CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`208684Orig1s000
`208685Orig1s000
`
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`
`

`

`QUALITY ASSESSNIENT
`
`Recommendation: Approve
`
`NDA 208684
`
`Review # l
`
`Emflaza (deflazacort) tablets
`
`6 mg, 18 mg, 30 mg, and 36 mg
`
`N/A
`
`Rx
`
`Marathon Phannaceuticals
`
`DISCIPLINE
`
`DIVISION/BRANCH
`
`Quality Review Team
`
`Drug Substance
`
`Ray Frankewich
`
`ONDP/DNDP I/Branch I
`
`Drug Product
`
`Microbiology
`
`Process Manager
`
`Andrei Ponta
`
`Mark Johnson
`
`Mark Johnson
`
`Michael Shanks
`
`ONDP/DNDP I/Branch I
`
`OPF/DPA/Branch I
`
`OPF/DPA/Branch I
`
`OPF/DIA/Branch I
`
`Yang Zhao
`
`ONDP/DB/Branchl
`
`
`
`———
`———
`———
`
`OPQ-XOPQ NDA 208684
`
`Page 1 0f 9
`
`Effective Date: 20 April 2016
`
`

`

`QUALITY ASSESSMENT
`
`SUBMISSIONS REVIEWED
`(SD #)
`
`NDA 208684
`
`DOCUMENT DATE
`
`DISCIPLINE(S)
`AFFECTED
`
`Received: 23-Jan—2017
`
`SD#: 0012
`
`SD#: 0014
`
`SD#: 0020
`SD#: 0021
`
`Received: 6-Sep-2016
`
`Drug Product
`
`Received: 11-Nov-2016
`
`Drug Product
`
`Received: 17-Jan-2016
`Received: 17-Jan-2017
`
`Drug Substance. Facilities
`
`(83:62:13): to SD#_ 0022)
`
`Received: 23-Jan-2017
`
`Drug Substance. Drug Product
`
`SD: 0024
`
`OPQ-XOPQ NDA 208684
`
`Page 2 0f 9
`
`Effective Date: 20 April 2016
`
`

`

`QUALITY ASSESSNIENT
`
`NDA 208684
`
`Quality Review Data Sheet
`
`1. RELATED/SUPPORTING DOCUMENTS
`
`Type
`
`Holder
`
`(b)(4) H
`
`
`Item Referenced
`(5) (4)
`
`II
`
`III
`
`HI
`
`III
`
`111
`
`III
`
`HI
`
`III
`
`Status
`
`Adequate
`
`Date Revnew
`Completed
`12/1/2016
`
`Adequate
`
`Comments
`.
`Renewed by M‘
`Cooper
`
`Rew'ewed by R.
`Frankewich for
`
`NDA but supplier
`withdrawn by
`applicant.
`
`N/Al
`
`N/Al
`
`N/A1
`
`N/A1
`
`N/A1
`
`N/Al
`
`N/A1
`
`1 Adequate information in application or no changes to information since previous reviews.
`
`B. Other Documents: IND, RLD, or sister applications
`
`DOCUMENT APPLICATION NUMBER
`
`DESCRIPTION
`
`)(4)
`
`formulation
`
`119258
`
`BA/BE studies to support the current NDAs
`208684 and 208585 for Deflazacort tablets
`
`and oral suspension, respectively
`
`NDA
`
`208685
`
`Application for Deflazacort 208684 tablet
`
`OPQ-XOPQ NDA 208684
`
`Page 3 0f 9
`
`Effective Date: 20 April 2016
`
`

`

`QUALITY ASSESSNIENT
`
`NDA 208684
`
`2. CONSULTS
`
`—_—-—
`—_—-—
`
`—_—-— —_—-—
`
`—_—-—
`
`OPQ-XOPQ NDA 208684
`
`Page 4 0f 9
`
`Effective Date: 20 April 2016
`
`

`

`QUALITY ASSESSNIENT
`
`NDA 208684
`
`Executive Summary
`
`1.
`
`Recommendations and Conclusion on Approvability
`
`The Office of Product Quality (OPQ) review team recommends that the Agency
`Approve NDA 208684 for Emflaza® (deflazacort) tablets. From a quality
`perspective, the application, as amended, provides adequate information to ensure
`that the applicant can consistently manufacture a product that is suitable for use
`by the intended patients.
`
`H.
`
`Summary of Quality Assessments
`
`A. Product Overview
`
`Duchenne muscular dystrophy (DMD) is a rare recessive X—linked disorder that
`results in progressive muscle weakness and loss of muscle mass, loss of
`movement, and ultimately death. The disease is caused by mutations in DMD, the
`gene encoding dystrophin, a sarcolemma protein critical to the structural stability
`of myofibers in skeletal and cardiac muscle. Dystrophin mutations induce a shift
`in the open reading frame of the dystrophin transcript, leading to the absence of
`fimctional dystrophin protein.
`
`One drug, eteplirsen, was approved via the accelerated approval pathway for
`treatment of DMD in September 2016. Use of eteplirsen, an antisense
`oligonucleotide that targets specific DMD mutations, is limited to a small subset
`of patients and there is limited clinical evidence of effectiveness. Otherwise,
`treatment is limited to off-label use of corticosteroids such as prednisone to delay
`loss of muscle strength and supportive measures.
`
`The applicant proposes use of deflazacort, a synthetic glucocorticosteroid
`structurally similar to prednisone and prednisolone, for treatment of patients with
`Duchenne muscular dystrophy. Deflazacort is an acetate ester prodrug; the active
`moiety is the 21-hydroxy metabolite.
`
`
`
`Deflazacort
`
`Prednisone
`
`Prednisolone
`
`OPQ-XOPQ NDA 208684
`
`Page 5 of 9
`
`Effective Date: 20 April 2016
`
`

`

`
`
`QUALITY ASSESSMENT
`
`NDA 208684
`
`Deflazacort was first marketed outside the US, under the trade name Calcort, in
`1982. It is currently available in several countries as tablets or oral
`ion for
`
`treatment of a varie of indications res nsive to
`ucocorticoids.
`
`
`
`Although physicians
`
`
`' one to treat patients with
`cort as an temative to p
`equen y use
`DMD, it is not approved for this indication in any cormtry.
`
`Marathon Pharmaceuticals has developed an immediate release tablet that is
`qualitatively similar to the Calcort tablets marketed by Sanofi-aventis. Under
`NDA 208684, the applicant proposes marketing of tablets containing 6 mg,
`18 mg, 30 mg or 36 mg deflazacort for treatment of DMD.
`
`Proposed Indication(s)
`including Intended Patient
`Population
`
`Treatment ofpatients with Duchenne muscular
`dystrophy. The patient population is expected to
`be males ranging in age from children to young
`adults.
`
`Duration omeunent
`
`Maximum Daily Dose
`
`The recommended dose
`
`routes of administration.
`
`Alternative Methods of
`Administration
`
`Deflazacort tablets may be crushed and mixed
`with applesauce. The mixture should be
`consumed immediately afier preparation.
`
`The applicant proposes an oral suspension under
`NDA 208685. There are no other alternative
`
`B. Quality Assessment Overview
`
`Drug Substance
`
`
`powder that is poorly soluble in water and has a
`Deflazacort is a white
`
`mt
`tween 254°C and 256°C. It is stable in the solid
`relativel hi meltin
`
`
`
`OPQ-XOPQ NDA 208684
`
`Page 6 of 9
`
`Effective Date: 20 April 2016
`
`

`

` QUALITY ASSESSMENT
`
`NDA 208684
`
`
`
`The bulk active '
`'ent AP used to manufacture commercial product will be
`
`s
`lied b
`. Due to its poor solubility, the API is
`
`. Information regarding the
`
`characterization, manufacture, and control of the API is incorporated by cross-
`reference t
`drug master file (DMF- The DMF has been
`reviewed and deemed adequate to support approval of the NDA. [Refer to M.
`Cooper review dated 12/l/2016.] The NDA itself includes a summary of general
`properties of deflazacort and the drug product manufacturer’s acceptance
`specification, with associated analytical procedures and method validation. The
`information provided in the NDA is adequate.
`
`lier,_ as the
`The original NDA submission provided for a second
`provided API used for
`primary source of API for Deflazacort tablets.
`clinical studies under IND 119258 and manufacture of some stability batches.
`_ DMF- was reviewed and deemed acceptable. [Refer to R.
`Frankewich review dated 12/6/2016] The information provided in the NDA is
`a
`uate and the
`licant has provided data to support equivalence of API
`. However, due to concerns abouta- contract
`manufacturer, the applicant has withdrawn
`as a supplier for
`commercial manufacture. The review team
`etermined that the contract
`
`manufacturer in question did not produce any materials used to support
`development of Deflazacort tablets. Thus, there is no material impact on the
`validity of investigational studies conducted using- sourced API.
`
`Drug Product
`
`The proposed products are immediate-release tablets that contain 6 mg, 18 mg,
`30 mg, or 36 mg deflazacort per tablet. The tablets contain conventional
`pharmaceutical excipients, i.e., colloidal silicon dioxide, lactose monohydrate,
`magnesium stearate, and pre-gelatinized corn starch, all of which comply with
`compendial standards.
`
`Deflazacort tablets are manufactured fro
`
` The data provided support the
`
`OPQ-XOPQ NDA 208684
`
`Page 7 of 9
`
`Efiective Date: 20 April 2016
`
`

`

` QUALITY ASSESSMENT
`
`NDA 208684
`
`lack of any significant effect on content uniformity or dissolution behavior over
`the ranges studied.
`
`The proposed regulatory specification for Deflazacort tablets includes test
`parameters that are typical for an immediate-release tablet. In general, the
`analytical procedures are straightforward and supported by adequate method
`validation studies. One issue, which does not afl'ect the overall recommendation,
`was identified during the review. The proposed dissolution medium for
`Deflazacort tablets contains 0.3% sodium la
`1 sulfate SLS .
`
`
`
`Deflazacort tablets are acka ed in
`
`HDPE bottles with
`
`closures. The 6 mg Deflazacort tablets are
`packaged in 100-count bottles; the remaining strengths are packaged in 30-c01mt
`bottles. Based on stability data provided in the application, a 36-month shelf life
`is granted for product stored at controlled room temperature.
`
`Methods Ver'g‘ication
`
`The I-IPLC methods for determination of assay and related substances in the bulk
`API and Deflazacort tablets were submitted to the Division of Pharmaceutical
`
`Analysis (DPA) for verification. DPA has determined that the methods are
`suitable for regulatory use with minor modifications. As the methods verification
`process is ongoing, standard language regarding cooperation with methods
`verification should be included in the action letter.
`
`Facilities
`
`All facilities that will be involved in commercial manufacture and testing of
`Deflazacort and Emflaza® (deflazacort) tablets are currently acceptable.
`
`C. Special Product Quality Labeling Recommendations
`
`There are no special labeling recommendations.
`
`OPQ-XOPQ NDA 208684
`
`Page 8 of 9
`
`Effective Date: 20 April 2016
`
`

`

`"*"~"
`w
`
`QUALITY ASSESSMENT
`
`"""""
`...-..........
`
`NDA 208684
`
`I). Finn] Risk Assessment for Deflazacort Tablets
`
`Excipients were chosen based on flleit
`previous use in Calcon lableis marketed
`outside the US and compatibility vaified
`during fuumlation development.
`The tablet malmfachner uses
`
`Deflazaeottexists
`fonn. Tablet II
`1 H
`
`r
`
`<6Datteeaseandonstabili1y.
`
`Routinecommls fothi
`mata'ials
`
`riskraw
`
`TedmgperUSP<61>
`
`omxopq NDA 208684
`
`Page 9 of 9
`
`Eflective Date: 20 Apn'l 2016
`
`

`

`Martha
`Heimann
`
`Digitally signed by Martha Heimann
`Date: 1/30/2017 12:12:45PM
`GUID: 504f845f00000ed260627d268a8cdc9d
`
`32 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`QUALITY ASSESSMENT
`
`Reviewer’s Assessment: Adequate
`
`The applicant’s claim for categorical exclusion is acceptable and adequate for approval ofthe
`application.
`
`Labeling
`
`Package Insert
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`Ihese highlights do not include all the information needed to use
`ERG-LAM“ safely Ild efl'etfiwly. See full prewribiug information for
`
`EMTLAZA. Behavmalandmooddiumbames: Myhchdeelphodginsomn,
`
`[Rn-"LAM“ (defiant-art) table“, for anal use
`EMFLAZA" (defluuort) oral suspension
`mm U.S. Approval: 1017
`
`-—-—-————INDICAIIONSANDI:SAGE———————————
`
`EMFLAZAisaconieosuoid indicatedint‘hetnmmto_
`Duchenne muscular dystrophy. (l )
`
`DOSAGE AND ADMINISTRATION
`.m. (a 1) —DRUG INTERACTIONS—
`
`Revised: 8/2016
`
`—ADV}ZRS£ REACTIONS—
`- Mostcommonadvusemacfions
`0%fotEMFLAZA)m
`Cudlingoid.
`weight increased. econ] obesity.
`
`To report SUSPECTED ADVERSE REACTIONS contact Marathon
`Pharmaceuticals, LLC at 1-866-562—4620 or
`DrugSafothEopharmEognmom or FDA at l-800-FDA-1088 or
`wwwfdaggvlnedwatth
`
`
`
`SM 17 for PATIENT COUNSEI'JNG lNFORl-IATION
`
`—-——————DOSAGE FORLIS AND STRENGTHS——-———
`0
`Tablets: 6mg,18mg, 30mgmd36m 3
`-
`222 22222-22 222222h
`----—-———-—————CON‘I'RAINDICAIIONs-—
`-——-~
`-
`Hypatensitivity to deflaacm or any of the inactive inyedimts in
`EMFLAZA (4)
`2
`
`2
`
`Reviewer’s Assessment: Adequate
`
`

`

`QUALITY ASSESSMENT
`
`The package insert contains the proprietary and established name. The dosage form and strength
`is also present on the label. This is acceptable.
`
`(b) “Full Prescribing Information” Section
`
`3
`
`DOSAGE FORDIS AND STRENGTHS
`
`
`Tablets
`
`0
`
`6 mg: White and round with “6" debossed on one side
`
`18 mg: White and round with “18“ debossed on one side
`30 mg: White and oval with “30“ debossed on one side
`
`36 mg: White and oval with “36“ debossed on one side
`
`Oral Suspension
`.
`22.75 mg/mL:
`
`(5)“)
`
`.
`.
`.
`whitish suspenswn
`
`m
`
`Reviewer-’5 Assessment: Adequate
`
`The dosage form and strength section contains the dosage form, strength, and identifying
`characteristics of the dosage form. However, the label contains excipient information which is
`not appropriate for this section.
`
`

`

`QUALITY ASSESSMENT
`
`11
`
`DESCRIPTION
`
`The active ingredient in EMFLAZA is deflazacort (a corticosteroid). Corticosteroids are
`adrenocortical steroids. both naturally occurring and synthetic. The molecular formula for
`deflazacort is C25H31N06. The chemical name for deflazacort is (l lB.l6B)—21—(acetyloxy)—
`l 1-hylroxy—2'-methyl-5'H-pregna—1,4-dieno[l7.16-d]oxazole-3.20-dione, and the structural
`formula is:
`
`
`
`0/
`
`Deflazacort is a white to off white. odorless fine powder and has a molecular weight of
`441.517. Deflazacort is freely soluble in acetic acid and dichloromethane and soluble in
`methanol and acetone.
`
`EMFLAZA is an immediate-release tablet in strengths of 6. 18. 30 and 36 mg and an
`immediate-release oral suspension in a strength of 22.75 mg/mL. Each tablet contains
`deflazacort and the following inactive ingredients: colloidal silicon dioxide. lactose
`
`monohydrate. magnesnun stearate. and pre-gelatmrzed corn starch. The oral suspension
`contains deflazacort and the following inactive ingredients: acetic acid. aluminum
`magnesium silicate. benzyl alcohol. carboxymethylcellulose sodium. polysorbate 80. purified
`water. and sorbitol.
`
`Reviewer’s Assessment: Adequate
`
`The description section contains the proprietary and established name, the dosage form, drug
`product excipients, route of administration, active moiety expression of strength, therapeutic
`class, chemical name, structural formula, molecular weight.
`
`The statement of strength may need to be reworded.
`
`16
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`How Supplied
`16.1
`EMFLAZA Tablets
`
`0
`
`6 mg are white. round with “6“ debossed on one side. They are supplied as follows:
`
`

`

`QUALITY ASSESSMENT
`
`NDC 42998-501-01
`
`Bottle of 100 tablets
`
`o
`
`o
`
`0
`
`18 mg are white. round with "l 8“ debossed on one side. They are supplied as follows:
`NDC 42998-502-03
`Bottle of 30 tablets
`
`30 mg are white. oval with “30“ debossed on one side. They are supplied as follows:
`NDC 42998-503-03
`Bottle of 30 tablets
`
`36 mg are white. oval with “36" debossed on one side. They are supplied as follows:
`NDC 42998-504-03
`Bottle of 30 tablets
`
`EMFLAZA Oral Suspension
`
`0
`
`22.75 mg/rnL is a whitish colored suspension. Supplied as 13 mL in a 20111L bottle
`
`packaged with two 1 mL oral dispensers.
`NDC 42998-505-21
`
`Reviewer’s Assessment: Adequate
`
`The how supplied section contains the following information: dosage form, strength, available
`units, and the identification of dosage form. This is acceptable.
`
`Storage and Handling
`16.2
`Store at [20 to 25°C (68 to 77°F). See USP controlled room temperattu‘e.
`
`Reviewer’s Assessment: Adequate
`
`The storage and handling information is included; however, the excursion temperatures are not
`included.
`
`Manufactured for:
`
`Marathon Pharmaceuticals, LLC
`
`Northbrook. IL 60062 USA
`
`EMFLAZA Oral Suspension made in Spain
`
`PC####X Month Year
`
`MARATHON 9a
`PHARMACEUTICALS. LLC V.
`
`cm
`
`EMFLAZATM
`
`mademarks of Marathon Pharmaceuticals. LLC.
`
`«m
`
`

`

`, CEDM
`
`Immediate Container Label
`
`Carton Labeling
`
`

`

`QUALITY ASSESSM ENT
`
`Reviewer’s Assessment: Adequate
`
`The label complies with regulatory requirements from a CMC perspective. It bears the “Rx only”
`statement, the NDC number, name of manufacturer, lot number, expiration date, net contents, bar
`code, strength, and the name (proprietary and established). Each strength is differentiated based
`on color: 6 mg is
`(mo 18 mg is
`(mo, 30 mg is
`«no, and 36 mg is
`(m4).
`
`Methods Verification Package - None
`
`Reviewer’s Assessment: Not Applicable
`
`Comparability Protocols - None
`
`Reviewer’s Assessment: Not Applicable
`
`Post-Approval Commitments
`
`Reviewer’s Assessment: Not Applicable
`
`Lifecycle Management Considerations
`
`Reviewer’s Assessment: Not Applicable
`
`List ofDeficiencies - None
`
`Primary Drug Product Reviewer Name and Date: Andrei Ponta, Ph.D.
`
`Secondary Reviewer Name and Date:
`
`

`

`Wendy
`Wilson- Lee
`
`Andrei
`Ponta
`
`Digitally signed by Wendy Wilson- Lee
`Date: 12/08/2016 01 34:30PM
`GUID: 50816dbc000085595ca3284bbca465a8
`
`Digitally signed by Andrei Ponta
`Date: 12/08/2016 12 22:51PM
`GUID: 53b58e0b00004a630e714ee170af4c26
`
`33 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`BIOPHARMACEUTICS
`
`NDA: 208684-0RIG—1
`
`Drug Product Name/Strength: EMFLAZATM (deflazacort) Tablets/6 mg, 18 mg, 30
`mg, 36 mg
`
`Route of Administration: Oral
`
`Applicant Name: Marathon Pharmaceuticals LLC.
`
`Product Background:
`
`EMFLAZATM is a corticosteroid indicated in the treatment of patients with Duchenne
`
`muscular dystrophy (DMD). The recommended dose of EMFLAZA is 0.9 mg/kg/day
`
`administered orally as a single daily dose. EMFLAZA tablets can be taken with or
`
`without food. The drug product can be administered whole or crushed and taken
`
`immediately afler being mixed in applesauce.
`
`Different Drug Product Formulations and Manufacturers:
`
`_ are former and current manufacturing sites for different
`deflazacort tablet formulations. In 2014, the manufacturing process and analytical test
`methods for the deflazacort 6 mg tablets were transferred from_
`— which is designated
`as the commercial manufacturer of deflazacort tablets.
`
`_ have the same formulations and manufacturing process-
`
`REWEWSUJIIIIIARY:
`
`Submission: Marathon Pharmaceuticals LLC., submitted this NDA for EMFLAZAIM
`(deflazacort) Tablets 6 mg, 18 mg, 30 mg, 36 mg under section 505 (b)(1) of the Federal
`Food, Drug, and Cosmetic Act.
`
`Reviewer ’5 Assessment:
`
`Dissolution Test: Thefollowing dissolution method and acceptance criterion are acceptable:
`Apparatus."
`USP Tvpe II (Paddle)
`Speed:
`50 rpm
`Medium:
`50 nIMNaH2P04 bufler + 0.3% SLS, pH 6.8
`Volume:
`500 mL
`
`Temperature:
`3 7 °C
`Dissolution acceptance criterion: Q:.% in 15 minutes
`
`

`

`
`
`Biowaiver Request: Based on the provided data, the biowaiver requestfor the proposed
`drug product 6 mg, 18 mg, and 30 mg tablet strengths is granted.
`
`Recommendation: From the Biopharmaceutics perspective, NDA 208684 for
`EMFLAZA’M (deflazacort) Tablets 6 mg, 18 mg, 30 mg, 36 mg is recommended for
`APPROVAL.
`
`List Submissions being reviewed:
`
`0 Original NDA 208684 submitted on Jun 09, 2016.
`
`o Applicant’s Response dated Jan 17, 2017 to the Information Request dated Jan 10,
`2017.
`
`o Applicant’s Quality Information Amendment dated Jan 19, 2017.
`
`Highlight Key Outstanding Issues from Last Cycle: None. This is the first review
`
`cycle.
`
`Concise Description of Outstanding Issues: None.
`
`BCS Designation
`
`The Applicant did not request a BCS designation for either deflazacort drug substance or
`tablets.
`
`Solubility: Deflazacort API is practically insoluble in water (0.1 mg/mL at 37 °C). It is
`
`soluble in DMSO (88 mg/mL at 25 °C) and ethanol (12 mg/mL at 25 °C). It is slightly
`
`soluble in methanol and acetone. It is freely soluble in acetic acid and dichloromethane.
`
`
`Table l. Solubility of deflazacort in different solutions (Page 97, Module 2.7.1).
`Solubility mull: - 37": - mastic-l stirring 1H and 2‘"
`
`
`
`Flltntlon on glass fiber filter 1|l'll
`Doionizod
`USP Mar
`USP buffer
`USP Mat
`
`
`water
`pH 1.2
`pH 4.5
`pH 6.8
`
`
`
`Permeability: No permeability data of deflazacort are provided in this NDA.
`
`

`

`Dissolution Method and Acceptance Criterion
`
`Dissolution method:
`
`The proposed dissolution method for deflazacort tablets 6 mg, 18 mg, 30 mg, 36 mg is as
`follows (Page 5, Module 3.2.P.5.2.2):
`Apparatus:
`USP apparatus 11 (Paddle)
`Paddle Speed:
`50 rpm
`Medium:
`50 mM NaH2P04 bufi'er + 0.3% SLS, pH 6.8
`Volume:
`500 mL
`
`Temperature:
`
`37 °C
`
`Rationale ot dissolution medium pH: With respect to the selection of the dissolution
`
`medium, 0.01 N HCl (500 mL) was initially tested for the deflazacort 6 mg tablets by
`
`(Page 69, Module 2.7.1).
`
`Therefore, the use of sodium phosphate buffer at pH 6.8 is acceptable.
`
`Rationale [or using the sugtactanti SLS, in the dissolution medium: With respect to the
`
`use of surfactant in the dissolution medium, it is reported by the Applicant that sodium
`lauryl sulfate (SLS) concentrations of 0.3%- ensure adequate and comparable
`solubility of deflazacort.
`
`Given the rapid dissolution (more than .% dissolved in 15 minutes) of the proposed
`deflazacort tablets 6 mg, 18 mg, 30 mg, 36 mg manufacturedat—
`(Table 3) tested with and without surfactant, the Applicant was asked in an Information
`
`Request dated Jan 10, 2017 to provide the rationale for the proposed SLS concentration
`
` #
`
`In the Applicant’s Response dated Jan 17, 2017 to this Information Request,
`
`the
`
`Applicant stated that
`
`

`

`Since the dissolution of all strengths of_ tablets is fast and not affected by
`SLS concentration, the use of 50 mM NaH2P04 buffer, pH 6.8 without SLS as the
`dissolution medium—for the quality control and stability testing of
`Deflazacort Tablets.
`
`Therefore, on Jan 19, 2017, a teleconference was held between the FDA and Marathon to
`
`discuss the need of including SLS in the dissolution medium, based on the observation of
`
`very rapid dissolution (more than % dissolved in 15 minutes) of the proposed
`
`deflazacort tablets manufactured at
`
`(Table 3) tested without
`
`surfactant.
`
`Reviewer ’s Assessment: The proposed dissolution method (USP apparatus II (Paddle)/50
`
`rpm/500 mL of 50 mM NaI-I2PO4 buffer + 0.3% SLS, pH 6.8) is acceptable.
`
`Although the dissolution medium of 50 mM sodium phosphate buffer at pH 6.8 without
`
`SLS is more adequate for this drug product, the use of the dissolution medium with SLS
`
`was accepted by this Reviewer
`
`Effect of critical quality attributes on the drug release profiles:
`
`Hardness: The Applicant reports that the proposed dissolution method owever, based on Figure 1, more
`
`dissolved in 15 minutes (Page 81, Module 2.7.1).
`
`

`

`
`
`Figure 1. Influence of tablet hardness on the dissolution profile of deflazacort tablets, 18
`
`mg (Page 81, Module 2.7.1).
`
`Particle Size: The Applicant reports that the dissolution method igure 2 supports the discriminating ability of the dissolution method
`
`with respect to API particle size.
`
`
`
`Figure 2. Influence of API particle size on the dissolution profile of deflazacort tablets, 6
`
`mg (Page 82, Module 2.7.1).
`
`Formulation Changes: The Applicant states that the proposed dissolution method is not
`
`discriminating for the relative amount of (Page 83, Module 2.7.1).
`
`

`

`Reviewer’s Assessment: The Applicant reports that the proposed dissolution method is
`
`discriminating for tablet hardness and API’s particle size. However,
`
`the proposed
`
`dissolution method is not discriminating for tablet hardness and the evaluated formulation
`
`changes; but the method is discriminating for the changes in deflazacort particle size
`
`distribution. Overall, this Reviewer considers that the proposed dissolution method is
`
`adequate for quality control purposes.
`
`Dissolution acceptance criterion:
`
`The Applicant’s proposed dissolution acceptance criterion for deflazacort tablets 6 mg,
`18 m , 30 mg, and 36 mg is:
`NLT % of the labeled amount of deflazacort dissolved in 15 minutes.
`
`Table 2. Different deflazacort formulations used for clinical studies mainly manufactured
`
`at
`
`(Page 9, Module 2.7.1 and Page 8, Module 3.2.P.5.4).
`is the commercial manufacturer of deflazacort tablets.
`
`
`
`

`

`Table 3. Dissolution profiles of the proposed Deflazacort Tablets manufactured at
`_, 6 mg (biobatch no.: 3150180), 18 mg (biobatch no.: B150186), 30 mg
`(biobatch no.: B150188), and 36 mg (biobatch no.: B150182) (Pages 13—16, Module
`2
`
`
`
`

`

`
`
`

`

`10
`
`
`
`Figure 3. Dissolution profile similarity for Deflazacort Tablets 6 mg, 18 mg, and 30 mg,
`36 mg manufactured a- using the proposed dissolution method (Page 85, Module
`2.7.1).
`
`The dissolution profiles of difi'erent strengths of deflazacort Tablets manufactured at
`_ are similar using the proposed dissolution method (Figure 3) and the rapid
`dissolution profiles for_ tablets (about '% dissolved in 15 minutes) were not
`afi'ected by the SL8 concentrations of- 0.3% (Table 3).
`
`Reviewer’s Assessment: Based on the provided dissolution data, the proposed dissolution
`acceptance criterion (Q='% in 15 minutes) is acceptable.
`
`Dissolution stability data:
`
`The Applicant provided dissolution data at 15- minutes of stability samples using the
`proposed dissolution method in the presence of surfactant SLS (Module 3.2.P.8). There
`
`are no apparent changes in the Applicant’s provided dissolution data of the stability
`
`samples in various storage conditions.
`
`Bridging of Products
`
`Reviewer’s Assessment: Different deflazacort formulations manufactured at different
`
`sites have been used in clinical studies (Figure 4, DP=drug product).
`
`10
`
`

`

`Figure 4. Different deflazacort tablet formulations used in clinical studies (Page 9,
`
`Module 2.7.1 and Page 8, Module 3.2.P.5.4).
`
`

`

`14
`
`proposed drug product (In vivo Characterization Waiver Request, Module 1.12.5). The
`different strengths of deflazacort tablets— (Table 4). The
`dissolution profiles of the 6 mg, 18 mg and 30 mg tablet strengths are comparable
`
`dissolved within the first 15 minutes for all tablet strengths, demonstrating similarity
`
`In addition, more than % of the drug is
`
`Biowaiver Request
`
`Reviewer's Assessment: The Applicant requested a waiver for the requirement to provide
`
`data from in vivo characterization of the 6 mg, 18 mg, and 30 mg tablet strengths of the
`
`

`

`15
`
`between different strengths (Page 2, In vivo Characterization, Module 1.12.5). Based on
`
`the provided data, the biowaiver request for the proposed drug product 6 mg, 18 mg, and
`
`30 mg tablet strengths is granted.
`
`Table 4. Quantitative and qualitative composition of deflazacort tablets 6, 18, 30 and 36
`mg.
`
`Deflazacort
`
`Monohydrate
`Pre-gelatinized
`Com Starch
`Colloidal Silicon
`Dioxide
`
`Magnesium
`Steamte
`
`Quality
`Standard
`
`In4mm
`
`NF
`
`NF
`
`NF
`
`NF
`
`
`
`
`Figure 11. Comparative dissolution profiles of the proposed Deflazacort Tablets 6 mg, 18
`
`mg, 30 mg, and 36 mg using the proposed dissolution method.
`
`REVIEWER’S OVERALL ASSESSMENT
`
`Dissolution Test:
`
`Method: The proposed dissolution method using USP apparatus 1] (Paddle)/50 rpm/500
`mL 50 mM NaH2P04 bufi'er + 0.3% SLS, pH 6.8 is acceptablefor the quality control of
`the proposed immediate release drug product, EMFLAZA’M Tablets 6 m , 18 m , 30 m ,
`
`36 mi as iart oi the batch release and stabilii testini.i
`
`
`
`15
`
`

`

`l6
`
`Acceptance Criterion: The proposed dissolution acceptance criterion ofNLT-% (Q) of
`the labeled amount ofdeflazacort dissolved in 15 minutes for the proposed EMFLAZA’M
`Tablets is acceptable.
`
`Biowaiver Reguest:
`
`The provided pharmacokinetic data, formulation
`the biowaiver request for the
`similar multimedia dissolution profile data support
`proposed drug product 6 mg, 18 mg, and 30 mg tablet strengths and therefore the
`biowaiver is granted.
`
`RECOMMENDA TI0N
`
`From the Biophamtaceutics perspective, NDA 208684 for EMFLAZA’M (deflazacort)
`
`Tablets 6 mg, 18 mg, 30 mg, 36 mg is recommendedfor APPROVAL.
`
`Primary Biopharmaceutics Reviewer Name and Date:
`
`Yang Zhao, Ph.D.
`Biopharmaceutics Primary Reviewer
`Division ofBiopharmaceutics
`Oflice ofNew Drug Products, OPQ
`
`01/23/2016
`
`Secondary Reviewer Name and Date:
`
`I concur with Dr. Yang Zhao 's assessment and recommendation.
`
`Okpo Eradiri, Ph.D.
`Biopharmaceutics Lead (Acting)
`Division ofBiopharmaceutics
`Oflice ofNew Drug Products, OPQ
`
`01/24/201 7
`
`Tertiary Reviewer Name and Date:
`
`I concur with Dr. Yang Zhao 's assessment and recommendation.
`
`Angelica Dorantes, Ph.D.
`Biopharmaceutics Branch Chief(Acting)
`Division ofBiopharmaceutics
`Oflice ofNew Drug Products, OPQ
`
`01/2 7/201 7
`
`l6
`
`

`

`Okponanabofa
`Eradiri
`
`Digitally signed by Okponanabofa Eradiri
`Date: 1/27/2017 02:39:33PM
`GUID: 50bdfe8d00003559ede66be3fd299f65
`
`Yang
`Zhao
`
`Digitally signed by Yang Zhao
`Date: 1/27/2017 01:01:01PM
`GUID: 56f958740001a1f9707b4476d760e12f
`
`8 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`MEMORANDUM
`
`DEPARTMENTOFHEALTHANDHUMANSERVICES
`
`PUBLIC HEALTH SERVICE
`
`FOOD AND DRUG ADlVflNISTRATION
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DATE:
`
`January 24, 2017
`
`FROM:
`
`Raymond P. Frankewich, Ph.D., Review Chemist, OPQ/ONDP/DNDAPI/Branch I
`
`THROUGH: Kasturi Srinivasachar, Ph.D., Branch Chief, OPQ/ONDP/DNDAPI/Branch I
`
`SUBJECT:
`
`Evaluation of Method Verification Results and Conclusions for NDA 208684 &
`
`208685
`
`TO:
`
`NDA 208684 and NDA 208685
`
`Reviews for NDA 208684 and 208685 for Drug Product were finalized on December 8, 2016, and
`for Drug Substance on December 9, 2016. No deficiencies were established for Emflaza®
`(Deflazacort) Tablets (NDA 208684) and Emflazao (Deflazacort) oral suspension (NDA 208685) in
`those reviews.
`
`A Methods Verification Request was submitted for NDA 208684 & 208685 on July 7, 2016.
`Verification was requested for the following analytical procedures:
`m4)
`0 HPLC Assay, Related Substance and Identification Test Method for deflazacort,
`(m4)
`0 HPLC Assay, Related Substance and Identification Test Method for deflazacort,
`0 Deflazacort Assay and Impurities, Identification by HPLC and Identification by UV for
`Deflazacort Tablets
`
`Method Verification Report, dated October 31, 2016, was submitted the same day. The report was
`authored by staff from CDER/OPO/OTR/DPA (DPA). The conclusions of the report were as
`follows:
`
`Thefollowing methods were evaluated and are acceptablefor quality control and regulatory
`purposes:
`
`O)(4)
`
`0 HPLC assay, related substances and identification test methodfor deflazacort
`0 HPLC assay, related substances and identification test methodfor deflazacorl
`Thefollowing methods were evaluated and are acceptable with modificationsfor quality control
`and regulatorypurposes:
`
`(I!) (9
`
`0 Deflazacort assay and impurities, identification by HPLC and identification by UVfor
`deflazacort tablets
`
`It the report it is noted that for the method used for the tablets, an unidentified impurity peak is
`observed at ”(0minutes (RT ”(4’) when one of the standard preparations is chromatographed.
`The level of the impurity was 3%, which exceeds the acceptance criterion for Individual
`
`

`

`Evaluation of MV for NDA 208684 & 208685
`
`Page 2 of 5
`
`Unidentified substances in the Related Substances section of the specification for drug product
`release (which is S 3%). The report indicates that this unidentified impurity peak does appear in
`chromatograms in the validation report provided by the applicant. The following description of the
`unidentified impurity peak is excerpted from the report.
`
`Thefirm does not identijy this peak in Figure 2, page 12. However, it is present as an unknown
`impurity throughout the validation report. Sample solution stability studies on pg. 49-50 ofthe
`validation report show an increase over time at ambient conditions. By 3 hours, the sample is
`twice the specification limit. DPA analyzed the sample within 12 hours ofpreparation at ambient
`conditions. The method does not include a statement about stability at room temperature while the
`analyst is preparing the sample. The only note states “
`sample solutions were shown to be stable
`3 hours when stored in refrigerator, protected by light. ”
`
`The problem appears to be that the unidentified impurity increases significantly following standard
`preparation, indicating the standard preparation is less stable than ideal. It appears that this might be
`addressed by the applicant including a statement in the analytical procedure description to use the
`standard and sample preparations within a particular period of time. It is noted in the experimental
`results that the peak at RT (m4) appeared in the chromatogram of the stande preparation.
`However, in the chromatograms provided in the analytical procedure description provided in sec.
`3.2.P.5.2 of the NDA (and the validation report provided in sec. P.5.3) this peak appears in the
`chromatograms of both the standard and sample preparations.
`
`In addition to this, it is noted that when the method for assay, related substances and identification
`by HPLC for deflazacort
`(”(0 was performed, deflazacort did not dissolve in diluent
`(m4)
`as required in the method. By contrast, the method for assay, related substances and
`identification by HPLC for deflazacort
`0(4) specifies dissolvin deflazacort
`before adding diluent. It was indicated that with the
`M ) method, deflazacort did
`m4). To resolve this issue, DPA
`dissolve
`recommended that instructions be included to dissolve deflazacort
`(mo before adding
`diluent.
`
`(5X4)
`
`Consistent with the recommendations in the report, the following items were sent to the NDA
`applicant (Marathon Pharmaceuticals LLC) in an electronic communication dated January 10, 2017.
`
`It is requested that thefollowing issues regarding the analyticalprocedures usedfor control of
`deflazacort drug substance and Emflaza® (deflazacort) Tablets be addressed. These analytical
`procedures were submitted in NDA 208684for Emflaza® (deflazacort) Tablets.
`
`Regarding the analyticalprocedurefor Deflazacort Assay and I