CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`208341Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`
`

`

`QUALITY ASSESSNIENT
`
`Recommendation: Approval
`
`NDA 208341
`
`Review 2
`
`_—
`
`_
`___
`
`SUBMISSION S REVIEWED
`
`DOCUMENT DATE
`
`DISCIPLINE S AFFECTED
`
`Presubmission
`
`09-Oct-2015
`
`Presubmission
`
`Original
`Amendment
`
`Amendment
`
`Amendment
`
`Amendment
`Amendment
`Amendment
`
`28-Oct-2015
`06-Jan-2016
`
`05-Feb-2016
`
`23-Mar-2016
`
`13-Apr-2016
`08—Jun-2016
`15-Jun-2016
`
`Original
`Amendment
`
`Amendment
`
`Amendment
`
`Amendment
`Labeling
`
`Quali Review Team
`
`Amendment
`
`
`Substance
`
`Chandramouli
`
`-- "mm
`-_‘““"‘S““2
`w— ”mm“
`-_'“°“S“““‘
`
`OPQ-XOPQ-TEM—0001v02 Effective Date: 13 Mar 2015
`
`

`

`CHENIISTRY REVIEW
`
`Table of Contents
`
`Table of Contents .................................................................................................. 2
`
`Quality Review Data Sheet................................................................................... 3
`
`Executive Summary .............................................................................................. 5
`
`Primary Quality Review ....................................................................................... 9
`
`ASSESSMENT OF THE DRUG SUBSTANCE .........................................................................9
`
`2.3.5
`
`DRUG SUBSTANCE: .......................................................................................9
`
`ASSESSMENT OF THE DRUG PRODUCT ............................................................................ 59
`
`2.3.P
`
`DRUG PRODUCT ........................................................................................... 59
`
`R2
`
`Comparability Protocols ...................................................................................95
`
`ASSESSMENT OF THE PROCESS ..........................................................................................96
`
`2.3.P
`
`DRUG PRODUCT ...........................................................................................96
`
`ASSESSMENT OF THE FACILITIES .................................................................................... 116
`
`2.3.5
`
`2.3.P
`
`DRUG SUBSTANCE .................................................................................... 116
`
`DRUG PRODUCT ......................................................................................... 121
`
`ASSESSMENT OF THE BIOPHARMACEUTICS ................................................................ 128
`
`ASSESSMENT OF MICROBIOLOGY ................................................................................... 144
`
`ASSESSMENT OF ENVIRONMENTAL ANALYSIS .......................................................... 145
`
`I.
`
`Review of Common Technical Document-Quality (Ctd-Q) Module 1 ........................ 146
`
`Labeling & Package Insert ........................................................................................................ 146
`
`II.
`
`III.
`
`List of Deficiencies To Be Communicated ................................................................... 157
`
`Attachments .................................................................................................................. 158
`
`2
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`OPQ-XOPQ-TEM—0001V02
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`m
`
`CHEMISTRY REVIEW
`
`_._..._._..
`
`Quality Review Data Sheet
`
`1. RELATED/SUPPORTING DOCUNIENTS:
`
`A. DMFs:
`
`HOLDER
`
`ITEM REFERENCED
`
`2
`
`STATUS
`
`DATE REVIEW
`COMPLETED
`
`COMMENTS
`
`3/17/16HI
`
`Ade
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`
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`
`de
`
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`
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`3/17/16
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`3/17/16
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`
`de
`
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`
`3/17/16
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`3/17/16
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`Ade uate.
`.0
`
`3/ 17/16
`
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`
`.te.
`te.
`
`/l7/l6
`/17/l6
`
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`
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`E
`
`3/17/16
`
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`
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`E
`
`3/17/16
`
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`Ade te
`Ade .te
`Ade
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`
`/17/l6
`/l7/16
`/17/16
`/17/16
`
`Ade
`
`te
`“E
`
`3/17/16
`
`OPQ-XOPQ-TEM-0001v02
`
`Effective Date: 13 Mar 2015
`
`

`

`mmo—nlwum
`
`m4
`
`111
`
`CHENIISTRY REVIEW
`mmmmtmnum
`
`
`m4)
`
`Adequate
`
`
`
`3/ 1 7/ 1 6
`
`
`B. Other Documents: IND, RLD, or sister applications
`
`
`DOCUMENT
`APPLICATION NUMBER
`DESCRIPTION
`
`1ND 118605
`
`2. CONSULTS:
`
`Sofosbuvir & Valpatasvir studies
`
`DISCIPLINE
`
`Biostatistics
`
`RECOMMENDATION
`
`DATE
`
`Clinical _
`
`_
`
`___
`
`Pharmacology/Toxicology
`
`Separate review
`
`CDRH
`
`4
`
`OPQ-XOPQ-TEM—OOOIVOZ
`
`Effective Date: 13 Mar 2015
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`

`

`CHENIISTRY REVIEW
`
`1.
`
`Recommendations
`
`Executive Summary
`
`A. Recommendation and Conclusion on Approvability
`All manufacturing facilities have now been determined to be in acceptable status. From
`the Product Quality perspective, NDA 208341 is recommended for approval.
`
`Labeling recommendations from the Product Quality perspective have been provided to
`the 0ND PM, and were considered during final labeling. All labels and labeling remain
`acceptable from the Product Quality perspective.
`
`1. Summary of Complete Response issues: NA
`2. Action letter language, related to critical issues such as expiration date: We also
`acknowledge receipt of information related to Epclusa (sofosbuvir and
`valpatasvir) 400mg/100mg fixed—dose combination tablet for your Gilead Access
`Program that was reviewed as part of this application.
`3. Benefit/Risk Considerations: Evaluation of the quality aspects of Epclusa tablets
`supports approval without consideration of specific benefit/risk aspects. This is a
`solid-oral dosage form with conventional packaging and simple dosing
`recommendations.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable NA
`
`11.
`
`Summary of Quality Assessments
`
`A. Velpatasvir Drug Substance - Quality Summary
`1. Chemical Name or IUPAC Name/Structure: Velpatasvir, Methyl {(1R)—2-
`[(25,453—2-(5- {2—[(2S,5S)—1-{(2S)-2-[(methoxycarbonyl)amino]-3-
`methylbutanoyl} -5-methylpyrrolidin-2-yl] - 1 , 1 1 -
`dihydro[2]benzopyrano[4',3':6,7]naphtho[l,2-d]imidazol—9—yl}-1H—imidazol-2-
`yl)—4-(methoxymethyl)pyrrolidin— 1 -yl]-2-oxo- 1 -phenylethyl} carbamate
`
`
`
`H .co —5
`
`OCH3
`
`2. Properties/CQAs Relevant to Drug Product Quality
`m4) and has
`Velpatasvir is
`M“). The material is
`no defined melting point. Identity and purity are the CQAs and physical attributes
`are not important.
`
`5
`
`OPQ-XOPQ-TEM—0001v02
`
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`

`

`CHEMISTRY REVIEW
`3. List of startin materials:
`
`
`
`liers of starting materials (site): Each starting material has been sourced from
`different suppliers and must conform to specification. Each drug substance
`manufacturing site qualifies the suppliers of the regulatory starting materials using
`their vendor qualification
`ocedures.
`
`4.
`
`
`
`5.
`
`6. Process
`
`a. Non-sterile” process. In addition to specifications for
`
`mtermediates and the drug substance, there are
`, 1so
`startin materr
`in-process controls.
`b. Critical equi ment: None
`
`7. Container Closure:
`
`
`
`-month when stored
`
`8. Retest Period & Stora Conditions
`
`
`A. Sofosbuvir Drug Substance - Quality Summary
`1. USAN: Sofosbuvir, Gilead Code Number: GS-7977
`2. The data for this drug substance has been reviewed and found acceptable in the
`previously approved NDA204671.
`3. Retest Period & Storage Conditions. The stabili data for sofosbuvir
`
`recommended eereee condition0H
`- with a retest period of. months.
`
`rts a
`
`B. Drug Product - Quality Summary
`1. Strength: Sofosbuvir 400 mg and velpatasvir 100 mg
`2. Description/Commercial Image: Pink (or red for the Access version) diamond-
`shaped film-coated tablets debossed with GSI on one side and 7916 on the other.
`3. S
`
`'
`
`. The specification includes tests for appearance,
`identity (by HPLC retention time and UV), assay -% for both actives),
`degradants, content uniformity (USP <905>), dissolution, and microbial limits
`and is acceptable. The analytical methods are described in reasonable detail and
`have been validated Satisfactory batch analyses are provided for 16 batches.
`Twelve months of data obtained at 25°C/60% RH and 30°C/75% RH and 6
`
`months of data obtained at 40°C/75% RH are provided for 3 batches of more than
`
`6
`
`OPQ-XOPQ-TEM-0001v02
`
`Effective Date: 13 Mar 2015
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`

`

`CHENIISTRY REVIEW
`
`33% of the planned commercial scale. Supporting stability data are provided for 9
`other batches. There are no out of specification results and no trends are observed.
`No changes were observed in the light cabinet. There is no routine testin for
`mu) but a limited drug product stress test showed
`a” 4)
`even
`
`M“)
`under stress conditions. Stability studies have been carried out where
`is used to make batches of tablets. The stability behavior of such batches is no
`different from batches made using
`M“). Eventually an end to end study
`using
`(m4) will be conducted to qualify a (‘2; month shelf life for the
`(b) (4)
`
`4. List of Excipients: copovidone, croscarmellose sodilun, magnesium stearate,
`microcrystalline cellulose. The fihn coats contain iron oxide red,(
`mm)
`in Access tablet only), polyethylene glycol m4) polyvinyl alcohol, talc,
`and titanium dioxide.
`
`5. Process Selection (Unit Operations Summary)
`a.
`
`4
`GM )
`
`b. Proven acceptable range (PAR) and target value for various process
`parameters are provided in the submission based on DOE and other
`studies.
`
`c. Hold times have adequate support, including on—going studies (as
`
`amended) for the
`typical for this dosage form.
`proposed and adequately supported by studies.
`d. Critical equipment.
`6. Container Closure. The tablets are packaged 28 count in 75 mL HDPE bottles
`containing a polyester D"’ coil. The bottles are closed with induction seals and
`child-resistant closures.
`
`M“).In-process controls are acceptableSand
`”mi
`
`(II) (4)
`
`7. Expiration Date & Storage Conditions: The expiration dating period is 24 months
`with the storage statement of “Store below 30°C”. The expiration dating period
`begins when
`m4).
`8. List of co-packaged components: None
`
`C. Summary of Drug Product Intended Use
`
`Proprietary Name of the Drug Product
`
`Non Proprietary Name of the Drug Product
`
`Sofosbuvir and Vel atasvir
`
`Non Proprietary Name of the Drug Substance
`PI‘OPosed Indicationfi) including Intended
`
`Sofosbuvir and Velpatasvil'
`Treatment of chronic infection with the
`
`100 m of velatasvir .er da
`
`Patient Population
`
`He atitis C virus
`
`Maximum Daily D059
`
`1 tablet/day (400 mg of sofosbuvir and
`
`7
`
`OPQ-XOPQ-TEM-0001v02
`
`Effective Date: 13 Mar 2015
`
`

`

`
`'"fl‘
`CHEMISTRY REVIEW
`
`Alternative Methods «Administration
`
`D. Biopharmaceutics Considerations
`1. BCS Classification:
`
`0 Drug Substance: SOF (Class H1); VEL (Class IV)
`
`0 Drug Product: With the proposed dissolution method, the drug product
`dissolves relatively fast but it cannot be categorized to rapidly dissolving
`or very rapidly dissolving drug product since one of the two APIs
`belongs to BCS Class IV. Cuuent dissolution acceptance criterion is Q =
`'% at 20 minutes for both SOF and VEL.
`
`2. Biowaivers/Biostudies
`
`o Biowaiver Requests: N/A
`0 PK studies: N/A
`
`0
`
`IVIVC : N/A
`
`E. Novel Approaches
`
`F. Any Special Product Quality Labeling Recommendations
`
`None
`
`G. Life Cycle Knowledge Information (see Attachment A)
`
`OVERALL ASSESSMENT AND SIGNATURES: EXECUTIVE SUNINIARY
`
` 8
`
`Effective Date: 13 Mar 2015
`
`OPQ-XOPQ-TEM-OOOIVOZ
`
`

`

`QUALITY ASSESSMENT
`
`ASSESSMENT OF THE BIOPHARNIACEUTICS
`
`18. Are the in-vitro dissolution test and acceptance criteria adequate for assuring quality
`control and consistent bioavailability of the drug product?
`
`The drug product SofosbuvirNelpatasvir Fixed-Dose Combination Tablet (400 mg/ 100
`mg) is developed to provide treatment to chronic hepatitis C virus (HCV) infection in
`adults. The drug product contains two drug substances: Sofosbuvir (SOF) and
`Velpatasvir (VEL). The SOF belongs to BCS Class III in crystalline form
`has high solubility (Table 1). The VEL belongs to BCS Class IV and it is
`free base. Table 2 shows the solubility of the VEL.
`
`mm and
`w“)
`0)“)
`
`The drug product is fonnulated as film-coated tablet with immediate release of both
`active ingredients.
`
`Table 1. SOF solubility at 37 °C
`pH (Media)
`Solubility(mgImL)
`
`1.21 (HCI)
`1.3
`
`2.0 (HCI)
`
`4.5 (Acetate Buffer)
`
`6.8 (Phosphate Buffer)
`
`5.0 (FeSSIF)
`
`
`
`
`2.0
`
`2.1
`
`3.6
`
`1.8
`
`6.5 (FaSSIF)
`
`2.1
`
`“M"
`Table 2. VEL solubility at 37 °C,
`W Solublllty(mgImL)
`
`l.2 (HCI)
`> 36
`
`2 (HCI)
`4.5 (Acetate Butter)
`
`4.1
`< 0.1
`
`
`
`5.0 (Acetate Butter)
`< 0.1
`
`6.8 (Phosphate Butter)
`< 0.1
`5.0 (FeSSIF)
`0.3
`
`6.5 (FaSSIF)
`
`< 0.1
`
`128
`
`OPQ-XOPQ-TEM—0001V02
`
`Effective Date: 13 Mar 2015
`
`

`

`
`
`Dissolution Method
`
`The proposed dissolution method is summarized in Table 3.
`
`Table 3. Proposed dissolution method
`
`Parameter
`
`Apparatus
`
`Volume
`
`Paddle Speed
`
`Medium pH
`Buffer and Concentration
`
`Setting
`
`USP Dissolution Apparatus 2 (paddle method)
`
`900 mL
`
`75 rpm
`
`5.0
`50 mM sodium acetate
`
`
`
`Surfactant and Concentration 0.5% w/v cetyl tn‘methyiammonium bromide (CTAB)
`
`Dissolution Method Development
`
`OPQ-XOPQ--TEM-0001v02
`
`Effective Date: 13 Mar 2015
`
`

`

`QUALITY ASSESSNIENT
`
`clinical studies (e. g. l4SXG001UR, l4SXG002UR and 14SXGOO3UR). There are no
`batches presented by the Applicant showing different in vivo performance and tested in
`vitro by the proposed dissolution method. It is not feasible to establish the biopredictive
`power of the proposed dissolution method.
`
`Reviewer’s Assessment: The Applicant claimed that the dissolutions of both drug
`substances are limited by the
`W4)
`
`D) (4)
`
`This is reasonable because the DP is formulated as immediate release drug and both
`APIs have high solubility in the proposed dissolution medium. The Applicant
`provided data demonstrating that the proposed dissolution method has
`discriminating capability against these two factors. The Applicant also conducted
`
`studies on the impact of variations of some of the CPPs and CMAs on dissolution.
`Results show the proposed dissolution method does not have discriminating
`capability against the studied CPPs in the PARs and CMAs including
`
`"’""
`
`Lacking
`of discriminating capability against the above parameters is not critical issue for the
`proposed dissolution method since the manufacturing process will be operated
`within PARS. In addition, the proposed in-process testing ensures the quality of
`(me. There is no available data to establish the
`
`biopredictive power of the proposed dissolution method. It is noted that the
`dissolution method discriminates for batches manufactured at
`
`Dissolution Acceptance Criterion
`The originally proposed dissolution criterion for both components was NLT 33% (Q)
`dissolved at 20 minutes. Figure 10 shows the dissolution profiles from 13 clinical and
`clinical stability batches. Obviously, the originally proposed dissolution acceptance
`criterion is too permissive as at 20 minutes, both dissolved PAIs are close to 83%.
`During the review cycle, the Applicant was asked to tighten the dissolution acceptance
`criterion based on the available relevant data. The Applicant agreed to tighten the
`acceptance criterion to Q: 8% at 20 minutes. According to the Applicant, this newly
`proposed dissolution acceptance criterion would pass batch 14SXGOOIUR while
`maintaining appropriate discriminatory capability for routine quality control testing of
`SOF/VEL tablets. Batch l4SXG001UR was used in pivotal Phase 3 clinical studies for
`efficacy but as shown in Figure 10, it has
`M“) compared to
`the other clinical batches. The Applicant was asked to explain how the manufacturing
`conditions of
`M“) of batch l4SXG001UR
`
`as claimed resulted in its
`
`“W". According to the Applicant
`
`139
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`OPQ-XOPQ-TEM—OOOIVOZ
`
`Effective Date: 13 Mar 2015
`
`

`

`QUALITY ASSESSNHENT
`
`(response to IR received on 01/06/2016), the phenomena could be reproduced in the
`development investigational study. However, the exact mechanism remained unclear.
`According to the Applicant, this particular batch did not behave differently in vivo. Its
`dissolution profile sets the lowest dissolution limit for the future batches. As mentioned
`by the process reviewer, Ying Wang above, Applicant’s studies results demonstrated that
`
`within intended commercial production rate range- tablets per minutei the
`
`tablet dissolution rates are similar and all meet the s ecification regardless of the
`
`. Batch l4SXGOOlUR was
`
`. Thus, the proposed range of
`
`
`production rate of the commercial manufacturing process excludes the ossibility of
`
`seeing batch similar to batch l4SXGOOlUR, which has‘.
`
`Figure 10. Sofosbuvir and Velpatasvir dissolution profiles from SOF/VEL clinical and
`clinical stability batches
`
`“I?
`
`.30
`
`8 B
`
`
`
`"/oSofosbuvu'Dissolved(+/SD) D
`
`D
`
`10
`
`20
`
`an
`
`40
`
`E)
`
`on
`
`Tim (min)
`
`
`
`
`
`
`%VblpatasvirDissolved(+/-SD).assssa
`
`Reviewer’s Assessment: As mentioned above, the biopharmaceutics review team
`recommended an acceptance criterion that rejects a batch (Lot l4SXG001UR) with
`. Although this batch was tested in clinical trials, the dissolution
`
`on the
`
`than the other two clinical trial batches il4SXG002UR
`profile is
`and 14SXG003UR, Fig 10). Thus, the impact ofiotentially
`
`profile of some batches was
`efficacy of the drug product resulting from
`discussed with the Clinical harmacolo 3 review team via email. It was
`
`140
`
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`
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`
`

`

`
`
`19. Are the changes in the formulation, manufacturing process, manufacturing sites during
`the development appropriately bridged to the commercial product?
`
`The proposed commercial formulation is the same as that used in the clinical studies.
`Clinical manufacturing and commercial manufacturing have similar processes.
`
`There are two proposed commercial manufacturing sites: GSIUC and—. The
`same manufacturing process will be applied at both sites. Dissolution data from
`
`representative drui product lots lSSXGOOlUR and DUI506B manufactured at GSIUC
`
`, respectively are shown in Figure 1 1 and thef2 analyses are
`and at
`summarized in Table 6 and Table 7. Data demonstrate that the two proposed
`commercial manufactrn‘ing sites have similar drug products.
`
`Figure 11. Sofosbuvir and Velpatasvir Dissolution Profiles fiom SOF/VEL Tablets Lot
`lSSXGOOlUR (GSIUC) and Lot DU1506B_)
`
`141
`
`OPQ-XOPQ-TEM-0001v02
`
`Eflecfive Date: 13 Mar 2015
`
`

`

`mama-arm...“
`
`QUALITY ASSESSMENT
`
`ummuim-m
`
`é
`
`g 80A
`E
`5 so
`fl'0
`9'a
`E 40mm
`.5r,_ 20
`O:1:
`9\° o
`
`
`
`- -o - lSSXGWIURtGSIUC)
`+ 0015058 1
`(b) (4)
`
`0
`
`
`1o
`20
`30
`40
`50
`50
`Time (min)
`
`- -o — Issxcomun (GSIUC)
`—0— DU15068
`0|) (4)
`
`
`
`
`
`u
`
`
`10
`20
`30
`w
`50
`50
`Time (min)
`
`100
`
`.5 80
`
`g
`1:5
`i an
`t‘
`32‘_ 40
`2ll:
`
`5 E
`
`S 20>
`'9“?
`
`Table 6. Sofosbuvir Dissolution Data Used inf2 Analysis for Tablets from Each
`Manufacturing Site
`
`Time (mil)
`
`0115061;
`M (4)
`
`Table 7. Sofosbuvir Dissolution Data Used in 12 Analysis for Tablets from Each
`Manufactming Site
`
`Tim:- (min)
`
`
`
`Dr 15063
`(It) (4)
`
`142
`
`OPQ-XOPQ-TEM—OOOIVOZ
`
`Effective Date: 13 Mar 2015
`
`

`

`QUALITY ASSESSMENT
`
`Reviewer’s Assessment: The two proposed commercial DP manufacturing sites are
`
`adequately bridged with provided dissolution data and f2 analyses.
`
`OVERALL ASSESSMENT AND SIGNATURES: BIOPHARMACEUTICS
`
`Reviewer’s Assessment and Signature: ADEQUATE.
`
`The Applicant conducted a comprehensive dissolution method development to
`identify the appropriate dissolution apparatus, dissolution medium and volume,
`surfactant type and concentration, paddle rotation speed,
`(m4) etc. The
`Applicant tightened the originally proposed dissolution acceptance criterion. The
`newly proposed dissolution acceptance criterion is supported by the dissolution data
`of batches tested in pivotal phase 3 clinical trials. Based on our discussion with the
`process reviewer, the risk in manufacturing batches with
`(hm)
`has been mitigated by the
`implementation of appropriate controls. The dissolution specifications shown in the
`table below are deemed acceptable.
`
`Medium
`
`USP Dissolution Apparatus 2 (Paddle Method)
`
`75 1pm
`50 nM sodilun acetate at pH 5.0 with 0.5% w/V
`C TAB
`
`(m4)
`
`Medium Volume
`
`900 mL
`
`Acce u tance Criteria
`
`5, 10, 20, 30 and 45 minutes
`Q = 23% at 20 minutes for both SOF and VEL
`
`The drug product is formulated as immediate release tablet with high solubility of
`the two APIs in the proposed dissolution medium. The proposed dissolution method
`has discriminating ability against the
`(m4)
`are the two factors that have direct impact on the
`. The method does not have discriminating ability against
`some CPPs (within PARS) and CMAs such as
`W"
`
`(b) (4)
`
`Lacking of discriminating capability against the above parameters is not
`critical issue for the proposed dissolution method since the manufacturing process
`will be operated within PARS. In addition, the proposed in-process testing ensures
`the quality of
`M“).
`It is worth mentioning that the
`dissolution method discriminates for batches manufactured at the
`
`143
`
`OPQ-XOPQ-TEM-OOO 1 V02
`
`Effective Date: 13 Mar 2015
`
`

`

`QUALITY ASSESSMENT
`
`There are no formulation and process changes for the to-be-market drug product.
`Data provided demonstrated the similarity of the two proposed commercial drug
`product manufacturing sites.
`
`NDA 208341 (Sofosbuvir/Velpatasvir Fixed-Dose Combination Tablet (400 mg/100
`mg» isW from a Biopharmaceutics
`perspective.
`
`Ge Bai, Ph.D., 02/29/2016
`Biopharmaceutics Reviewer
`Office of New Drug Product
`Division of Biophannaceutics
`
`Division of Biopharmaceutics
`
`Secondary Review Comments and Concurrence:
`
`I concur with the primary reviewer’s assessment of the biopharmaceutics section.
`Sandra Suarez Sharp, Ph.D., 03/02/2016
`Biophannaceutics Reviewer
`Office of New Drug Product
`
`To assure drug product safety and confirm no microbial contamination dining drug product
`manufactluing, microbial examination will be conducted. Testing will be perfonned at release
`and at the beginning and end of shelf—life for the first three commercial and annual commitment
`lots of drug product (Section
`). The acceptance criteria established according to
`haimouized pharmacopoeial monographs USP <1 1 l l> and Ph. Emu 5.1.4 will be applied.
`
`Reviewer’s Assessment: Adequate
`
`The proposed microbial test is adequate for solid oral dosage form.
`
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`QUALITY ASSESSNIENT
`
`OVERALL ASSESSMENT AND SIGNATURES: MICROBIOLOGY
`
`Reviewer’s Assessment and Si
`
`ature: Recommended for approval from
`
`microbiology perspective
`
`Ying Wang, Ph.D.
`2/17/2016
`
`02/25/2016
`
`Secondag Review Comments and Concurrence:
`
`I concur.
`
`Upinder Atwal, Ph.D.
`Acting Branch Chief
`DPA I/Branch III
`
`The applicant requests a categorical exclusion fi‘om the requirements to prepare an
`environmental assessment imder 21 CFR 25.31(b) on the grounds that the expected introduction
`concentration of sofosbuvir and velpatasvir at the point of entry into the aquatic environment,
`(hm) ppb and mm ppb, respectively,
`is less than 1 pait per billion. The sofosbuvir value takes
`into account the other sofosbuvir-containing formulations, Sovaldi and Hawoni. To the
`applicant’s knowledge no extraordinaiy circumstances exist.
`
`Reviewer’s Assessment: Adequate. The claim is reasonable and should be accepted. In
`
`an e-mail of 3/4/16 James Laurenson, ONDP concurs. There are no hormonal effects in
`
`mammalian species, even at very high doses relative to the EICs.
`
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`
`
`OVERALL ASSESSMENT AND SIGNATURES: ENVIRONMENTAL
`
`
`
`I. Review of Common Technical Document-Quality (Ctd—Q) Module 1
`
`Labeling & Package Insert
`
`1. Package Insert
`
`(a) “Highlights” Section (21CFR 201.57(a))
`
`
`
`DOSAGE FORMS AND STRENGTHSu-m—__...._
`
`Tablets: 400 mg sofosbuvir and 100 mg velpatasvir
`
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`QUALITY ASSESSNIENT
`
`Information
`Provided in NBA
`
`Reviewer’s Assessment
`
`Product title, Drug name (201.57(a)(2))
`Proprietary name and EpclusaTM
`established name
`(sofosbuvir and
`velpatasvir) tablets.
`for oral use
`
`Dosage form. route
`of administration
`
`Tablets. oral
`
`Controlled drug
`substance symbol (if
`a . :licable
`
`
`Conclusion: Adequate
`
`A concise sunnnary
`of dosage forms and
`stren - hs
`
`Tablets: 400 mg
`sofosbuvir and 100
`m- vel - atasvir
`
`Adequate
`
`Conclusion: Adequate.
`
`(b) “Full Prescribing Information” Section
`
`# 3: Dosage Forms and Strengths 121CFR 201.57gqg4n
`
`_ Information Provided in NBA
`Available dosage forms
`
`vel . atasvnr
`
`A description of the identifying Pink. diamond-shaped. fihn-coated
`characteristics of the dosage
`tablets. debossed with “G81“ on one
`forms. including shape. color.
`side and “79 16“ on the other side
`coating. scoring. and
`imu-rintin . when a u . licable.
`
`Adequate
`
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`

`QUALITY ASSESSMENT
`
`#11: Description ngCFR 201.57gc1112n
`
`Epclusa is a fixed-dose combination tablet containing sofosbuvir and velpatasvir for oral
`administration. Sofosbuvir is a nucleotide analog inhibitor of HCV NSSB polymerase and
`velpatasvir is an NSSA inhibitor.
`
`Each tablet contains 400 mg sofosbuvir and 100 mg velpatasvir. The tablets include the
`following inactive ingredients: copovidone. croscarmellose sodium. magnesium stearate,
`and microcrystalline cellulose. The tablets are film-coated with a coating material
`containing the following inactive ingredients: iron oxide red, polyethylene glycol,
`polyvinyl alcohol. talc, and titanium dioxide.
`
`Sofosbufir: The IUPAC name for sofosbuvir is (S)-Isopropyl 2-((S)-(((2R,3R.4R.5R)—5-
`(2.4-dioxo-3.4-dihydropyrimidin—l(2H)-yl)-4-fluoro-3 -hydroxy-4-methyltetrahydrofuran-
`2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate. It has a molecular formula of
`C22H29FN309P and a molecular weight of 529.45. It has the following structural formula:
`
`H
`N
`
`0
`
`>.o
`o
`o
`NFLZU
`©/
`HOF
`
`o
`
`Sofosbuvir is a white to ofl‘-white crystalline solid with a solubility of at least 2 mg/mL
`across the pH range of 2—7.7 at 37°C and is slightly soluble in water.
`
`Velpatasvir: The IUPAC name for velpatasvir is Methyl {(1R)-2-[(2S,4S)-2-(5-{2-
`[(ZS,SS)-l-{(25)—2-[(methoxycarbonyl)amino]—3-methylbutanoyl}-5-methylpyrrolidin—2-
`yl]- l ,1 1-dihydro[2]benzopyrano[4',3':6,7]naphtho[1.2-djimidazol-9-yl}-lH-imidazol-2-
`yl)—4—(methoxymethyl)pyrrolidin—l-yl]-2-oxo—l-phenylethyl}carbamate. It has a
`molecular formula of C49Hs4N308 and a molecular weight of 883.0. It has the following
`structural formula:
`
`Velpatasvir is practically insoluble (less than 0.1 mg/mL) above pH 5, slightly soluble
`(3.6 mg/mL) at pH 2, and soluble (greater than 36 mg/mL) at pH 1.2.
`
`_ Information Provided in NBA
`
`148
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`Effective Date: 13 Mar 2015
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`

`QUALITY ASSESSMENT
`
`Proprietary name and estabhshed
`name
`WWW
`" tion
`
`Epclusa ‘V' (sofosbuvir and
`vel tasvir tablets, for oral use
`
`NA
`
`Active moiety expression of
`strength with equivalence statement
`for salt if a y - licable
`The tablets include the
`Inactive ingredient information
`following inactive ingredients:
`(quantitative, if injectables
`21CFR201.100(b)(5)(iii)), listed by copovidone, croscarmellose
`USP/NF names.
`sodium, magnesium steaiate, and
`microcrystalline cellulose. The
`tablets are film-coated with a
`
`. y I licable
`Pharmcological/ therapeutic class
`
`coating material containing the
`following inactive ingredients:
`iron oxide red, polyethylene
`glycol, polyvinyl alcohol, talc, and
`titanium dioxide.
`
`Sofosbuvir is a nucleotide analog
`inhibitor of HCV NSSB
`
`polymerase and velpatasvir is an
`NSSA inhibitor.
`
`Chemical name, structural formula, Sofosbuvir: The IUPAC name for
`molecular weight
`sofosbuvir is (S)-Isopropyl 2—((S)-
`(((2R,3R,4R, 5R)-5-(2,4—dioxo-
`3,4-dihydropyrimidin—l (2H)-yl)—4-
`fluoro-3-hydroxy-4-
`methyltetrahydrofinan-Z-
`yl)mefl10xy)-
`(phonoxy)phosphorylamino)propa
`noate. It has a molecular weight of
`529.45. It has the following
`
`
`
`Velpatasvir: The IUPAC name for
`velpatasvir is Methyl {(1R)-2-
`[(28,4S)-2-(5-{2-[(ZS,SS)-l-
`{(28-2-
`[(methoxycarbonyl)amino]-3-
`methylbutanoyl} -5-
`methylpyrrolidin—Z-yl]-l ,l l-
`dihydro[2]benzopyrano[4',3‘:6,7]n
`
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`
`

`

`(methoxymethyl)pyrrolidin-l -yl]-
`2-oxo-l-phenylethyl} carbamate. It
`has a molecular weight of 883.0.
`It has the following structural
`
`mg/mL) at pH 1.2.
`
`Other important chemical or
`physical properties (such as pKa,
`
`Sofosbuvir is a white to ofi-white
`
`crystalline solid with a solubility
`of at least 2 mg/mL across the pH
`range of 2—7.7 at 370C and is
`slightly soluble in water.
`Velpatasvir is practically insoluble
`(less than 0.1 mg/mL) above pH 5,
`slightly soluble (3.6 mg/mL) at pH
`2, and soluble (greater than 36
`
`#16: How Supplied/Storage and Handling 121CFR 201.57“! 12!!
`
`Each EPCLUSA tablet contains 400 mg of sofosbuvir and 100 mg of velpatasvir, is pink,
`diamond-shaped, film-coated, debossed with “GSI” on one side and “7916” on the other. Each
`bottle contains 28 tablets (NDC 61958-2201-1), polyester coil, and is closed with a child
`resistant closure.
`
`Store below 30 °C (86 °F). Dispense only in original container.
`
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`
`

`

`QUALITY ASSESSNIENT
`
`_ Information Provided in NBA
`
`sofosbuvir and 100 m vel atasvir.
`
`100 tablets
`
`Identification of dosage forms. Pink. diamond-shaped. film-coated
`e.g.. shape. color. coating.
`tablets. debossed with “681" on one
`scoring. imprinting. NDC
`side and “7916“ on the other side
`number
`
`Adequate
`
`Special handling (e. g.. protect Dispense onlyin original container
`from li-
`t. do not freeze
`
`Adequate
`
`Store below 30 °C 86°F
`Conclusion: Adequate
`
`Manufactuner/distributor name listed at the end of P13 following Section #17
`
`_—
`Manufacturer/distributor name (21 Manufactured and distributed by:
`Adequate
`CFR 201.1)
`Gilead Sciences. Inc.
`Foster Ci
`. CA 94404
`
`2. Container and Carton Labeling
`
`1) Immediate Container Label
`
`The US container label is as follows.
`
`1 5 l
`
`OPQ-XOPQ-TEM—OOO l v02
`
`Effective Date: 13 Mar 201 5
`
`

`

`QUALITY ASSESSMENT
`
`Efifective Date: 13 Mar 2015
`
`The Access container label is as follows.
`
`OPQ-XOPQ-TEM-0001v02
`
`

`

`QUALITY ASSESSMENT
`
`
`
`Reviewer's Assessment: Adequate.
`
`153
`
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`
`Efi'ective Date: 13 Mar 2015
`
`

`

`QUALITY ASSESSNIENT
`
`Comments on the Information Providedin
`NDA
`
`loprietary name,
`- stablished name (font
`. ize and prominence (21
`FR 201 . 10(g)(2))
`
`I pclusa
`
`Conclusions
`
`Adequate
`
`' 01. 10(d)(l): 21 .CFR
`v 01 .100(b)(4))
`
`I' oute of administration
`' 1.CFR 201.100(b)(3))
`
`I et contents* (21 CFR
`r 01 .51(a))
`
`I ame of all inactive
`' gredients (; Quantitative
`Ingredient information1S
`
`, lCFR 201.100(b)(5)**
`
`0 ral. Not on container label
`
`8 tablets
`
`Adequate
`
`Adequate
`
`I ot on container label. This is acceptable“
`
`Adequate
`
`Adequate
`
`I ot number per 21 CFR l' esent
`
`Adequate—_
`
`I xpiration date per 21
`FR 201.17
`
`I' esent
`
`v 1 CFR 201.100 0
`
`1
`
`Store below 30°C (86°F) (see insert)
`not I uired
`
`Adequate
`
`I
`
`IC 61958-2201-1
`
`Adequate
`
`I
`
`IC nmnber
`.er 21 CFR 201.2)
`requested, but not
`equired for all labels or
`labeling), also see 21 CFR
`r 07.35(b)(3)
`
`I: ar Code per 21 CFR
`P 01.25(c)(2)***
`
`I' esent
`
`Adequate
`
`I anufactured for: Gilead Sciences, Inc., Foster
`
`*21 CFR 201.51(h) A drug shall be exempt from compliance with the net quantity declaration
`required by this section if it is an ointment labeled “sample”, “physician’s sample”, or a
`substantially similar statement and the contents of the package do not exceed 8 grams
`**For solid oral dosage forms, CDER policy provides for exclusion of “oral” from the container
`label
`
`154
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`

`

`""'"‘"""
`lama;
`
`QUALITY ASSESSMENT
`
`“""""'"‘
`.._....._-_..
`
`Conclusion: Adequate
`
`2) Carton Labeling
`(Carton is for the Access product only; main panels Shown).
`
`
`
`155
`
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`
`Efl'ective Date: 13 Mar 2015
`
`

`

`QUALITY ASSESSNIENT
`
` oprietary name, established
`I ame (font size and
`prominence (FD&C Act
`02(e)(l)(A)(i). FD&C Act
`
`
`
`02(e)(1)(B). 21 CFR
`01.10(g)(2))
`
`
`Comments on the Information Provided in
`>
`
`.
`Conclusnons
`
`Epclusa
`
`A dequate
`
`
`
`
`Strength (21CFR 201 . 10(d)(1);
`, 1.CFR 201 . 100((d)(2))
`
`Sofosbuvir, velpatasvir tablets 400 mg / 100 mg
`
`A dequate
`
`I et contents (21 CFR 201.51(a))
`
`28 tablets
`
`I ot number per 21 CFR
`‘ O p—‘ L_I 00
`
`I xpiration date per 21 CFR
`‘ o p—i :i
`
`I ame of all inactive
`
`' Igredients (except for oral
`gs); Quantitative ingredien
`l ormation is required for
`Ijectables)[ 201.10(a).
`
`I'
`'
`
`, 1CFR201.100(d)(2)]
`
`Sterility Information (if
`» pplicable)
`
`‘Rx only” statement per 21
`FR 201.100(d)(2), FD&C
`A ct 503(b)(4)
`
`Present
`
`E>>EaaE.E.
`
`Storage Conditions
`
`Store below 30°C (86°F)
`
`ON p—i \OLII °I°
`
`-X
`
`I
`
`IC nlunber
`
`
`
`er 21 CFR 201.2)
`requested, but not required
`I or all labels or labeling), also
`ee 21 CFR 207.35(b)(3)
`
`v 01.25(c)(2)**
`
`I ame of
`I anufacturer/distributor
`
`I anufactured for: Gilead Sciences, Inc., Foster
`City, CA 94404. Manufactured by:
`M“)
`
`A dequate
`
`A dequate
`
`A dequate
`
`A dequate
`
`A dequate
`
`A dequate
`
`‘ “1”“
`
`A dequate
`
`‘See package insert for dosage
`I' ormation” (21 CFR 201.55)
`
`
`
`Present
`
`A dequate
`
`(b) ‘3
`
`>EE.(D
`
`156
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`

`

`
`
`I' oute of Administration (not
`I equired for oral, 21 CFR
`I 01.100(d)(1) and (d)(2))
`
`A
`
`Conclusio