`
`A. DMFs:
`
`Item
`
`See DS
`summry
`
`See DS
`
`smmnry
`
`See DP
`review
`
`See DP
`review
`
`
`
`
`
`
`
`
`Date Reviewmm mm Comm
`
`
`
`
`
`
`
`
`18825
`
`Type II
`
`Type III (if
`applicable)
`
`Type IV (if
`applicable)
`
`B. Other Documents: HVD, RLD, or sister applications
`
`DOCUMENT
`
`APPLICATION NUMBER
`
`DESCRIPTION
`
`IND for this product
`
`— 1ND 113456
`
`2. CONSULTS
`
`DISCIPLINE
`
`
`
`STATUS RECOMMENDATION -w
` —_—-—
`
`—_—-—
`Phanmcology/Toxicology _—-—
`—_—-—
`
`_——-—
`
`Executive Sulmnary
`
`Page 2
`
`

`

`QUALITY ASSESSNIENT
`
`Executive Summary
`
`I.
`
`Recommendations and Conclusion on Approvability
`
`This NDA '6 recommended ibr APPROVAL fiom the product quality perspective.
`
`H. Sunny of Quality Assessments
`
`A. Product Overview
`
`Th's nnnolithic film-coated table containing 4 active ingredients and '3 indicated for HIV
`treatnnnt. Cobicistat is a CYP3A inhibitor intended to increase the plasnn levels of
`darunavir.
`
`Proposed Indication(s) including
`Intended Patient Population
`
`Treatment of HIV infection in patients 12 years and
`older
`09(4)
`
`dose Maxinmm Daily Dose
`
`Duration of Treatment
`
`Chronic, until resistance develops
`
`One tablet per day taken with food
`
`Alternative Methods of
`Adnl'nistration
`
`Instructions tbr splitting hto two pieces using a
`tablet-cutter, and imundiately consuming the entire
`
`B. Quality Assessment Overview
`Drug Substances:
`The CMC 'nfimmtion of the drug substance, darunavir ethanolate, '5 cross-refirenced
`to DMF 18825 (Jamsen Phanmceutica NV is the holder). This DMF was last reviewed
`by M. Kabir on Oct 17, 2017 and lbund adequate. NDA 210455 also cross-refirenced the
`approved NDA 21976 sponsored by Jamsen Products LP and the IND 62477 spomored
`by Janssen Research and Development LIE. The specification provided in NDA 210455
`'6 tighter than the specification provided in the DMF 18825, and includes
`W0 particle
`size control as well as chemical attrbutes.
`
`The CMC ilfimmtion of the drug substance, cobicistat on silicon dioxide, 'n cross-
`refierenced to DMF
`W0 is the holder). DMF # W0 reviewed
`by M. Kabir on Apr 4, 2018 and found adequate. No fithher armndrrent is submitted to
`date. The applicant abo cross-referenced these approved applications: NDA 207561
`Genvoya, NDA 203094 Tybost, and NDA 205395 Prezcobix The specifications lbr
`cobicistat on silhon dioxide proviied in NDA 210455 '5 equivabnt to the specifications
`provided tbr flie approved reference NDA 203094 and conparable with the specification
`provided in DMF
`00(4) of the cobic'stat on silicon
`diox'fle.. The difference in the acceptance crierion
`00(4) between the
`NDA (none detected) and the DMF (NMT g%
`09(4)). The applicant clarified in file
`NDA armndnnnt of Mar 6, 2018 that Synlum tabbts Will only bermnulactured wing
`
`Executive Smnmary
`
`Page 3
`
`

`

`QUALITY ASSESSNIENT
`
`cobicistat on silicon dioxide that meets the acceptance criteria
`l'sted in the NDA.
`
`(we)
`
`is cross-referenced to the
`The CMC 'nlbrnntion of the drug substance, emtricitabine,
`approved NDA 21500 Eniriva, and these approved applications are also referenced:
`NDA 21752 Truvada, NDA 207561 Genvoya, and NDA 208215 Descovy. The
`specification for errlricitabine provided in fllis, NDA 210455, is equivalent to the
`specification provided for ii the refierenced NDA 21752, and includes
`00(4) particle
`size control as well as chemical attrbutes.
`
`The CMC inlbmntion of the drug substance, tenofovir alafenamide fumarate (IAF), is
`cross-referenced to the approved NDA 207561 Genvoya, and NDA 208215 Decovy is
`also referenced. The specification tor TAF provided in NDA 210455 '3 equivalent
`to the
`specification provided in these referenced NDAs, and includes
`0W) particle size
`control and melting poilt, as well as chemical attrbutes.
`
`Elenrntal analyses were conducted on six drug product batches as per ICH Q3D and the
`results are i) he wih the ICH Q3D guilelines. The applicant agreed (May 10, 2018
`anendnlant)
`09“) in the specifications for
`the drug Slbstances. The revised specificatiom will be provided through the annual report
`submsions in early 2019, both fix the NDAs and the DMFs.
`
`For additimal infinntion, see Mohd Shahjahan Kabir’s Drug Slbstance Review, below.
`
`Drug Product:
`(m4)
`Synrum 's a fixed dose, immediate release conbntion tablet containing
`darunavir ethanolate
`(m4) mg of cobic'stat
`(”N0 200.0 mg of
`emtricitabine, and 11.2 mg of tenofbv'r alafenmide finmrate (equivalent to 10.0mg
`tenoibvir alafemmide).
`
`Syntum tablets are yellow, film-coated tablets (22 mm by 10 11m in she) fliat are
`debossed with “8121” on one side and “JG” on the other. Drug product specifications
`were based on release data from 16 drug product batches used in clinical and stability
`studies, pin stability results.
`09(4)
`
`The label contaiis the following instructiom, “For patients who are umble to swallow the
`whoka tablet, SYMIUZA my be split iito two pieces using a tablet-cutter, and the entire
`dose should be consurmd immd'ntely alter splitting” Note that the drug product does
`not contain a fimctionl score lire. Spliting the tablets is only to facilitate administration,
`not to create anoflier drug product dose. The inpact of splitting tablets has been studied
`in the Phase 1 study TMC114FD2HIXIOO4, us'ng the commrcial drug product
`tbrmlhtion The PK data assessed as part of file study dennnstrated that the relative
`bioavailability (Cmax, AUClast, and AUCoo) of the diflerent conponents (darlmavir,
`
`Executive Slunmary
`
`Page 4
`
`

`

`QUALITY ASSESSNIENT
`
`cobicistat, emtricitabine, and tenoibvir alaienamide) was not impacted, except fit an 11%
`decrease in tenotbvir ahfiemmile Cmax, whi:h '5 not considered clini:ally rehvant. The
`labeling imtluction fir splitting the table and comuming the entire dose immediately '3
`acceptable from the product quality perspective.
`
`09(4)
`Syntum tablets are packaged in a high-density polyethylene bottle, with
`child—resistant closure, toil 'nduction seal, and a desiccant pouch. Each bottle contain 30
`tablets. Rebase and stability data were provided on 3 primary stability batches produced
`at the commrcial drug product nnmrlacturing facility
`00(4). The three
`batches were produced at approximately 42% of the intended comrc'nl batch size. A
`36-111mm expiration dating period '3 granted based on acceptable stability data of 24
`Imnths at 25 °C /60% RH and 30 °C /75%, and 6 nnnths at 40 °C /75% when Syntuza 's
`stored at USP Controlled Room Tenperature in the commrcial 120-cc HDPE bottkes. In-
`use stability data ako hdbates tint the drug product remains stable lbr 6 weeks at 25
`°C/60% RH and 30 °C/75% RH.
`
`For additioml infirntion, see Andrei Ponta’s Drug Product Review, below.
`
`Biopharmaceutics :
`The following acceptance criteria and d'ssolution Imfliods are acceptable, based on
`evaluation of dissohtion data provided in the application:
`
`Acceptable Dissolution Method and Acceptance Crltcrta
`
`Component
`
`
`
`.I’ccd.ppUaSratus.RPMS}
`
`Medium
`
`I
`
`.
`
`Volume
`
`Dissolved
`
`Cumulative “IoofDrug
`I (II)
`'I
`. Q= :Iat:0minutes
`‘Q:
`0 at 15 umlulcs
`\
`
`(Label Claim) '
`
`_obicistat II (Paddle)
`‘
`.
`
`,
`
`Citrate Phosphate Buffer.
`
`PH4-3
`
`No brilging study ‘3 needed as the proposed commrcial Emulation, presentation and
`drug product namrlacturing site is the sane as that of the drug product used '11 the Phase
`III studies.
`
`For additioml infirution, see Zmojun (Joan) Zhao’s Bioplnrnnceutbs Review, below.
`
`Process:
`
`(hm
`
`Executive Summary
`
`Page 5
`
`

`

`QUALITY ASSESSMENT
`
`Executive Summary
`
`
`
`

`

`QUALITY ASSESSNIENT
`
`CFR 25.31(a), which is fit actions that do not increase the use of active nniety. Forthe
`other three s1bstames, the applicant claimed excllsions in accordance with 21 CFR
`25.31(b), which is fin actions fliat increase the use of the active moiety, but ibr whbh the
`estinmed concentration of the substance at the point of entry into the aquatic
`environnnnt—tlxe expected introduction comentrat'nn (EIC)—will bebebw 1 part per
`billbn (1 ppb). The required statean ofno extraordinary circumstances was inchded
`ibr the latter three substances, and was infierred ibr the darumvir.
`'Ihe chins ibr an
`
`exclusion from an EA are acceptable.
`For additional infimmtion, see Janns Lauremon’s EA Review, below.
`
`C. Special Product Quality Labeling Recommendations (NDA only)
`Product quality reconnendatiom for label'ng have been conveyed to the 0ND PM fi)r
`consideration as the labeling 's finalized. See Andrei Ponta’s Labeling Review, bebw.
`
`D. Final RiskAssessment (see Attachment)
`
`Executive Smnmary
`
`Page 7
`
`

`

`Stephen
`Miller
`
`Digitally signed by Stephen Miller
`Date: 6/13/2018 02:25:07PM
`GUID: 508da7210002a000609476bbecd040f0
`Comments: ATL for NDA 210455
`
`

`

`QUALITY ASSESSMENT
`
`BIOPHARMACEUTIC S
`
`Product Background:
`
`NDA: 210455 (505(b)(l)).
`
`Drug Product Name / Strength: SYMTUZA (Darlmavir, Cobicistat, Erntricitabine
`Tenotbv'r Ahfenamide) IR Tablets, 800 rug/150 mg/200 rug/10 mg
`
`and
`
`Route of Administration: Oral
`
`Applicant Name: Janssen Products, LP
`
`Review Summary:
`'8 indicated as a conplete
`The proposed fixed dose corrbination (FDC) SYMTUZA tablet
`reg'men ibr the treatment ofHIV-1 inflection in adults and pediatric patients 12 years of age and
`older.
`
`This 505(b)(l) New Drug Application does not contain a new chemical entity (NCE). The
`proposed FDC drug product contains the fifllowing tour drug substances:
`
`0 Danmavir
`protease.
`
`(D), an inhibitor of the human immunodeficiency virus
`
`(HIV-l)
`
`Cobicistat (C), a PK enhancer of Damnavir.
`
`Emtricitabine
`(NRTI).
`
`(F), a mickeoside
`
`analog HIV-1 reverse tramcrbtase inhibitor
`
`o Tenoibvir Ahfenamide (TAF), a nuckaoside analog HIV-l reverse tramcr'ptase
`inhibitor.
`
`The Biopharrmceutics review '3 focused on the evaluation and acceptability of the proposed
`dissolution methods and acceptance criter'n and the evaluation of the need for bridging.
`
`Based onflie provided d'ssolution data, the ibllowing d'ssohltion methods and acceptance criteria
`are acceptable:
`
`Accepafle Dissolution Mthod and Acceptance Criteria
`
`Conponent
`
`AUSaratus
`pp
`
`S
`(RPIMs)
`
`Medium
`
`Volume
`
`
`
`Curmlative % ofDrug
`Dissolved
`(label Claim)
`
`(5)
`Q (4)
`
`.
`at 30 mnutes
`
`_Danmvir
`_obicistat lI (Paddle)
`
`-11—ricitabiue/Tenofov11'Alafenamde
`
`2% Tweenm 0.05 M
`
`Phosphate Buifer. pH 3.0
`
`Citrate Phosphate Butfer.
`
`pH4.2
`
`900le|::
`
`:It:0mnutes
`at 15 ninutes
`
`|
`
`OPQ—XOPQ-TEM-m01v03
`
`Page 1 of 26
`
`Effective Date: 18 Feb 2016
`
`

`

`QUALITY ASSESSM ENT
`
`ibrnnlation, presentation and drug
`No bridg'ng study '3 needed as the proposed commercial
`product manufacturing site is the same as that of the drug product wed in the Phase 1]] stud'es.
`
`List Subnl'ssions being reviewed (table):
`
`Recommendation:
`
`Subnl'ssion(s) Reviewed Document Date
`
`Origiml Subn'msion
`
`9/22/2017
`
`From the Bioplnrrmceutics perspective, NDA 210455 ibr SYMI'UZA (Darumvir, Cobicistat,
`
`Emtlicitabine and Tenoibvir Ahfienamide)
`recommended ibr APPROVAL.
`
`IR Tablets, 800 mg/150 mg200 mg10 mg '3
`
`Th's 505(b)(1) New Drug Application does not contain a new chemical entity (NCE). The
`proposed FDC drug product contain the following four dmg substances:
`
`REVIEW
`
`(HIV-1) protease
`(D), an inhibitor of the human inmunodeficiency virus
`0 Damnavir
`developed by the Applicant
`and approved i1 NDA 21976 Premlta® (Damnavir
`ethanolate) tablets.
`approved in NDA 203094 Tybost®
`o Cobic'stat
`(C), a PK enhancer of Darunavir,
`(Cobicistat) tablets, NDA 206353 Evotaz® (Atamnavir Sulfiite and Cobicistat) Tablets,
`NDA 207561 Genvoya® (Cobicistat; Elvitegravir; Etmicitabine; Tenotovir Alafiemmide
`Fumarate) Tablets, NDA 205395 Prezocobix® (Cobicistat and Darunavir Etlmnolate)
`tablets and NDA 203100 Stnbild® (Cobic'stat; Elvitegiavir; Enmicitabine and Tenofovir
`D'Boproxil merate) Tablets.
`
`0
`
`Fmtlicitabine (F), a nucleoside analog HIV-1 reverse transcriptase inhibitor, approved in
`NDA 21500 Emhiva® (enlricitabine) Capsules
`and NDA 21896 Emtriva®
`(eniricitabine) solution
`
`0 Tenolbvir Alafenamile (TAF), a nucleoside analog HIV-l reverse transcriptase inhibitor,
`approved in NDA 208215 Descovy® (Emtlicitabine and Tenotbvir Alafenamide) tablets,
`
`BCS Designation
`
`The Applicant did not request an oflicial BCS designation.
`
`Drug Substance Solubility:
`
`Sohlbflity of the dmg substances are provided as shown below:
`
`0PQ—XOPQ—TEM—0001v03
`
`Page 2 of 26
`
`Effective Date: 18 Feb 2016
`
`

`

`
`
`QUALITY ASSESSM ENT
`
`Table l Solubility Profiles of Drug Substance
`Solubility
`(m’ulL) '
`
`pH at Solution
`
`Solvent
`0.1 N H(‘1
`
`l'SPvPli. Eur.
`Solubility Dessrription
`Soluble
`
`_ tat
`C b.
`° “‘5
`20°C
`
`t
`
`a
`
`SOttA'lacetrc acid _— Sparingly soluble
`50m.“sodiumphmpmbm n“ Manny-Mutt
`50 tu.\l sodium phosphate buffer
`'.'.5
`Practically insoluble
`
`
`
`
`
`
` a
`
`50 nt.\1 sodium phosphate bufl'ei'
`Water
`lktuuuued using reference standard lot RSI-With! at 20 * S “t"
`
`8.2 “ Practically insoluble
`Practically inwlublc
`
`I'SP/PI. Eur. Solubility Description
`
`_
`.
`Cobmstat _on
`Simon (home
`0
`at 20 C
`
`0 l N 11C] n Spariugly soluble
`0.01 N HCl
`Slightly soluble
`50 mM sodium acetate buffer. pll 1.5 — Slightly soluble
`50 mM sodium phosphate buffer. pH 6.8
`Practically insohtble
`-_
`Solubility ol'eobieistat measured from a suspension of cobieistat on silicon dioxide. detcnnincd from lot PP-1001-0002 at
`a
`20 J. 5 ‘C. The pH ofthe final solution was not determined.
`Solubility in g-'100 in].
`Ph. EuruUSP Definition
`21-! of Solution
`Solution
`Very slightly soluble
`7.6
`0.015
`Water
`Very slightly soluble
`10
`0.096
`0.1 N H(‘l
`Very slightly soluble
`2.]
`0.025
`0.01 N H(‘l
`Very slightly soluble
`2.0
`0.025
`Citrate-PIC] Buffer pH 2
`Very slightly soluble
`50
`0.013
`(‘iti'ate-NaOH BulIer pH 5
`Very slightly solttble
`7.0
`0.014
`Phosphate Buffer pH 7
`Very slightly soluble
`90
`0.016
`Bomte-KCl-NaOH Buffer pH 9
`Very slightly soluble
`12.0
`0.014
`Phosphate-NaOH Bufier pH 12
`Very slightly soluble
`1.1
`0.083
`Simulated Gastric Fluid
`
`Simulated Intestinal Fluid
`0.016
`74
`Very slightly soluble
`
`Solvent
`
`
`
`Solvent
`
`0.1 N HCl
`
`0.1 N NaOH
`Methanol
`
`Water
`Acetonimle
`
`Isopropyl acetate
`
`Solubility (ing’inL)
`
`l'SPfPII. Eur. Solubility Desct'iplion
`
`_
`
`-
`
`.
`
`Freely soluble
`
`Freely soluble
`Freely soluble
`
`Freely soluble
`Slightly soluble
`
`Very slightly soluble
`
`Aqueous Merlin
`Water. pH 2.0 tH('l)
`Water. final pH 3.8
`Water. pH 4.5 (20 mM acetate buffer)
`Water. p11 6.8 (50 um phasplmte buffer»
`Water. p11 8.0 t 50 um pho>phate buffert
`
`Solublllty‘ (mgImIJ
`.
`.
`..
`‘.
`‘
`
`.
`.
`
`l‘Sl’fPli. l-Zur. Solubility
`Description
`Soluble
`Spanmzly soluble
`Slightly soluble
`Slightly soluble
`Slightly soluble
`
`Permeability:
`
`No data are provided.
`
`OPQ—XOPQ—TEM—0001v03
`
`Page 3 of 26
`
`Effective Date: 18 Feb 2016
`
`

`

` QUALITY ASSESSM ENT
`
`Drug Substances:
`Darunavir
`
`
`
`
`Cobicistat
`
`Emlricitabine
`
`
`
`Formulation:
`
`The proposed dmg product '3 a yellow-brown, caps11b-slnpe¢ immediate rekase D/C/F/TAF
`FDC film-coated - tablet debossed wifll “8121” on one side and “JG” on the other.
`
`OPQ-XOPQ-TEM-(D01v03
`
`Page 4 of 26
`
`Effective Date: 18 Feb 2016
`
`

`

`
`
`QUALITY ASSESSM ENT
`
`Table 2: leitative and Quantitative Corrposition of the Drug Product
`
`
`
`Dissolution Method and Acceptance Criteria
`
`The Applicant proposes two d'ssolution methods (Table 4), based on the diflierence in dose and
`sohbility of the 4 drug s1bstances in the proposed FDC drug product.
`
`0 The proposed dissolution rmthod ibr Darumv't is the sane as the approved nethod in the
`Applicant’s NDA 21976 Prezistao (Darumvir) Tablets, 600 mg 1 and method ibr
`Dammvir
`in the Applicant’s NDA 205395 Prezocobix® (Cobicistat and Darunavir
`Ethanohte) tabbtsz.
`
`(Prirmry Review), finaldate 12/18/2017
`1 DARRTS: NDA 21976, REV-QUALBIOPHARM-Zl
`2 \\cds es ub l\e\-'§prod\nda205395\0045\nfi\3 2-b ody-data\322-drug-pro d\active-all-pres entations\322 5-contr-drug-
`rod\32 52-ana
`- roc\ana
`ical— roced1ue-dar—ds-tm-12983. df
`
`OPQ-XOPQ-TEM-m01v03
`
`Page 5 of 26
`
`Effective Date: 18 Feb 2016
`
`

`

` ' “A. n
`I
`‘
`QUALITY ASSESSMENT
`
`and Tenofovir
`ibr Cobicistat, Elmicitabine
`nlefliod
`o The proposed d'ssolution
`Ahfiemmide is the sauna as the approved method ibr Cobic'stat in the Applicant’s NDA
`205395 Prezocobix® (Cobic'stat and Darunavir Eflnnohte) tablets 3.
`
`Table 4: Proposed Dissolution Methods
`
`Tenofiwir
`
`‘
`
`
`
`.
`
`2% Tween in 0.05 M phosphate
`Bufl‘er, pH 3.0
`
`.
`Citrate Phosphate Bufl‘er, pH 4.2
`
`mm
`
`The Applicant provided justification for the choice of d'ssolution apparatus, d'ssolution medium,
`and agitation speed ibr each method in the Phanmceut'nal Development Report (Module 3.2.P.2).
`
`Dissolution Method for Danmavir (DS-IMD-l7520)
`
`
`
`3 \\cds es ub 1\evspmd\uda205395\0000\nfi\3 2-b ody-data\3ZQ-dmg-pro d\active-all-pres entations\329 5-contr-dmg-
`pmd\32252-anabat-prodanaMical-procedure-cob-di-OW396.2df
`
`0PQ-XOPQ-TEM-0001v03
`
`Page 6 of 26
`
`Effective Date: 18 Feb 2016
`
`
`
`

`

`g...“
`
`Baum;
`
`
`QUALITY ASSESSMENT
`
`J...“
`
`
`
`Reviewer’s Assesunt: Ampable.
`tin proposed dissolt'nn rmflnd (DS-'IMD-l7522) fir
`Based on the proviied 'nfimmt'nn,
`Cobnistat/Ennricitabire/Tenofivir Ahfirmnile '3 :
`A
`:
`‘
`e
`
`FDC dug prodmt. The proposed d'ssoh'nn nelhod
`
` orprocess pararmters.
`
`Dissolution Acceptance Criteria: Acceptable
`
`The Applicant proposed the iblbwing dissoht'nn acceptance criter'n based on the dissolution
`resuls obtaimd on the plnse II[ cl'n'nal batches (SBCI-I, SXVC,
`'INYC and TN'YF)s and
`reg'stration batches (S'IKF, S'IKG and STKH).
`
`Component
`
`Damnavir
`
`Cobicistat
`
`Tenofiwir
`t] E
`'de
`
`rntricitabn
`
`(Q)at15m'“
`
`Dissolved (label Chin) -
`o(Q)at30
`Curmhtive %ofDrug
`
`/o((Q)at20 l
`
`Darlmavir
`
`'Ihe Applitant proposed an acceptance criterion of Q
`dissolution profibs (Figll'e 7) andthe amomt ofS2
`
`0 at 30 nines based on the average
`testing requied.
`
`Figure 7D'ssoht'nn Profiles of Darunavi' fin Representative Batches
`
`
`
`Cobicistat
`'I‘he App]i:ant proposed an aoceptame crierion of Q =-% at 20 mines based on the average
`d'ssolntion profiles (Figure 8) and the annmt ofSZ and S3 testing requied.
`
`5 Appendix I
`
`OPQ-XOPQ-TEM-m01v03
`
`Page 20 of 26
`
`Effective Date: 18 Feb 2016
`
`

`

` QUALITY ASSESSM ENT
`
`8 Dissohtion Profihs of Cobb'stat ibr Re resentative Batches
`
`
`
`Emlricitabine
`
`The Applbant states that Enlr'citabine 's a higlly sohbb conpound, which '3 dissolved within
`15 mimtes innedia covering flme hysiologbal pHIange (1-6.8)and 11113 the Applhant proposed
`
`an acceptance criterion ofQi at 15 miIutes.
`
`figure 9 D'ssolution Profiles of Enticitabine fin Representative Batches
`
`
`
`Tenofovir Alafenamide
`
`The Appl'nant states tint Enlr'nitabine k a highly sohble conpound, which '3 dissolved within
`15min1tes inmed'n covering
`hysiobg'nal pHrange (1-6.8)and thus the Applicant proposed
`an acceptance criten'on of Q
`0 at 15 mimites.
`
`OPQ-XOPQ-TEM-m01v03
`
`Page 21 of 26
`
`Effective Date: 18 Feb 2016
`
`

`

`‘ .A. H
`
`
`
`m;
`
`QUALITY ASSESSMENT
`
`‘ .A.n
`
`
`
`“chum-aha-
`
`Figure 10 Dissohtion Profiles of Tenoibvi Ahfienamide fir Representative Batches
`
`Reviewer’s Assess-t:
`
`'IIBAppEaII’s proposeddissoh'nn acceptame crier'n areacceptabh basedonthe proviled
`
`data (Figures 7-10 am] QM).
`
`Bridging of Formulations: NlA
`
`No bridging "s needed as the proposed commercial Emulation 6001 (iJchlding tie debossing,
`yellow film-coat and nnnutactu'ing sie) was used '11 file D/C/F/I‘AF pivotal Phase 3 studies
`'IMC1141FD3013
`and
`'IMC114FD2HI'X3001,
`and
`'n
`a
`bioequivalence
`study
`(TMC114FD2HTX1001)
`that compared the imended commrchl D/C/F/I'AF FDC GOO]
`fimnlation to the conbirntbn ofthe separate agms (DRV + COBI + F/I‘AF).
`
`R
`
`Regional Information
`
`Comparability Protocols: None
`
`Post-Approval Commitments: None
`
`Lifecycle Management Considerations: None
`
`List ofDeficiencia: None
`
`Recommendations:
`
`From the Bbplmrmceutics perspective, NDA 210455 ibr SYMI'UZA (Darlmv't, Cobicistat,
`
`Fmtrbitabine and Tenoibvir Alafienamide)
`recommnded ibr APPROVAL.
`
`IR Tablets, 800 rug/150 rug/200 rug/10 mg '3
`
`Primary Biopharmaceutics Reviewer Name and Date: Zhuojun Joan Zhao, PILD. 2/22/2018
`
`Secondary Reviewer Name and Date: Elsbeth Chikltale, PILD. 3/40018
`
`OPQ-XOPQ-TEIVI-(XJOIVOS
`
`Page 22 of 26
`
`Effective Date: 18 Feb 2016
`
`

`

`fl .4. H
`
`m2.)
`
`QUALITY ASSESSM ENT
`
`‘ .1.n
`
`”CHM—u...- 1
`
`APPENDIX I: Drug Product Batches Employed in Clinical Studies
`Ding Subsmnce
`A—
`Lot
`Packaged Batch
`sm
`Date
`Identification
`
`Damnavir: A15CC1 164a Janssen Colt)
`Cobicisnt PP-1001-4018
`Emidubine: 1057142
`Tenofiwitmac: 5477-P56/lS—003'-
`Damnavir. A15CC1160‘(Janssen Cotk), A15CC1163'
`(Janssm ka)
`Cobicisut: PP-1001-4018"- PP-1001-3026"
`cm '
`: PP-OO664011"
`PP-0066-4056"
`PP—0066-4043
`Ahfenamide:
`
`eno
`
`-
`
`w-
`Damnlvir. A15DC1261'ganssen Cork)
`Cobicimt: PP-1001-3026
`Emicihbine: 1057142
`Tenofovir Ahfmmnide: 73
`
`-
`
`-
`
`(Gilead Alberta)
`
`Duunmrit: AlSDClZGl' Janssen Cork)
`Cobicimt: PP-1001-3026
`Enmicihbine: 1057142
`
`Tenofiovit Ahfmnnide: 7340-03-DC-7P'l (Gilead Alberta)
`Damnnvir: A15CC1163' Jansen)
`Cobidml: PP-1001-3026
`Enniciubine: PP-0066-40
`Tenofiovir Ahfemmide: 7
`
`(Gilead)
`
`0mm: Al4GCl987‘Umssen). A14GC1989' (1mm)
`Cobiu'sut: PP-1001-2016
`Emm'ciubine: PP
`Tenofiovir Allfenlmide: 547 -
`
`Formulation
`
`Batch
`Size
`(kg)
`
`24 Apr 2016
`
`6001
`
`19 Novembel' 2015
`
`G001
`
`VPVP, VPVS
`(VPVN)
`
`Pallleornf
`
`6 October 2015
`
`6001
`
`TYYFVFBS
`
`Pullmanf
`
`16 Sept. 2015
`
`6001
`
`ma-
`
`Pallet»:f
`
`25 June 2015
`
`6001
`
`sxv1=-
`
`13 February 2015
`
`0001
`
`
`
`cummsm
`Identification/Stability Use
`
`TMCI 14FD2H'1'X3001
`
`TMCl 141FD3013
`
`TMCl 14FD2HTX3001
`(VPVS)
`TMC1141FD3013 (WVS)
`Ill—use Subility (VPVP)
`
`mc1 1411153013 (nnm
`TMClMI-‘DZH'IXSOOI
`(TYYF)
`may (VFBS)
`TMCl l411-‘D3013
`
`TMCI 14101211130001
`
`

`

`— .A' n
`
`min:
`
`QUALITY ASSESSM ENT
`
`‘ .A.n
`
`acumen-annu- ‘
`
`Drug Substance
`Lot
`
`Mannfictun'ng
`Site
`
`Date
`
`Foundation
`
`Packaged Batch
`Batch
`Clinical Study
`Identification
`Size
`Identification/Stability Use
`
`TMCl l4FD21-1TX1002
`
`Damnavir: Al41-‘C1863' (Ianssen)
`sncr- pm‘
`29 August 2014
`6001
`'1'MC1 14IFD3013
`Cobicistt: PP-1001-2016'
`Emicithine' PP-0066-4011
`Tennfovit Alafenamide: 5477-?56-13-401-
`Darunavil': 211319064 EIAO61'(Janssen)
`Cohicistt 93SO‘CC-2l”l (Gilead)
`Emnicithine: ”COS-1100106
`Tenofiovir Alafenamide: 7340—0 -
`
`DB] 103131,
`DB] 10332
`(DBllO3B)
`
`ea
`
`Palheon‘
`
`12 October 2011
`
`Phase 1
`
`
`
`
`
`GS-US-299-0101
`(DBl 103B 1)
`GS-US-299-0102
`(DBl 10331, DBl 10332)
`
`Damnavit: 21619064 EIAO61' (Janssen),
`ZRSl9064EID491'O
`Cohicistt: PP-1001-1002
`
`Emnidthine: ”m
`
`Tenofiovit Alafenamide: 7340-031-AC-1Pd (Gilead)
`
`D31201131
`(DBIZOIB)
`
`Palheon‘
`
`25 May 2012
`
`Phase 2
`
`GS-US-299-0102
`
`
`
`
`Damnavir: A12FC2130' (Janssen)
`Cohieistt: 9350-CC-31"l (Gil
`
`Emicithine: ”COS-1101231 l . F'l‘C05-11011261f
`W: 7340-03-DC-2P‘(Gi1ead)
`
`' Janssenl’halmacenficaLLitdeIslnniCo.CiIIe1-1d
`
`DBIZMBI
`(DBIZMB)
`
`Palheon'
`
`28 November 2012
`
`Phase 2
`
`GS-US-299-0102
`
`GileadAlhenaULC
`
`Al
`
`Canada
`
`

`

`fl...“
`
`
`
`QUALITY ASSESSMENT
`
`APPENDIX 11: Batch Overview of Release Dissolution Results6
`
`l. Dammvir
`
`Dissolution
`
`5min
`
`10min
`
`Mean Percent Dissolved (Minimum-Maximum)
`15min
`20min
`30min
`45min
`
`60min
`
`90min
`
`Batch
`STKF
`
`STKG
`
`STKH
`
`SBCHa
`
`SXVC”
`
`TNYC
`
`TNYF
`
`36
`
`(34—39)
`36
`
`(33-42)
`29
`
`(21-37)
`46
`(37—50)
`14
`(1 1-19)
`47
`
`(36-54)
`46
`
`63
`
`(62-64)
`66
`
`(63—67)
`61
`
`(55-65)
`64
`(60—67)
`46
`(39-53)
`67
`
`(36-71)
`69
`
`77
`
`(77-78)
`78
`
`(77—79)
`79
`
`(76-80)
`75
`(71—79)
`68
`(63-72)
`78
`
`(71-82)
`79
`
`86
`
`(85-86)
`87
`
`(86—87)
`87
`
`(86-88)
`82
`(78—86)
`80
`(78-82)
`85
`
`(80-88)
`86
`
`95
`
`(94-95)
`95
`
`(94—96)
`95
`
`(94-96)
`90
`(88—93)
`91
`(89-92)
`92
`
`(88-95)
`91
`
`101
`
`103
`
`104
`
`(100-101)
`101
`
`(100—102)
`101
`
`(100-102)
`97
`(95—99)
`98
`(97-99)
`97
`
`(95-98)
`97
`
`(102-103)
`104
`
`(102-105)
`103
`
`(102-104)
`98
`(97—101)
`99
`(98-100)
`98
`
`(94-99)
`98
`
`(103-104)
`105
`
`(103-106)
`104
`
`(102-104)
`99
`(98—102)
`100
`(100-101)
`98
`
`(95-100)
`99
`
`(98-100)
`(97-99)
`(96-98)
`(90-93)
`(83-87)
`(76-81)
`(64-71)
`(42-48)
`' Results reported for stability samples fi'om the 9 month time point at the 25 °C/60% RH storage (packaged batch
`SBCT) with commercial test method
`" Results reported for stability samples from the 6 month time point at the 25 °C/60% RH storage (packaged batch
`SXVF) with commercial test method
`
`2. Cobicistat
`
`Batch
`
`STKF
`
`STKG
`
`STKH
`
`SBCH'
`
`SXVC"
`
`TNYC
`
`TNYF
`
`5min
`48
`
`(43-53)
`47
`
`(44-51)
`45
`
`(40-52)
`63
`
`(55-71)
`26
`(15-36)
`66
`
`(60-68)
`48
`
`10min
`74
`
`(71-75)
`74
`
`(72-75)
`74
`
`(70-77)
`79
`
`(73-85)
`64
`(49-67)
`81
`
`(78-82)
`77
`
`Dissolution
`
`Mean Percent Dissolved (Minimum—Maximum)
`15min
`20min
`30min
`45min
`83
`87
`91
`92
`
`(80-85)
`83
`
`(82-85)
`82
`
`(81-83)
`86
`
`(82-89)
`80
`(73-82)
`89
`
`(87-91)
`86
`
`(85-88)
`88
`
`(86-89)
`86
`
`(86-87)
`90
`
`(87-94)
`87
`(84—89)
`91
`
`(89-93)
`91
`
`(89-92)
`93
`
`(91-94)
`90
`
`(88-92)
`94
`
`(91 -97)
`94
`(92-95)
`94
`
`(92-96)
`95
`
`(91-93)
`96
`
`(94-98)
`93
`
`(92-95)
`95
`
`(93-97)
`96
`(94-97)
`96
`
`(94-98)
`95
`
`60min
`93
`
`(92-94)
`95
`
`(94-97)
`92
`
`(90-94)
`96
`
`(95-98)
`96
`(95-97)
`96
`
`(95—98)
`96
`
`90min
`94
`
`(92-96)
`96
`
`(94-97)
`93
`
`(92-94)
`97
`
`(95-98)
`97
`(95-99)
`96
`
`(95-99)
`97
`
`(96-98)
`(95-97)
`(94-97)
`(93-96)
`(88-94)
`(82-88)
`(74-81)
`(36-57)
`' Results reported for stability samples from the 9 month time point at the 25 °C/60% RH storage (packaged batch
`SBCT) with commercial test method
`5 Results reported for stability samples from the 6 month time point at the 25 °C/60% RH storage (packaged batch
`SX'VF) with commercial test method
`
`6 p
`
`\\cds es ub l\evsprod\nda210455\0000\m3\3 2-body-data\322-drug-Qrod\active-film-coated-tablet\32p_5-contr—drug-
`rod\32256-m'stif-specm'lstification-of-specifications.pdf
`
`OPQ-XOPQ-TEM-(DOIVOS
`
`Page 25 of 26
`
`Effective Date: 18 Feb 2016
`
`

`

`l .e' l‘
`
`UALITY ASSESSM EN
`
`3. Emln'citabine
`
`Batch
`STKF
`
`STKG
`
`STKH
`
`SBCl-Ia
`
`SXVC"
`
`TNYC
`
`TNYF
`
`5min
`94
`
`(92-96)
`94
`
`(92-95)
`89
`
`(84-95)
`102
`(100-103)
`55
`(30—73)
`100
`
`(97-101)
`92
`
`10min
`99
`
`(98-99)
`99
`
`(98-100)
`99
`
`(97-101)
`102
`(101-103)
`95
`(80—99)
`100
`
`(99-102)
`101
`
`Dissolution
`
`Mean Percent Dissolved (Minimum—Maximum)
`15min
`20min
`30min
`45min
`99
`99
`100
`100
`
`(98-99)
`99
`
`(98-100)
`100
`
`(98-101)
`102
`(101-103)
`100
`(98—101)
`100
`
`(99—102)
`102
`
`(99-100)
`99
`
`(98-100)
`100
`
`(99-101)
`102
`(100-103)
`101
`(99—103)
`100
`
`(99-102)
`102
`
`(99-100)
`100
`
`(99-100)
`100
`
`(99-101)
`102
`(100-103)
`102
`(100—104)
`100
`
`(99-101)
`103
`
`(99-100)
`101
`
`(98-109)
`100
`
`(99-101)
`102
`(100-103)
`102
`(100—103)
`100
`
`(99-101)
`103
`
`60min
`100
`
`(100-100)
`100
`
`(98-101)
`100
`
`(99-101)
`102
`(101-104)
`101
`(100-103)
`100
`
`(99-101)
`102
`
`90min
`100
`
`(99-101)
`100
`
`(99-101)
`101
`
`(99-101)
`102
`(101-103)
`102
`(100—104)
`100
`
`(99-102)
`104
`
`(78-100)
`
`(100-102)
`
`(101-103)
`
`(101-103)
`
`(102-105)
`
`(102-104)
`
`(102-103)
`
`(102-104)
`
`I Results reported for stability samples fi'om the 9 month time point at the 25 °CI60% RH storage (packaged batch
`SBCT) with commercial test method
`5 Results reported for stability samples from the 6 month time point at the 25 °CI60% RH storage (packaged batch
`SXVF) with commercial test method
`
`4. Tenofiwir Alafienamide
`
`Batch
`STKF
`
`STKG
`
`STKH
`
`SBCH'
`
`SXVC"
`
`TNYC
`
`TNYF
`
`5min
`82
`
`(80-84)
`79
`
`(77-80)
`75
`
`(70-82)
`95
`
`(93-99)
`45
`(26-62)
`93
`
`(91-96)
`80
`
`10min
`94
`
`(93-96)
`90
`
`(89-92)
`92
`
`(91-94)
`97
`
`(93-99)
`85
`(70-92)
`96
`
`(94-98)
`95
`
`Dissolution
`
`Mean Percent Dissolved (Minimum-Maximum)
`15min
`20min
`30min
`45min
`96
`96
`95
`95
`
`(94-98)
`92
`
`(91-95)
`95
`
`(94-96)
`98
`
`(94-99)
`94
`(89-97)
`97
`
`(95-99)
`96
`
`(95-98)
`93
`
`(92-96)
`96
`
`(95-97)
`98
`
`(97-100)
`95
`(92-98)
`98
`
`(96—100)
`97
`
`(94-97)
`94
`
`(93-96)
`97
`
`(96-98)
`98
`
`(94-100)
`97
`(94-98)
`98
`
`(96-100)
`98
`
`(95-97)
`95
`
`(93-97)
`97
`
`(96-98)
`98
`
`(95-100)
`97
`(94-100)
`98
`
`(97-101)
`98
`
`60min
`96
`
`(95-98)
`95
`
`(93-98)
`98
`
`(96-99)
`99
`
`(97-102)
`98
`(95-100)
`99
`
`(96-101)
`98
`
`90min
`96
`
`(95-98)
`95
`
`(94-98)
`98
`
`(96-99)
`100
`
`(96—102)
`99
`(95-101)
`99
`
`(96—101)
`99
`
`(97-102)
`(96-101)
`(96-101)
`(96-101)
`(95-100)
`(94-98)
`(92-97)
`(67-89)
`' Results reported for stability samples from the 9 month time point at the 25 °CI60% RH storage (packaged batch
`SBCT) with commercial test method
`b Results reported for stability samples fi'om the 6 month time point at the 25 °CI60% RH storage (packaged batch
`SXVB with commercial test method
`
`OPQ-XOPQ-TEM-m01v03
`
`Page 26 of 26
`
`Effective Date: 18 Feb 2016
`
`

`

`Zhuojun
`Zhao
`
`Elsbeth
`Chikhale
`
`Digitally signed by Zhuojun Zhao
`Date: 3/07/2018 12:09:39PM
`GUID: 508da6fd000284770cf4eecbae074722
`
`Digitally signed by Elsbeth Chikhale
`Date: 3/07/2018 12:18:38PM
`GUID: 50743ccc000031928b54eba1769a5df9
`
`

`

`QUALITY ASSESSNIENT
`
`A'ITACHIWENT I: Final Risk Assessments
`
`A. Final Risk Assessnxent —NDA
`
`a) Dmg Product
`
`Final Risk Table for Damnavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Tablets
`From Initial Risk Identification
`ReviewAssessment
`
`
`
`Attribute/
`“9”“ that
`M.“
`Risk Mitigation
`“3"“
`Lifecycle Considerations/
`CQA
`can Impact the
`Rm}
`Appmach
`RISk
`Comments
`CQA
`Ranking
`Eva].
`
`
`stable n1 the tablet
`
`Physical
`stability
`(solid state)
`
`Based 011 cobicistat
`
`Conte nt
`
`Based on TAF
`
`loading
`
`momma-limits—
`
`
`
`uniformity
`
`fissolution—
`BCS
`Class II & IV
`
`
`
`Damnanr and
`cobicistat
`
`Final Risk Assessment
`
`

`

`Stephen
`Miller
`
`Digitally signed by Stephen Miller
`Date: 6/13/2018 02:22:58PM
`GUID: 508da7210002a000609476bbecd040f0
`Comments: ATL for NDA 210455
`
`

`

`QUALITY ASSESSNIENT
`
`ENVIRONNIENTAL
`
`Smmnry: The applicant provided an environmental assessment (EA) fin darunavir, and
`
`chm fin categorical exclusions from EAs for cobic'stat, enmicitabine, and tenofiwir
`
`alafenamide (TAF). FDA determined that darunavir qualifies fin anexchsion in
`
`accordance with 21 CFR 25.3l(a), which is fin actions that do not increase the use of
`
`active moiety. Fortle oflier three substances,
`
`the applicant claimed exclusions in
`
`accordance with 21 CFR 25.3l(b), which is fin actions that increase the use of the active
`
`neiety, but fin which the estimated concentration of the substance at the point of entry
`
`into the aquatic environnent—the expected introduction concentration (EIC)—will be
`
`below 1 part per billion (1 ppb). The required statenent of no extraordinary
`
`circunstances was included fin the latter three substances, and was inferred fin
`
`darunavir. The chins fin an exclusion from an EA are acceptable.
`
`R
`
`Regional Information
`
`Environmental
`
`The appl'eant provided an enviromiental assessnent (EA) fin darunavir, and chins fin
`
`categorical exclusiors from EAs fin cobic'stat, eniricitabine, and tenofiwir ahfe-mide
`
`(TAF). For darunavir,
`
`the applicant provided anEA with an EIC of
`
`(moppb, chiming
`
`that the EA illustrated how this substance would not result in a sigiifeant environnental
`
`inpact. Both the EA and EIC are the sane as what was s1bmitted fin NDA 205395. Both
`
`EAs refiar to the orighnl EA fin fliis substance, under NDA 021976. During the FDA
`reviews of the earlier EAs—under NDAs 205395 and 021976—FDA had determined that
`
`darunavir woukl not result in a significant inpact on the environment. The FDA review
`
`fin NDA 205395 also involved additional confirntory analys's.
`
`Forthe oflier three substances—cobic'stat, emtlicitabine, and TAF—the applicant
`
`submitted chins fin categorical exchsions from EAs in accordance with 21 CFR
`
`25.31(b), which 's fin actiors that increase the use of the active moiety, but fin which the
`
`estimated concentration of the substance at the point of entry into the aquatic
`
`envionnent—the expected introduction concentration (EIC)—will be below 1 part per
`
`billion (1 ppb). Exclusion chins for these substances ako have been examined in sone
`
`detail in previous NDAs, ie., NDAs 205395 and 203100 fin cobic'stat, NDA 021752/S-
`
`055 fin emtricitabine, and NDA 210251 fin tenofiwir (the active 1miety of TAF). The
`
`required statenent of no extraordinary circumstances was included fin these substances.
`
`Reviewer’s Assessment: Mdequate/Inadequate}
`
`For darunavir, a categor'eal exchsion from an BA in accordance wih 21 CFR
`2531(3), which is fin actions fliat do not increase the use of active nniety,
`is more
`
`OPQ-XOPQ-TEM-OOOIVOS
`
`Page 1 of 2
`
`Eflective Date: October 15, 2017
`
`

`

`QUALITY ASSESSNIENT
`
`appropriate than an EA because of the no increased use and the ex'sting EA The
`requied statermnt ofno extraordilary cicun‘stances, per 21 CFR 25.l5(a) and (c), is
`interred due to the submsion of anEA and the claim ofno significant environImntal
`impact. For cob'xfstat, enlrbitabine, and TAF, no indbation ofpotenti